Hypothyroidism: Health Implications

#### **Chapter 7**

## Cytokine Storm in Hypothyroidism in Infertile Women

*Neha Sharma, Sanghapriya Mukherjee and Aparajita Kushwaha*

#### **Abstract**

Thyroid dysfunction interferes with several aspects of reproduction along with pregnancy. Hypothyroidism in females leads to an elevated level of hormone prolactin which decreases levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and finally causes infertility. Obesity acts upon the reproductive cycle by decreasing oestrogen metabolism stimulating menstrual disturbance along with an ovulation. But till date, one of the most underestimated obstacles in fertility is inflammation. Hypothyroidism leads to inflammation in secondary epithelial cells of thyroid gland. This affects immune, nervous system and endocrinal functions of body. Inflammation contributes to oestrogen dominance, a hormonal state that consists of having too little progesterone in the body compared to oestrogen. This leads to progesterone resistance, prevention of progesterone hormone receptors from working properly. This condition also leads to infertility in hypothyroid females. Therefore, not only hormonal profile is sufficient to check up for reproductive problems in the female, but also inflammatory markers like IL-6 and CRP should be added to this profile.

**Keywords:** hypothyroid, cytokine storm, infertility, inflammation, inflammatory markers

#### **1. Introduction**

The risk of facing thyroid problems is nearly 10 times higher for women than for men. For the normal functioning of the ovaries and maturation of eggs, there is a correlation between reproductive hormones (oestrogen and progesterone) and thyroid hormones in females [1]. The balancing of thyroid hormones is thus essential for fertility in women (**Figure 1**). The function of reproductive hormones can be altered by hyper- or hypo-secretion of thyroid hormones and result in thyroid-related infertility [2].

Apart from thyroid hormone imbalance, infertility has a lot to do with the lifestyle of a woman. Hormones released by the thyroid gland can have a variety of effects on the reproductive systems like delay or early onset of puberty, amenorrhea, ovulation, miscarriage, premature birth, etc. Smoking, drinking, stress, consumption of fast food, depression, delayed conception and age are some of the other factors responsible for infertility.

**Figure 1.** *Outline diagram for awareness. (Courtesy: Dr. Neha Sharma).*

#### **2. Hormonal regulation of menstrual cycle: oestrogen and progesterone**

In females, usually most oestrogen and progesterone are released by ovarian follicles and corpus luteum, and by placenta at the time of pregnancy. The secretion reaches its peak in 7 days after ovulation and then declines if conception and implantation occur. Two types of oestrogen are produced: oestradiol and oestrone. Small amounts of oestrogen are produced by cells of corona radiata, theca interna and corpus luteum [3].

The main role of oestrogen is endometrial growth, follicle development or ovulation, increased proliferation of epithelial cells in vagina and uterus, stimulation of synthesis of proteins like contractile proteins in myometrial muscle fibres [3].

Other functions of oestrogen include promoting endometrial growth, increasing bone formation, increasing hepatic synthesis of binding proteins, increasing level of circulating coagulation factors II, VIII, IX, X, III and plasminogen and increasing adhesiveness of platelets.

Functions of progesterone are:


Oestradiol as well as progesterone both act on the endometrium: Oestradiol promotes the growth of constituents of the endometrium, while progesterone helps to change from a proliferative pattern into a secondary pattern. When the levels of oestrogen and progesterone fall, it leads to the end of the cycle as endometrium cannot be maintained further, and as a result menstruation occurs [4].

#### **3. Gonadotropin releasing hormones (GnRH)**

GnRH activates a surge of LH preceding ovulation [3]. Hypothalamic GnRH is released in an exciting manner by caudate nucleus of hypothalamus. GnRH

production is acted upon by oestradiol or catecholamine neurotransmitters. It reaches to anterior pituitary by hypothalamo-pituitary portal plexus.

Function of GnRH:


#### **3.1 Prolactin**

Prolactin is secreted through cells of adenohypophysis. The main function of prolactin is the initiation and maintenance of lactation. For ductal growth and development of breasts, prolactin is a must. This is required for synthesis of specific milk proteins (casein, gamma lactalbumin). Although the exact intracellular mechanism of prolactin action is yet not known, prolactin regulates transport of lipoproteins in adrenal gland, testis and ovary to ensure the continuous supply of LDL for steroid genesis. It also promotes synthesis of enzymes of androgen pathway, which facilitates the conversion of pregnenolone to dehydroepiandrosterone and/or dehydroepiandrosterone sulphate [5].

Release of prolactin is under a tonal inhibitory control through hypothalamus. This is also influenced through:


Hyperprolactinemia is the most common in hypothalamic–pituitary disorder found in clinical endocrinology [1]. PRL concentration is also increased in women who have a problem in fertility like anovulation, with or without menstrual irregularity, amenorrhea and galactorrhoea. Causes of hyperprolactinemia include:


Hyperprolactinemia can interrupt ovarian physiology at various levels, including steroidogenesis, follicular maturation and ovulation, the process of luteinisation and corpus luteum function [7].

#### **3.2 LH and FSH**

The gonadotrophins FSH and LH are hormones that are protein in nature secreted by anterior pituitary [1]. LH and FSH are glycoproteins as they are made up of two peptide chains, alpha and specific beta subunit. Both hormones are glycosylated, which determines their bioactivity and half-life.

Secretion of gonadotrophins, LH, FSH is controlled by luliberin. This stimulates the emission of LH effectively than follitropin production, plasma levels of sex

#### *Cytokine Storm in Hypothyroidism in Infertile Women DOI: http://dx.doi.org/10.5772/intechopen.102044*

hormone by positive and negative feedback. It is also controlled by hormone Inhibin, which is produced by the Graafian follicles [3].

FSH and LH work on gonads to trigger gametogenesis and synthesis of hormones associated with it. At the follicular stage, FSH and LH trigger oestrogen production by the developing follicle.

LH and FSH have significant actions on the ovary:


When Graafian follicle enlarges, it increases the amount of oestrogen and oestradiol production. Within mid-cycle, surge of LH is seen, so ovulation takes place and the Graafian follicle is changed into corpus luteum by progesterone activity [4].

FSH also reaches its peak at the end of the follicular stages, a part of the surge of pre-ovulatory gonadotrophin (**Figure 2**) [6].

### **4. Thyroid stimulating hormone (TSH)**

The thyroid stimulating hormone, also called thyrotropin, is secreted from adenohypophysis in reaction to thyroid releasing hormone (TRH). It is a glycoprotein in nature, containing 209 amino acids [3]. It is chiefly associated with the growth of thyroid gland and stimulation of its hormonal activity [5].

Functions of TSH.

1. It has a wide range of activity on the follicular cells:

	- Increases oxygen consumption.
	- Increased glucose utilisation.
	- Increased carbon dioxide production.
	- Increased formation of phospholipids.
	- Increased synthesis of RNA and protein [8, 9].

binding of iodine to thyroxine as well as subsequent coupling to form thyroid hormone on the surface of thyroglobulin molecules [10].

	- a. Strengthening metabolism of carbohydrates, proteins and lipids.
	- b. Reinforcement of growth and development.
	- c. Regulation and transportation of water and electrolytes.
	- d. Stimulation of the cardiovascular system.
	- e. Stimulation of the Central Nervous System [11].

#### **5. Hypothyroidism**

Hypothyroidism is a condition characterised by elevated serum thyroid stimulating hormone level and decreased serum levels of T3 and T4 due to under activity of the thyroid gland. According to NHANES (National Health and Nutrition Examination Survey), in the last 6 years, the prevalence of hypothyroidism is 4.6% [12]. Thyroid disorders, hypothyroidism or hyperthyroidism are more common in females than in males.

#### **5.1 Causes of hypothyroidism**

The causes of hypothyroidism are divided into six categories:


Symptoms of hypothyroidism include cold intolerance, fatigue, lethargy, decreased metabolism, weight gain, brittle nails and dry skin.

#### **5.2 Consequences of hypothyroidism**

Thyroid disease is associated with a wide range of metabolic abnormalities, owing to the fact that thyroid hormones act on majority of the metabolic pathways.

### **6. Infertility**

What is infertility?

Infertility is defined as an inability to conceive after 1 year of regular intercourse without contraception. WHO defined infertility as 'a disease of the reproductive system which is explained by inability to achieve pregnancy after twelve months or more of regular unprotected intercourse' [14].

#### **6.1 Types of infertility**

First degree or primary infertility.

When a couple is not able to conceive even having unprotected intercourse over a period of minimum 1 year, it is defined as the first degree or primary infertility [15]. Second degree or secondary infertility.

Secondary infertility occurs when a couple cannot conceive for the second time even after regular intercourse without any contraceptives. To count as secondary infertility, the first childbirth should not have occurred with the help of any kind of fertility medication or procedures like IVF [15].

#### **6.2 Causes of infertility**

Problems of infertility start from hormonal dysfunction of the hypothalamic pituitary gonadal axis. The major cause of infertility is a disorder of oocyte production, ovulation, healthy sperm production, fallopian tube dysfunction, and lastly, improper implantation of the embryo in the uterine wall.

Sexually transmitted diseases like gonorrhoea and syphilis may also lead to infertility. PCOD, obesity, thyroid issues and imbalanced hormones of the menstrual cycle can

also lead to infertility through a surge in the cytokine levels of the body (cytokine storm). Multiple studies show that cigarette smoking, narcotics and drugs have been established to impair fertility in both males and females (**Figure 3**). Smoking has unfavourable effects on tubal function, secretion of hormones and cervical mucus production [16].

**Figure 3.** *Causes of infertility (Courtesy – Dr. Neha Sharma).*

Ingestion of alcohol has also been shown as a reason to decrease gonadotrophin levels or irregularities in ovulation.

#### **6.3 Factors affecting infertility**

Fertility of a couple is defined as fertility of both the partners. High fertility of one partner, to some extent, can balance the low fertility in the other partner. Low fertility in both partners can however lead to first- or second-degree infertility [17].

Another significant factor influencing fertility is the age of the female partner. Fertility in both males and females is at its peak in the mid-twenties. In females, it starts to decline sharply after 30 years [2]. As many couples do not conceive a child at an early age, postponement of pregnancy decreases the number as well as the quality of egg, reducing the chances of getting pregnant. Females also go through an unwanted sequel of circumstances such as endometriosis, pelvic inflammatory disease (PID) and uterine fibrinoids. All these complications lead to the release of cytokines in the form of interleukins and C-reactive proteins, which further contribute to the already existing infertility in females [15].

It is not easy to determine the exact cause of infertility as there are many factors that bias. The cause can be recognised only after proper investigations.

#### **6.4 Association of female infertility with hypothyroidism**

Hypothyroidism is common in males and females. A range of reproductive disorders ranging from abnormal sexual growth to menstrual cycle irregularities or infertility have been connected to thyroid disorders. Morphological changes of follicles in hypothyroidism may be an outcome of higher prolactin production that blocks both secretion as well as action of gonadotropins [4]. Enough supplementation of thyroid hormone restores prolactin and normalises ovulatory function [3]. Hypothyroidism itself possibly will contribute to infertility because thyroid hormones may be necessary for maximum production of both oestradiol and progesterone hormones (**Figure 4**).

#### **7. Obesity**

Obesity represents excess body fat or is defined by a basal metabolic rate of more than 30 ky/m<sup>2</sup> . Elevated levels of TSH; hypothyroidism does not always result in weight problems but may cause obesity in some cases.

Subclinical hypothyroidism, marked by elevated TSH concentration with normal concentration of peripheral thyroid hormones (T3 andT4) has been consistently found in obese individuals. Lipid profile findings of obese individuals show marked dyslipidemia, involving high levels of serum TG, LDL, TC and low serum HDL level [14]. A recent report from coronary artery risk development in young adults (CARDIA) shows that among physiologically infertile women, probability of infertility is twice in African and American women as compared to others [15]. Economic problems have led to limited access to diagnosis and treatment of various diseases, resulting in selective underestimation of thyroid dysfunctions and hypothyroidism related infertility [18].

Thyroid affects various aspects of reproduction; especially pregnancy is adversely affected by thyroid dysfunction [19].

An understanding of the implications of obesity and hormonal balance and fertility may help couples facing challenges in conception to give the reproductive health and better opportunity and take steps to improve the reproductive capacity and probability of a healthy pregnancy.

#### **Figure 4.**

*Hypothyroidism and infertility. (Courtesy – Ms. Aparajita Kushwaha, Ms. Sanghapriya Mukherjee).*

Consequences of obesity on ovarian function.


Obese adipocytes act as secretary cells and release adipose cytokines, chemokines and cytokines. The secretion of inflammatory agents like IL-6 and TNF-@ is considerably increased in obese individuals. These contribute towards producing a low-grade chronic systemic inflammation. Thyroid hormones can affect the metabolism of cholesterol and triglycerides, where depression of cholesterol concentrations caused due to an increase in hepatic LDL levels, or decreased LDL clearance can be seen. As a result, total cholesterol or LDL levels are increased in hypothyroid individuals.

Obesity is not only associated with infertility but also with various other health problems including hypertension, cardiovascular diseases, diabetes and hormonal imbalances. The effects of obesity expand across conception, gestation, parturition and also post-parturition. Excess weight gain negatively impacts efficacy of treatment and results of served reproductive techniques. Therefore, high body fat and obesity cause a rise in oestrogen production that body perceives as birth control confining the chances of acquiring pregnancy (**Figure 5**).

#### **8. Stress**

Stress is most common in women. Stress is normally underestimated because of dysfunction in reproduction. Stress-induced anovulation (SIA) usually termed

#### **Figure 5.**

*Relationship between obesity and inflammation. (Courtesy – Ms. Aparajita Kushwaha, Ms. Sanghapriya Mukherjee).*

functional hypothalamic amenorrhea (FHA) and functional chronic hypothalamic anovulation, which causes infertility, increases acute and chronic health burden in women of all ages.

Chronic psychological and physical stress is common among hypothyroid individuals. This causes an elevated production of cortisol which aggravates release of IL-6incirculation [21].

Increased level of IL-6 tends to suppress immune system and endocrine system. This is responsible for production of acute phase protein, i.e., CRP.

Effects of IL-6 are mediated through regression of BDNF (Brain-Derived Neurotropic Factor). Downregulation of BDNF causes decreased connectivity in between anterior singulating cortex and several limbic areas like hippocampus. Increased level of IL-6 in stress causes FHA (functional hypothalamic amenorrhea). This leads to defects in the mechanism operating the anterior pituitary gland resulting in delayed ovum maturation, decreased FSH and decreased LH, which results in infertility.

IL-6 synthesis through peripheral blood mononuclear cultures of chronically stressed individuals has been reported to be higher than that of cultures from control subjects when stimulated by LPS, in a study conducted on older adults [22].

IL6 is a multifunctional cytokine with essential roles in inflammatory response or in leading T-cell differentiation in acquired immunity. IL-6 is broadly expressed in reproductive tract or gestational tissues of women, as well as maintains a regulatory role in embryo implantation or placental development, and immune adaptations are required for tolerating pregnancy. Elevated IL-6 is recurrently evident in altered cytokine profiles, feature of unexplained infertility, recurrent miscarriage, preterm delivery and preeclampsia. Especially, there is undeniable evidence representing altered IL-6 trans-signalling in female prone to recurrent miscarriage, with higher IL-6 bioavailability potentially suppressing generation of CD4 cells and T-cells, regulatory cells necessary for tolerance of pregnancy.

Inadequate local IL-6 may also lead to fetal loss since IL-6 appearance is reduced in the endometrium of females due to recurrent miscarriage [23].

CRP is an acute phase response protein synthesised by liver. Small levels of CRP are present normally in blood but increase rapidly in response to inflammatory conditions [22]. Hypothyroidism can increase chronic subclinical inflammation which raises IL-6 levels, resulting in raised levels of CRP. Hypothyroidism is associated with relatively increased inflammatory marker levels [24]. Psychological stress causes a rise in CRP, which can lead to a poor prognosis as well as pregnancy complications [25].

Stress, eating habit and infertility:

Infertility often results in immense pressure leading to a lot of stress and anxiety. Depression tends to induce unhealthy eating habits. Due to excessive consumption of unhealthy food, it paves way to obesity and an increase in the level of the

**Figure 6.** *Cytokine storm in hypothyroid subjects. Courtesy: Ms. Sanghapriya Mukherjee, Ms. Aparajita Kushwaha.*

**Figure 7.** *Summary: hypothyroidism and infertility. (Picture courtesy: Dr. Neha Sharma).*

inflammatory markers (cytokine storm), and finally resulting in probability of conception to almost zero (**Figures 6** and **7**).

#### **9. Conclusion**

In women of reproductive age, hypothyroidism poses a great risk to their fertility. Hypothyroidism triggers a cascade of physiological irregularities and also makes women more prone to diseases.

Though obesity is not necessarily a part of symptoms and effect of hypothyroidism, it is not uncommon for hypothyroid women to be obese. Various factors contribute towards excess weight gain in hypothyroid women, mainly, hypothyroidism-induced depression and hormonal changes, which usually results in unhealthy eating habits and eventually weight gain. The accumulation of fat cells or obese adipocytes acts as secretary cells and secrete IL-8, IL-6 and TNF-α (inflammatory agents) causing a low-grade inflammatory response.

Hypothyroid women also suffer from chronic physiological and mental stress. Chronic stress causes elevated levels of cortisol which triggers increased secretion of inflammatory agents like IL-6 and CRP.

Hypothyroidism induces obesity, stress, anxiety and depression, thus cumulatively causes inflammation in the body, which leads to difficulty in conception, frequent miscarriages and infertility in severe cases.

*Cytokine Storm in Hypothyroidism in Infertile Women DOI: http://dx.doi.org/10.5772/intechopen.102044*

#### **Abbreviations**


### **Author details**

Neha Sharma\*, Sanghapriya Mukherjee and Aparajita Kushwaha Department of Biochemistry, Geetanjali Medical College and Hospital, Udaipur, Rajasthan, India

\*Address all correspondence to: neha16.sharma@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 8**

## Evolution of Thyroid Enhancement of Embryogenesis and Early Survival

*Arjay Pataueg, Earl T. Larson and Christopher L. Brown*

#### **Abstract**

Iodine imparts protective antioxidant actions that improve the fitness of invertebrate organisms, and peptides carrying iodine initially appear to have served in a defensive capacity. Tyrosine carries multiple iodines in some echinoderms, and these peptides transferred to progeny serve both protective and signaling purposes. This parental relationship appears to be the most likely evolutionary basis for emergence of the vertebrate thyroid endocrine system, and its critically important development-promoting actions in larval and (later) fetal ontogeny. Thyroxine (T4) and Triiodothyronine (T3) induce settlement and stimulate transitions to alternative feeding modes in some echinoderms. This transgenerational relationship has been conserved and elaborated in vertebrates, including humans, which share common ancestry with echinoderms. Thyroid insufficiency is damaging or can be lethal to larval fishes; egg yolk that is insufficiently primed with maternal thyroid hormones (TH) results in compromised development and high mortality rates at the time of first-feeding. Maternally-derived TH supplied to offspring supports the onset of independent feeding in fishes (eye, mouth, lateral line, swim bladder and intestinal maturation) and survival by comparable developmental mechanisms in placental mammals. Fishes evolved precise control of TH secretion and peripheral processing; early metamorphic and feeding mode actions were joined by controlled thermogenesis in homeotherms.

**Keywords:** Thyroid hormone, T3, T4, embryogenesis, larvae, fetus, metamorphosis, survival

#### **1. Introduction**

Thyroid hormones have historically been associated with their thermoregulatory roles [1] and with the control of metamorphosis, as classically described in frogs [2]. A critically important role in human fetal development [3] is also well known, and is the basis for extensive thyroid status testing of pregnant women, and for the widespread use of iodized salt [4]. Comparative and evolutionary perspectives on thyroid regulatory biology had a relatively recent arrival. The ability to measure thyroid hormones [5] led to analysis of patterns of regulatory involvement not only in amphibian metamorphoses and human fetal development, but far more broadly among vertebrates throughout early differentiation. The origin of these actions seen throughout the vertebrates can be traced to consistent associations of thyroid

hormones with the successful transition from larval to juvenile forms, generally accompanied by transitions to different modes of feeding and nutrition, or movement to different habitats. Recent research suggests that larval stimulation and signaling by iodinated peptides originated in invertebrates, and that the substantial survival implications of this form of maternal chemical communication in offspring ensured its evolutionary retention [6]. Conversely, it follows that the untoward consequences of hypothyroidism can be severe or lethal. The harsh impacts of hypothyroidism in fetal humans originated in connections between iodinated peptide signaling and successful larval differentiation in advanced invertebrates, a trait that has been consistently conserved and elaborated among the vertebrata. Insufficient human maternal thyroid stimulation results in the tragic syndrome known as cretinism [3], characterized by extremely deficient fetal development, central nervous system disorders, severe retardation, abnormal digestive and skeletal differentiation, stunting, lethargy, and a sharply reduced lifespan.

#### **2. Evolutionary origins of the vertebrate thyroid system**

Iodide is a large and biologically active anion, with a capacity to reduce reactive oxygen species, and it performs protective antioxidant functions in a range of invertebrate and algal organisms [7]. It is also involved in numerous biosynthetic activities. Some multicellular organisms concentrate iodide and it is often found bound to proteins or peptides [8], particularly the amino acid tyrosine, which can carry multiple iodides. Tyrosine is derived from phenylalanine and can be processed further into dopamine and other catecholamines, and it is essential for the synthesis of thyroid hormones tri-iodothyronine (T3) and thyroxin (T4). The latter two compounds consist of paired tyrosine residues with three or four attached iodides, respectively.

Tyrosines become iodinated spontaneously in marine environments, and are found throughout marine invertebrates. T4 synthesis is an ancient process, occurring when iodinated tyrosines are coupled together, and some invertebrate physiological functions have been tentatively ascribed to it [9]. Iodinated signaling is an antiquated process, probably beginning with receptors in invertebrates responding to exogenous iodinated tyrosines coming from either seawater or marine algae [10]. Certain mollusks have been found to possess genes for peroxidases, one of which is similar to thyroid peroxidase, which binds iodine to thyroglobulin in vertebrates. While mollusks do not have thyroglobulin, one of their peroxidases incorporates iodine into thyroid hormone-like molecules. This may reflect the first incidence of endogenous production of thyroid like-hormones [11]. Specialized cells for the processing of iodinanted tyrosines are present in protochordates, and are organized into thyroid-like tissues, e.g. the endostyle [12]. In agnathans, the larval endostyle is retained and reorganized in adult lampreys into thyroid follicles with iodineconcentrating capacity. Lamprey metamorphosis is at least partly thyroid hormonedriven, and is characterized by a transition from larval filter feeding to ingestion of captured materials, and the larval endostyle is altered after metamorphosis into a thyroid gland with functional follicles [13]. Interestingly, the endostyle in lampreys develops around the time of yolk sac absorption [14]. In the other cyclostome group, hagfish, the thyroid primordium appears in the area of the head adjacent to the yolk sac [15]. These examples suggest a possibility of maternal thyroid signaling in larval cyclostomes.

An emerging body of evidence suggests that signaling by iodinated tyrosines was linked to changes in feeding modes before the evolution of protochordates and chordates, and that numerous physiological functions of thyroid- and thyroid-like

iodinated peptides can be found in echinoderms. Maternal / larval signaling in the echinoderms may be the ancestral origin of the maternal / juvenile regulatory relationship that prevails throughout the vertebrates, and which figures prominently in *Homo sapiens*.

#### **2.1 Echinoderms: Iodothyronines in larval signaling**

Although echinoderms have relatively simple anatomical characteristics, their embryos are classified as deuterostomes, which means the mouth develops after the anus, and chordates are also classified thusly [6]. For this reason, they are thought to share a common ancestry with chordates [16]. This common ancestor has not yet been identified but some ideas of its characteristics are being deduced using comparative genomics [17]. Iodinated tyrosines, including thyroxin, are found in a variety of living tissues including monocellular algae [18] and echinoderm embryos [19], where there is ample evidence of maternal signals carrying out beneficial regulatory roles in early development [20, 21]. A good case can be made for the echinoderms having evolved a regulatory mechanism in development that enabled progeny to respond to signals by shifting developmental modes and feeding patterns, a pattern of transgenerational communication which has been conserved to contribute later to the adaptation of juvenile vertebrates to diverse and changing environments [22].

Some evidence supports the hypothesis that dietary sources of iodide served initially as antioxidants and evolutionarily later as signaling mechanisms to promote DNA expression, thereby initiating and facilitating successful invertebrate metamorphoses [6]. Because these actions promote changes that distinctly enhance the rate of larval survival, their selective value is high and these traits promote their own conservation and propagation. Most echinoderms distribute free-swimming larvae that mature, metamorphose, and settle as benthic organisms; some are dependent on exogenous feeding prior to settlement, while others can metamorphose without feeding [20]. Many echinoderm larvae exhibit changes in developmental rate or status and distinct modifications of their developmental mode in response to iodothyronines including exogenous thyroid hormones. Exogenous T3 and T4 both accelerate development, metamorphosis and settlement in sand dollars (*Leodia sexiesperforata*), and appear to facilitate a transition from obligate larval feeding to an alternative mode in which metamorphosis occurs independently of exogenous nutrition [21], foretelling important advancements in vertebrate reproduction. The capacity for endogenous TH synthesis is theorized to have replaced dependence on dietary TH (an exogenous messenger), facilitating the endocrine regulation of larval development, and generating some degree of internal control over the induction of metamorphosis [19]. Endogenous synthesis of TH has been confirmed in larval sand dollars (*L. sexiesperforata)*, sea biscuits (*Clypeaster rosaceus*), and sea urchins (*Strongylocentrotus purpuratus*) [21].

The role of iodinated tyrosine shifts in echinoderms from the provision of iodine for protective purposes and responsiveness to exogenous signals, to the emergence of a regulatory endocrine system that can alter the timing of physiological and morphological changes to increase developmental competence. In the case of sea urchins, exposure to either exogenous or endogenous T4 promotes the initiation of larval exoskeleton synthesis [21].

The effectiveness of larval regulatory signaling by TH is dependent not only on the availability of hormones of either exogenous (dietary or maternal iodotyrosines) or endogenous origin (TH biosynthesis). In the case of sea urchins, activation of the MAPK protein kinase pathway occurs after binding of thyroxin to receptors [21]. Genes for hormone receptors, appropriate intracellular response mechanisms,

deiodinase enzymes and other components may be required. The roles of these signals in the acquisition of metamorphic capability in relation to exogenous larval feeding [11] is the fundamental relationship that has been conserved throughout evolution for the promotion of GI system and other physiological adaptations, enabling successful transition to exogenous feeding in fishes [22, 23] and higher vertebrates. The ancestral deuterostome likely laid the foundation for regulation of the timing of larval metamorphoses in teleost fishes, as closely associated with the initiation of exogenous feeding. We see this pattern conserved in both echinoderms [24, 25] and hemichordates [26]. These groups comprise ambulacraria, the sister clade of chordates [27].

#### **2.2 Hemichordates: Iodine or bromine?**

Hemichordates (acorn worms) are the sister group to echinoderms in the ambulacraria, the sister clade of chordates. Hemichordates and echinoderms diverged approximately 876 mya whereas ambulacraria diverged from chordates 896 mya [27]. While one species of acorn worm (not actual worms), *Saccoglossus horsti*, has been shown to iodinate tyrosine by incorporating I131 into monoiodotyrosine [28], other species seem to manage this process differently. Acorn worms of the genera *Ptychodera*, *Glossobalanus* and *Balanoglossus*, use bromine instead of iodine [29]. They brominate indoles and phenols, the bromoindoles being similar to iodoindoles in other species. These halogenated phenols give the animals a characteristic smell described by many as iodophoric [29]. These chemicals seem to serve an antiseptic role rather than any sort of metabolic or metamorphic role [29]. Instead, embryogenesis and metamorphosis in indirect developing acorn worms seems to be controlled by FGF (firbroblast growth factor) [30]. Therefore, if iodothyronine control is a basal deuterostome trait, then it seems to be lost in hemichordates. An alternate explanation is that it was evolved separately in echinoderms and chordates. Much more work needs to be done on this group to elucidate whether other species consolidate iodine and if actors other than FGF play a role in embryogenesis and metamorphosis.

#### **2.3 Protochordates: TRIAC and an endostyle**

Protochordates are one of the three members of the phylum chordata along with urochordates (tunicates) and vertebrates. They are considered to be the basal chordate group [31]. The representative member of this group is the lancelet (Amphioxus), comprised by two genera, *Branchiostoma* and *Asymmetron.* The active form of iodinated tyrosine in amphioxus is triiodothryoacetic acid (TRIAC), rather than the triiodothyronine (T3) used among vertebrates [12]. TRIAC differs from T3 by having only two rings instead of three. Both T4 and T3 are found in amphioxous, but it is TRIAC, a metabolite of T3 that is the active form [32]. T4 is converted peripherally to T3 by deiodination and T3 is converted to TRIAC by deamination [33]. Amphioxus embryos lack large amounts of yolk and extra-embryonic tissues. This sets them apart from the vertebrates and is thought to be a basal chordate trait [31]. As far as the authors know, no studies have been done on thyroid hormone content of protochordate yolk. It is entirely possible that TH could be present in the yolk and it has not been detected as of yet. It is important to note that in ambulacraria, direct developing larvae have large amounts of yolk and indirect developing (planktonic) larvae do not [32, 34].

It is established that TRIAC controls the metamorphosis of amphioxus from a pelagic larva to a benthic post-larva [35, 36]. Metamorphosis is triggered by TRIAC binding to thyroid hormone receptors (TR). The expression of these receptors is

greatest just before metamorphosis [33]. In amphioxous, the endostyle is the site of T4 production. The endostyle has already been thought to be the thyroid homolog in larval cyclostomes [13], but the endostyle appears to be serving as a thyroid homolog in both larval and adult amphioxous [12]. As previously stated, T4 and T3 are produced in the endostyle and metabolized in the periphery. To be more specific, this deiodination and deamination takes place in the hepatic caecum, which is thought to be the homolog of the vertebrate liver [12]. Indeed, in vertebrates T4 is converted to T3 in the liver [8].

#### **2.4 Maternal thyroid signaling in larval fishes**

Female fishes deposit thyroid hormones against a concentration gradient in eggs during ovarian maturation [37]. Larval fishes are completely dependent on thyroid hormones of maternal origin until endogenous biosynthesis begins, and the regulatory capacity of the thyroid system has been attained. From that point forward, the thyroid system products in juvenile fishes have roles in organ system maturation, and the functionality of that system becomes dependent on adequate dietary sources of iodine [23].

Groupers are a family of marine fishes with small larvae that require relatively small food organisms. Cultured larval groupers are subject to large-scale mortality at the time of first feeding, but a switch from cultured rotifers to wild copepods provides a much more substantial supply of iodine, in response to which a sharp increase in larval survival has been attributed [38]. Some investigators have ascribed initial successes with larval groupers using copepods as a first feed entirely to differences in nutritional content [39], although iodine content of copepods and enhancement of digestive enzyme secretion in response to the copepod diet have been noted by other investigators [40]. These end-points are entirely consistent with established endocrine regulatory responses to micronutrient deficiencies in captive-reared populations, as reviewed previously [41] and as discussed further, below.

Thyroid hormones stimulate an integrated complex of developmental events that are crucial for early survival, collectively enabling fish larvae to make the transition from yolk absorption to active feeding [23]. Sensory, locomotor and digestive system maturation are essential for active feeding, and mortality on a substantial scale routinely occurs in captivity around the time of initial feeding [40]. In some cases, that has been attributed to an insufficiency of maternally-derived thyroid hormones [42, 43], sometimes in response to dietary iodine deficiencies. Perception of food items depends in part on eye and lateral line function, and olfactory organ input; pursuit of prey involves efficient swimming and neutral buoyancy, and the processing of food, absorption and utilization of nutrients hinge on the effective production of digestive enzymes. The maturation of the aforementioned physiological systems is strongly regulated by thyroid hormones of maternal origin, and all of these mechanisms become active on or slightly before the time of first-feeding [44, 45]. Early maturational events in the central nervous system are also dependent on maternally-derived thyroid hormones, enabling the processing of and responsiveness to critically important information.

#### **2.5 Functional sensory systems**

The detection of potential prey items by larvae typically involves mechanosensory detection of vibrations by the lateral line and the use of vision and/or smell to locate potential prey. The thyroid axis promotes neuromast proliferation and maturation and induces expansion of the neuromast population in the trunk in

zebrafish [46]. First-feeding typically occurs around day 5 in zebrafish, and is coincident with the onset of visual, lateral line, and locomotor function and acquisition of the capacity to digest prey organisms. The onset of lateral line function requires maturation of neuromasts, as well as peripheral nerve transmission and processing by the central nervous system (CNS). In addition to the development of lateral line components, maternally-derived thyroid hormones promote differentiation and maturational changes in the CNS [47, 48].

The eyes also differentiate and become functional in response to maternal thyroid signaling, just before the onset of feeding in zebrafish [45]. Experimental applications of Insulin-like Growth Factor-1 (IGF-1) receptor blockers and analysis of IGF-1 gene expression revealed that eye differentiation in response to maternal TH signaling is transduced by IGF-1. Treatment with exogenous TH causes expression of IGF-1 genes, thereby accelerating initial eye function by up to three or four days [45]. A parallel assortment of somatosensory deficiencies is reported in response to mammalian neonatal hypothyroidism [46].

#### **2.6 Locomotor system maturation**

Fin maturation is characterized by the development of fin rays and changes in the morphology of dorsal, caudal and other fins beginning just after hatching, as embyronic forms proceed in transitions into free-swimming larvae [49]. Fins and scales are established targets for thyroid-induced maturation [50, 51] and their functionality is critically important in the successful transition to autonomous feeding. Skeletal development in fins is homologous with vertebrate limb bone development [52], and regulatory actions appear to be homologous. Hypothyroid mammals are subject to severely compromised locomotor function, with evidence of musculoskeletal deficiencies, exaggerated behavioral and cognitive inhibition, and displays of increased immobility and anxiety-related behaviors [53].

In addition to fin and musculoskeletal development, buoyancy is essential for energy-efficient pursuit of prey. Larval fishes with undifferentiated or uninflated swim bladders are unable to swim efficiently and they can readily become a component of the heavy mortalities associated with failed transitions to first feeding. Swim bladder ontogeny and inflation are under the control of maternal thyroid hormones [42, 43], and TH-induced swimbladder maturation and initial function are transduced by IGF-1, as is eye development [45]. A significant improvement in swimbladder inflation rate is attributed to TH exposure [42] and a strong relationship (p < 0.005) was reported between egg T3 content and survival to two weeks post-hatching in striped bass (*Morone saxatilis*), with a correlation coefficient of 0.922 [42]. Mammalian lungs are evolutionary derivatives of the piscene swim bladder, and functional use of modified swim bladders for respiratory purposes is widespread among taxonomically diverse fishes [52]. Respiratory failures are listed among responses to hypothyroidism in humans, which according to the American Thyroid Association can result in lung function slowing "to the point that they can no longer keep up critical function" [54].

#### **2.7 Production of digestive enzymes**

Aquisition of the capability to find and ingest food does not ensure larval survival; numerous cases have been reported of larvae ingesting zooplankton or other organisms followed by failures to process, absorb and utilize their nutritional content. Maturation of the intestine is also controlled by maternal thyroid signals, and in cases in which those signals are lost or weakened, acutely underdeveloped and frail larvae with poor prospects for survival can be produced. In the Japanese

#### *Evolution of Thyroid Enhancement of Embryogenesis and Early Survival DOI: http://dx.doi.org/10.5772/intechopen.100409*

eel *Anguilla japonica*, for example, Kurokawa et al. [55] observed that eel leptocephali started feeding at day 7 and reportedly found ingested rotifers in larvae up to 13 days of age with no physical or immunohistochemical evidence of digestion or absorption. Growth in these leptocephali essentially stops at the completion of yolk absorption on day 7, and is usually followed by mortality within a few days [55]. Larval Anguillids are notoriously difficult to rear in captivity, and practical closure of the eel life cycle has eluded hatchery technologists for more than half a century. One possible explanation is that adult eels that mature in captivity fail to deposit adequate stimulatory endocrine signals into their eggs [56], producing seriously hypothyroid larvae with debilitating developmental deficiencies, including a sharply reduced capacity to produce digestive enzymes.

Increasing the content of the thyroid hormone T3 in marine fish eggs advanced the timing of the onset of digestive function, and significantly improved the rate of survival [57]. Further study of numerous species of larval fishes revealed that the expression of genes encoding digestive enzymes was induced by thyroid hormones [58, 59] coincident with the time of first feeding, which was interpreted as an indication that maternal signaling is a critically important determinant of the onset of intestinal digestive competence and consequently of survival. It is noteworthy that extensive and debilitating digestive system deficiencies and often acute failures are routinely reported in humans in response to hypothyroidism [60].

#### **2.8 Maternal endocrine status is a prime determinant of egg quality**

*Egg quality* was a characteristic of fish eggs that for many years had a circular definition – egg quality was defined as the capability of eggs to produce viable larvae for reasons that were speculatively considered and often dismissed as technically out of reach. Poor egg quality was attributed in earlier reviews to a combination of unknown genetic and nutritional variables, but regulatory materials such as endocrine signaling compounds (hormones and maternal mRNAs) were not yet being considered [61]. Thyroid signals deposited in fish eggs were recognized by some investigators as key determinants of egg quality more than 25 years ago [44] although numerous recent analyses of egg quality have completely overlooked the contribution of maternal thyroid hormones to larval success.

Some fish species are very reluctant to spawn in captivity, and captive-reared fishes released into wild environments often exhibit substantially compromised reproductive performance [62]. An inhibitory dopanimergic neural pathway is activated in response to a variety of stresses including environmental alterations, resulting in blockage of gonadotropin synthesis and release and imparied reproductive competence [63]. The degree of inhibition is variable, ranging from no inhibition whatsoever to erratic reproductive performance to complete reproductive failure. For this reason, challenging species are often treated with Ovaprim, the innovative spawning inducer developed by R. Peter and H-R Lin, which combines GnRH analogs and a dopamine receptor blocker [64]. Nevertheless, fertile eggs that produce larvae capable of hatching are not necessarily adequately provisioned with essential regulatory compounds to negotiate larval-juvenile metamorphoses. For these reasons, additional attention should be paid to the adequacy of maternal endocrine status during oogenesis.

Some species such as the striped bass (*M. saxatilis*) display highly variable production of viable eggs in captivity; two nearly identical-looking gravid females can display fertility rates of 4% and 94% (personal observation, unpublished). This may reflect variable endocrine status of broodstock females, since the deposition of essential regulatory hormones during oogenesis is determined by patterns of circulating hormones in maternal fishes. Larval survival in this species is highly

dependent on the concentration of T3 maternally deposited into eggs [42, 43]. Maternal endocrine status during ovarian maturation can be severely altered by variations in dietary iodine, stress, and other factors. For example, the iodine content of wild marine zooplankton was vastly higher than that of conventional aquaculture feeds, and a 700-fold concentration difference was reported in a comparison with *Artemia*. This difference was reflected in reduced circulating TH levels and an increased frequency of developmental deformities in *Artemia*-fed larval Atlantic halibuts (*Hippoglossus hippoglossus*) [65].

#### **2.9 The net effect of maternally-stimulated sensory, locomotor, and digestive developments**

The combined effect of maternally-derived thyroid stimulation during yolk absorption is the maturation of sensory (mechanoreceptor and visual) organs, fins and the swimbladder, and advancement of the timing of the onset of digestive capacity. These maturational events, together with maturation of CNS processing capability, convey a sharply increased degree of larval fitness and a much more likely successful transition to independent feeding.

Nearly complete mortality has been reported for some larval marine teleost cohorts, under both wild and hatchery conditions. In some cases, wild larvae reportedly have nearly no chance of survival during the yolk absorptive and early feeding phases, even in the absence of predators [66]. Early failure of large cohorts profoundly impacts recruitment strength and can shift patterns of speciation. Attention to and management of maternal thyroid provisioning of fish eggs has reportedly increased larval survival by up to five-fold [42].

The survival value imparted by endocrine regulatory contact with mother fishes has probably been a driving factor in the emergence of viviparity, which has occurred repeatedly among phylogenetically diverse fishes [23]. Prolonging the exposure of offspring to maternal hormones can result in nearly complete survival among the relatively mature K-selected progeny of live-bearing fishes. More primitive shark species are oviparous, but in the relatively modern viviparous placental sharks, maternal thyroid hormones are transferred to developing larvae over longer periods of time, where they promote advancements of growth, maturation, and development of juveniles [67].

Rudimentary signaling is done in echinoderms with iodinated tyrosine, in some cases with double-stranded thryoxin molecules. Protochordates show a leap forward with an actual organ, the endostyle, and production of T4, T3, peripheral deiodination and deamination and TRIAC signaling. However, neither of these are subject to the fine regulation found in vertebrate thyroid systems. Fishes evolved numerous thyroid-related mechanisms that are characteristic of sophisticated vertebrate endocrine systems, including efficient hormone synthesis with thryoglobulin (TG), pituitary control of TH synthesis, hypothalamic control of pituitary regulatory mechanisms, sensitive multi-level feedback adjustment to regulate hormone synthesis and secretion, binding proteins, multiple hormone receptors, and an elaborate system of regulatory devices involved in the peripherial processing of TH. These can alter the ratios of highly biologically active T3 to the much less potent T4, as one means of fine-tuning local hormone concentrations and resultant levels of hormone activity. Most T3 is derived from the deiodination of T4, and monodeiodination can generate the much more highly biologically active T3. It is also possible to deiodinate T4 into the biologically inactive isomer reverse-T3 (rT3), as reported in some teleosts [68]. For these reasons T4 has become recognized as essentially a prohormone that is capable of being processed into alternative endocrine products [69] with variable degrees of bioactivity. One net effect is that changing T3/T4 ratios

#### *Evolution of Thyroid Enhancement of Embryogenesis and Early Survival DOI: http://dx.doi.org/10.5772/intechopen.100409*

can be precisely regulated as needed, and these ratios serve in higher vertebrates as indicative of metabolic states and thyroid system health.

Regulation of larval differentiation providing competence for first feeding is subject to some degree of plasticity. Glucocorticoids have some capacity to alter thyroid system activity by influencing the deiodination mechanisms mentioned above, thereby increasing the magnitude of generation of T3. It has been proposed that alterations in maternally-circulating cortisol and other glucocorticoids can modify thyroid system function in ways that have adaptive value to fish embryos and larvae [70], by accelerating or delaying larval metamorphoses. Small alterations in the rate or timing of development can result in disproportionately large changes in anatomical or physiological outcomes, contributing importantly to adaptive radiation [52]. Integration of patterns of change in circulating thyroid and corticoid hormones have been reported in amphibian and flatfish metamorphoses, and the two endocrine systems are suspected to be functionally integrated [71].

An endocrine system with such precise control mechanisms emerged in fishes with a vital protective role toward offspring, and has been conserved. The finely-tuned control of thyroid bioactivity described above was adapted in a straightforward manner to the roles TH play in thermogenesis among birds and mammals [72].

Among important cellular mechanisms of action of maternal TH signals, many are mediated by hormonal stimulation of mitochondria. We have reported both the proliferation and activation of mitochondria in larvae in response to maternal TH signals, particularly in the intestine, the swimbladder, and neuromast cells of the lateral line [72]. Mitochondrial stimulation appears to be the basis for controlled thermogenesis in mammals, in specially-adapted brown fat tissues that evolved. It therefore appears likely that the elaboration of thyroid function initially for the enhancement of larval survival at the time of first feeding provided the mechanistic and regulatory basis needed for the later genesis of precisely-controlled thermogenesis.

#### **3. Evolutionary implications of maternal thyroid contributions**

Maternal/larval regulatory signaling has been described with an emphasis on the emergence of such interactions in advanced invertebrates, protochordates and lower vertebrates. This relationship has profound survival implications and has been retained and amplified in higher vertebrates, including humans. Comparative views of the origin and prototypical functions of physiological and biochemical interactions during development are briefly summarized in **Table 1**; a comparative perspective can be of substantial practical value [52].

Among reproducing fishes, a suite of adaptive developmental changes profoundly alters the likelihood of a successful transition from yolk absorption to exogenous feeding. Survival of this process is most likely if sensory, swimming, and digestive physiology are activated simultaneously prior to or at the time of first feeding. Visual and lateral line sensitivity, functional fins, a fully-inflated swim bladder, and the maturation of digestive enzyme secretory capability all contribute to the acquisition of nutrients after the exhaustion of yolk supplies. The development and early maturation of all of these physiological systems is under the control of thyroid signals of maternal origin that are deposited in yolk. Deficiencies of maternally-derived TH can have lethal consequences, especially in the transition to first-feeding. None of these peripheral or mechanistic functionalities are of value without effectient central processing, and regulation of the early maturation of the CNS is a major role of maternal endocrine regulation.

#### **Table 1.**

*Evolutionary advancement of maternal regulation of larval/fetal ontogeny.*

Maternal hormonal regulation of the fitness of offspring is so directly relevant to survival that it has been retained and amplified throughout vertebrate evolution. Specific consequences of neonatal hypothyroidism are numerous and can collectively be lethal, whether considered in the context of larval fishes or human infants. Central nervous system differentiation, the maturation of sensory, digestive, and locomotor organ systems all respond to maternal signaling, and they collectively facilitate transitions from embryonic and larval existence to more autonomous juvenile life.

#### **4. Conclusions**

Antioxidant functions of iodine generated a set of benefits to the parental transfer of iodinated compounds to offspring, eventually giving rise to the use of iodinated tyrosines for this purpose. These iodinated amino acids, in some cases in the form known in vertebrates as thyroid hormones, assumed signaling roles in some echinoderms, triggering metamorphic changes and alterations of modes of feeding. These signal-driven changes had substantial phenotypic value with advantages

*Evolution of Thyroid Enhancement of Embryogenesis and Early Survival DOI: http://dx.doi.org/10.5772/intechopen.100409*

to survival, and consequently have been observed multiple times in echinoderms and chordates. Maternal provisioning of fish eggs provides a means of promoting development, altering the timing of metamorphosis and enhancing survival at the time of first-feeding, with some degree of plasticity. Regulatory maternal endocrine relationships with offspring have been retained in humans and other vertebrates, in which they are essential for normal development and survival.

#### **Acknowledgements**

Stipends in support of the investigators were provided by FAO World Fisheries University (WFU) Pilot Programme, and are deeply appreciated. Facilities and some supplies were made available by the WFU Pilot Programme, for which we are grateful. Professor Charles Bai generously shared research facilities with us, enabling our spawning and rearing of larval zebrafish to proceed.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Arjay Pataueg1† , Earl T. Larson2† and Christopher L. Brown1 \*

1 FAO World Fisheries Programme, Pukyong National University, Busan, South Korea

2 Department of Biological Sciences, St. Johns River State College, Orange Park, Florida, USA

\*Address all correspondence to: brownchristopher38@gmail.com

† These authors contributed equally to this work.

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 9**

## Molecular Mechanisms of Glucose Uptake Regulation in Thyroid Cancer

*Shabnam Heydarzadeh, Ali Asghar Moshtaghie, Maryam Daneshpour and Mehdi Hedayati*

#### **Abstract**

Common capabilities of thyroid malignant cells are accelerating metabolism and increasing glucose uptake to optimize energy supply for growth. In tumor cells, keeping the power load required for cell survival is essential and glucose transporters are capable of promoting this task. GLUT-1 and GLUT3 are promising goals for the development of anti-cancer strategies. The lack of oncosuppressors has dominant effect on the membrane expression of GLUT1 and glucose uptake. Overexpression of hypoxia-inducing factors, in thyroid cancer, modulates the expression of some glucose transporter genes. Although the physiology of the thyroid gland has been excellently explained, metabolic regulation in thyroid cancer is inevitable. In this section, we investigated the proliferation pathways of pivotal regulators and signal molecules around GLUT regulation in thyroid cancer, including PTEN, p53, MicroRNA, iodide, BRAF, HIF-1, PI3K-Akt, TSH, c-Myc, and AMPK. Impaired energy regulation and cell metabolism are the most critical symptoms of most cancers. As a result, understanding the mechanisms of glucose transport in the normal and pathological tissues of the thyroid may be very crucial and offer tremendous insights into the science of analysis and remedy of thyroid disease.

**Keywords:** thyroid cancer, glucose uptake, regulator, glucose transporter

#### **1. Introduction**

In glucose metabolism, glucose transport in the plasma membrane, known as the rate-limiting step, is mediated by carriers belonging to the facilitative glucose transporter (GLUT) and the sodium-coupled glucose co-transporter (SGLT) proteins families. While SGLTs require energy to perform the task of glucose transport, GLUT allows glucose to be transported below its concentration gradient without energy dependence [1]. GLUT1 is one of the fourteen GLUT isoforms that have a strong affinity for glucose and express unusual expression of plasma membranes [2, 3]. High expression of GLUT1 is positively correlated with proliferation index and is equivalent to malignant characteristic. In this case, there are poor foresight in different types of cancer, including prostate [4], thyroid [5, 6], colon [7, 8], melanoma [9], liver [10], breast [11, 12], and ovary [13, 14].

Almost many cancer cells change cellular metabolism due to high proliferation rates, which can lead to a stressful metabolic phenotype. Tumor cells are able to alter metabolism from oxidative to glycolytic phenotype. This effect is called Warburg, which is a specific metabolic feature of the tumor and a major metabolic feature. Research on tumor metabolism suggests that rapid cell proliferation, tumor progression, and resistance to cell death should be maintained by altering cellular metabolism in which glycolysis and glutaminolysis are regulated [15]. Glucose transfer occurs in neoplastic cells across the plasma membrane, the first step in limiting the rate of glucose metabolism. There is evidence that a decrease in GLUT1 can suppress cell proliferation, so regulating glucose transporter expression and activity has a significant effect on glucose supply in cancer cells [16]. Several studies have shown the immunohistochemistry of GLUT 1 in cancer cell research [17–19]. High expression of GLUT1 on plasma membranes is related to exactly the same degree of differentiation. Also, the biological invasion of thyroid cancer (TC) is commonly occurred in ATC compared to other different types. GLUT1 is located on the plasma membrane and their expression can be assessed by using PET [20].

One hallmark of cancer cells; especially TC cells are showing high glucose uptake than the normal thyroid samples. Tumor cells regenerate their metabolism by increasing the transportation of glucose to promote cell survival. Malignant cells increase the transportation of glucose through the cell membrane by inducing a family of facilitative glucose-transporting proteins (GLUTs) that are highly classifiable in terms of tissue-specific distribution and different tendencies to glucose and different transport capacities. In most cases, thyroid cancer cells often show overexpression of the GLUT1 and GLUT3 proteins that respond to hypoxia. Malignant cells are typically less able to utilize oxidative metabolism, but aerobic glycolysis is rapidly increased and oxidative phosphorylation remains constant. Increased glycolysis is the main source of energy in cancer cells, but due to the lower energy function in the glycolytic pathway, malignant cells increase the rate of glucose transport in the plasma membrane to compensate for the energy obtained [21–25].

Recently, the relationship between tumor differentiation and glucose metabolism in thyroid cancer has been investigated. The metabolic profile of glucose is differently related to differentiation in well-differentiated and poorly differentiated thyroid cancer. During Suh H. Y. et al. studies based on genetic mutation, the metabolic profile of TC cells was not simply linked with differentiation. The expression of GLUT had an opposite relationship with differentiation in TC. Glycolysis enhancing had a positive relationship with the well-differentiated TC, and on the other hand, showed a negative relationship with poorly differentiated TC. In the papillary type of TC, glycolysis signature showed a positive correlation with differentiation rate, while GLUT signature had a negative correlation with differentiation rate. On the other hand, in the poorly differentiated type of TC, both GLUT and glycolysis showed a negative relationship with the differentiation rate. Their results were in agreement with previous investigations because poorly differentiated type with overexpression of GLUT requires more glucose uptake. In general, it is considered that the relationship between the differentiation and glycolysis may follow a U-shape pattern. The results of different rates for GLUT and glycolysis in PTC were the BRAFV600E mutation status. The PTC cells containing BRAFV600E mutation had high GLUT signature and low glycolysis signature than PTC cells that did not contain BRAFV600E mutation [26].

It is reported that GLUT1, GLUT3, GLUT4, and GLUT10 are expressed in all thyroid parenchymal cells, without attention to their histological status. GLUT1 is more expressed in thyroid cancer tissues than in normal and benign samples obtained from the same patient. Other GLUTs have not been reported to be altered in comparison to GLUT1 in the same patient's pathological tissues. These results

#### *Molecular Mechanisms of Glucose Uptake Regulation in Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.101937*

indicated that GLUT1 is theoretically responsible for the observed increase in glucose uptake during carcinogenesis [27, 28]. Overexpression of hexokinase I and increased intracellular glucose phosphorylation in thyroid tumors have been shown to be a signal of tumor invasion. The degree of tumor differentiation in thyroid cancer is consistent with the expression of GLUTs. While poorly differentiated types (anaplastic) have a high expression of GLUT (mainly GLUT1), in contrast, well-differentiated tumors (follicular and papillary) often have a weak expression of GLUT1. GLUT-3 has been reported to be predominant in papillary thyroid cancer [20, 29]. Based on the results of the research, there was a significant expression of GLUT1, GLUT3, and GLUT4 in the cytoplasm and/or membrane of PTC. In PTC cells, GLUT3 and GLUT4 expression pattern were higher than GLUT1 one [30].

The expression of GLUT1 and GLUT3 induced by hypoxia is not similar in benign and malignant thyroid tissues as well as non-neoplastic samples. The dissimilarity in expression levels of GLUT1 and GLUT3 are related to the sample histology. The hypoxia-induced GLUT1 and 3 have a role in the progress of PTC and may be contributed to the panel of significant markers of thyroid cancer. High expressions of GLUT1 and GLUT3 proteins showed a direct relationship with high levels of GLUT1 and GLUT3 mRNA in similar samples of TC. In spite of that, in some of the neoplasm samples, the GLUT1 or GLUT3 band and also mRNA levels were very low. The best interpretation for these detections is the influence of the hypoxia-induced GLUTs by the cancer cell microenvironment and oxygen-related transcription factors [31].

Unusual expression of GLUT proteins is controlled by multiple signal transduction pathways, including the phosphoinositide 3-kinase (PI3K) / AKT pathway [32]. In the thyroid glands, AMPK plays an important physiological role in the uptake of thyroid iodide and can play a role in carcinogenesis. It is recently found that in TC cells, AMPK can increase glucose uptake through the inducing of GLUT 1 and hexokinase (HK) activity [33, 34]. Lack of PTEN expression can lead to the AKT pathway inhibition that was linked with superficial expression of GLUT1 and the possibility of TC diagnosis by FDG-PET [35].

Thyroidectomy and radioactive iodine therapy are common treatments for patients with thyroid cancer but often are not more effective. Recent advances in molecular therapies aimed to understand the molecular pathogenesis of thyroid cancer were promising in the development of early detection and appropriate treatment strategies for thyroid cancer. This is mainly due to the detection of molecular alterations [36]. Although the physiological function of the thyroid gland is well established, its metabolic compatibility is unclear, especially in thyroid cancer. This review argues for recent significant advances and key factors, including inhibiting or stimulating glucose uptake in thyroid cancer that may be useful for future therapeutic purposes in this disease.

#### **2. Targeting glucose transportation in cancer cells**

It has been well known from the time of Warburg's hypothesis that cancer cells were found to show the high need for energy and metabolism. It has been reported that almost 90% of cancers showed high glucose metabolism. In addition, these cells, despite having oxygen, can reduce the oxidative phosphorylation pathway and are in favor of the pyruvate conversion to lactate. ATP synthesis is not the top priority of the upregulation of glucose transport. Glycolysis is approximately 18 times more efficient than the oxidative phosphorylation process, so cancer cells need more glucose uptake into cells to compensate for low ATP production [37–39]. Although the Warburg effect was observed more than 80 years ago, its

**Figure 1.** *Positive and negative regulators of glucose uptake.*

interpretation is still argumentative and evolving. Cancer cells do not tend to convert all of the glucose from regulated transport into pyruvate, but rather turn some of the metabolic mediators of glucose into the pentose phosphate pathway (PPP), which is a metabolic pathway, branched off from glycolysis that provides metabolic intermediates for the synthesis of biomass [40–42]. At present, clinical and basic science studies have shown that the Warburg effect is a potential and intelligent cancer research area [43]. Targeting glucose metabolism and transport has been suggested as a useful target for cancer therapeutic intervention [39, 44, 45]. Glycolytic switching in cancer, in addition to greater potential for invasion and metastasis [46], increases the susceptibility of cancer to external interference due to their greater dependence on aerobic glycolysis [47–49]. The discovery of GLUT inhibitors may indicate the development of drugs that can be used as anticancer agents, possibly in addition to conventional chemotherapy or new immunotherapies for further study [50]. There is strong evidence that the expression, activity, and intracellular movement of GLUTs as malignant biomarkers are regulated by different signaling molecules and pathways. In this study, we investigated the proliferation pathways of key positive and negative regulators and signal molecules including PI3K-Akt, HIF-1, MicroRNA, PTEN, AMPK, BRAF, c-Myc, TSH, iodide, and p53, which consist of GLUT regulation in thyroid cancer cells (**Figure 1**).

#### **3. Negative regulation of glucose uptake**

#### **3.1 PTEN**

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is known as a protein and lipid phosphatase that suppresses tumors and negatively regulates cell growth and metabolism. This gene is often mutated in many advanced human cancers [51]. PTEN expression and activity may be affected by intragenic mutations or epigenetic silencing and post-translational changes. Histone de-acetylation is one of the factors that shut down the genetic process that affects PTEN expression. Researches have shown that inhibition of histone deacetylase can save PTEN

#### *Molecular Mechanisms of Glucose Uptake Regulation in Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.101937*

expression and reduce the AKT pathway as well as glucose transport [52]. Loss of PTEN as tumor suppressor gene, possessing an inhibitory role on PI3K / AKT signaling pathway, has also been involved in FTC progression.

Scientific researchers have identified the relationship between plasma PTEN levels and sporadic PTC and their involvement as biomarkers. The observation of PTEN promoter hypermethylation in approximately 50% of PTCs and 100% of FTCs proposes that it may have a contribution to thyroid carcinogenesis [53, 54]. Glucose uptake signaling pathways that occurred during thyroid cancer is poorly recognized since now. Genetic manipulations showed that PTEN as an oncosuppressor agent have participation in GLUT1 expression and glucose uptake in TC cells. Lack of PTEN expression can block the AKT pathway and is associated with the possibility of rapid detection of thyroid cancer by FDG-PET. PTEN binds to SNX27 and prevents it from accessing the VPS26 retromer complex, thus blocking GLUT1 glucose transporter recycling to the plasma membrane, leading to impaired cellular glucose uptake [55, 56]. PTEN can also affect glucose metabolism by dephosphorylating the insulin-1 receptor substrate, thus inhibiting insulin signals and insulin growth factors that are also associated with glucose metabolism [52].

The PI3k class I (PI3KC1) -AKT pathway and AKT downstream effector AS160 (GTPase rab activator) are involved in GLUT1 cell surface exposure in thyroid cancer cells [57, 58]. PTEN lipid phosphatase activity is a determinant of PTEN inhibitory action on the AKT pathway which antagonizes the activation of the AKT pathway. This can reduce the availability of phosphatidylinositol [3–5] -tris phosphate (PIP3), which is a phosphate donor for AKT phosphorylation. This prevents the expression of GLUT1 in the plasma membrane and ultimately the anti-cancer function. It has not been revealed whether PTEN protein phosphatase activity also affects PI3K activity and GLUT1 regulation on plasma membranes. It has been reported that even the AKT pathway can be regulated by PTEN through protein phosphatase activity [52].

#### **3.2 P53**

Environmental, genetic, and hormonal factors are the main roots of human malignancy incidence [59], among which genetic factors indicate an extraordinary role in carcinogenesis. Different types of incidence and progression of thyroid cancer are characterized by the gradual accumulation of somatic mutations and/ or gene rearrangement with different frequencies and properties [60, 61]. Today, the absence of p53 family members indicates the pathogenesis of poorly differentiated thyroid tumors. Inactive P53 is a genetic variant that distinguishes anaplastic thyroid cancer from well-differentiated thyroid cancer. The p53 mutation usually occurs in undifferentiated thyroid tumors (50–80% in ATCs) [60, 62]. In addition, recent studies have shown that genetic variation of p53 is distinguished in 40% of papillary thyroid cancer and 22% of follicular thyroid cancer [63, 64].

PTEN and P53 play a key role in driving GLUT1 in the plasma membrane. They are key regulators of glucose metabolism and autophagy, which are the most common deleted or mutated suppressors in human cancer [65–67]. Expression of PTEN and P53 can be the cause of glucose uptake and glycolytic enzymes inhibition, stimulation of apoptotic cell death, and mitochondrial oxidation induction, accordingly counteracting with the Warburg effect. They block the PI3k-AKT–mTOR signaling, so it can regulate cell growth. TC cells with an unusual expression of PTEN or p53 are more likely to consume glucose. These two regulators have been shown to stimulate tumor cells to overcome hypoxia-induced metabolic stress and glucose depletion. It also inhibits caspase-dependent apoptosis, autophagy, promotes cell migration, and invasion [68–70].

Point mutations in p53, which occurred in the domain of its binding to DNA, have been associated with malignancy and have abolished its inhibitory activity on the transcriptional activity of GLUTs. Among the GLUTs, GLUT1 and GLUT4 gene promoters are the dominant types that are affected by the P53 mutation in a dose-dependent manner. This results in an increase in glycometabolism and cellular energy, which is known to facilitate tumor cell growth. P53 has shown a significant inhibitory effect on GLUT4 compared to GLUT1. This may be due to the fact that GLUT1 is a general "housekeeping" transporter of glucose, whereas GLUT4 is a tissue-specific and insulin-sensitive glucose carrier [71, 72].

#### **3.3 MicroRNA**

MicroRNAs (miRNAs) are classified into oncogenic and tumor suppressor miRNAs. Onco-miRNAs are elevated in human cancers that inhibit cell growth and apoptosis, whereas tumor-suppressive miRNAs are downregulated in human cancers and can prevent cancer progression [73–75]. MiRNAs are non-coding, evolutionarily conserved RNAs that bind to the 3'-UTRs of messenger RNAs and are referred to as negative regulators following transcription [76]. Recent research suggests that a TC invasion is frequently characterized by a lack of miRNA regulation. MiR-146b, MiR-221, and MiR-222 are invasive PTC predictors [77–79].

MiR-718, which is a known negative regulator of proliferation, metastasis, and glucose metabolism, exhibits anti-cancer activity in PTC. MiR-718 can diminish the intensity of PTC cells by inhibiting the Akt–mTOR messaging pathway. MiR-718 expression was significantly decreased in malignant samples compared to normal papillary thyroid tissue. Due to the study of miR-718's influence on PDPK1, p-Akt, Akt, and p-mTOR, it was determined that p-Akt and p-mTOR were reduced following PTC treatment with MiR-718. MicroRNA was found to have a detrimental influence on the primary stages of the Akt– mTOR signaling pathway. It follows the regulation of the proliferation, migration, and invasion of PTC cells. The Akt–mTOR signaling pathway has been shown to play an important role in tumor cell glucose metabolism and phenotypic severity. Overexpression of MiR-718 has a significant effect on reducing energy production in PTC cells. Taken together, these results suggest that microRNAs such as miR-718 negatively regulate metabolic activity in thyroid cancer cells [80, 81].

MiR-125a-5p has been demonstrated to act as a tumor suppressor and glucose metabolism regulator in a range of malignancies, most notably TC [82]. Due to the fact that lactate is the end product of glycolysis in tumor cells and can be easily measured, its detection shows the rate of glucose metabolism. MiR-125a-5p reduces lactate synthesis, ATP production, and glucose uptake in TC cells, resulting in a blockage of glycolysis, decreased migration, and cell invasion. The MiR-125a-5p/ CD147 axis has been suggested to possibly play an important role in the aerobic glycolysis of thyroid cancer cells. Because GLUT1, HK2, MCT1, and MCT4 are important glycolysis-related proteins, their expression levels are significantly regulated by the miR-125a-5p/CD147 axis (**Figure 2**) [83, 84].

#### **3.4 Iodide**

Iodide is responsible for regulating the activity of thyroid cells. The number of glucose carriers in the plasma membrane can be reduced by the iodine auto-regulation function of iodine. In fact, it not only affects glucose metabolism through the oxidation pathway but also through an inhibitory effect on the glucose-facilitating transport system. Iodide is able to inhibit TSH-induced stimulation of glucose transport. The role *Molecular Mechanisms of Glucose Uptake Regulation in Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.101937*

#### **Figure 2.**

*Metabolic diversity between the Normal and cancer cells of the thyroid. Normal cells primarily consume glucose through the oxidation of pyruvate to CO2 by the TCA cycle. TC cells convert most glucose to lactate, regardless of the availability of O2, through the overexpression of some special glucose metabolism-related proteins. MiR-125a-5p blocks the effect of CD147 on lactate transporters such as MCT1/MCT4 that is resulted in low viability, migration, and invasion of TC cells.*

of thyroid hormone in the automatic regulation of iodine has also been recognized, but T3 and T4 do not block glucose transportation. Iodide can block the Vmax of glucose transport without any interference on Km. Therefore; iodine has not any function through the affinity to glucose, but can result in a low number of available transporter sites. As a consequence, the inhibitory role of iodine on glucose uptake in thyroid tissues may be crucial in both physiological and pathological status, as well as metabolism and nucleic acid mediators [85]. Poor differentiation is associated with upregulation of GLUT1 in TC cells that led to severe malignant biological phenotypes. The dedifferentiation process of FTC cells is associated with iodine loss. In addition, it was reported that thyroid malignancies become more eager for glucose during the dedifferentiation. This inverse communication between iodine and glucose (measured by 18FFDG PET/CT) was determined as the flip-flop phenomenon (**Figure 3**). This pattern is distinguished in different patients as well as in different locations of the tumor in one patient [20, 86].

#### **3.5 BRAF**

BRAF is a cytoplasmic serine–threonine protein kinase that shows a crucial role in thyroid carcinogenesis. Finding of BRAF mutation as a common change in TC is important knowledge. The BRAF mutation may initiate the transition of PTC to ATC [87]. The differentiated thyroid cancers with mutant-type BRAF show more levels of GLUT-1 than those with wild-type BRAF. These results suggest that tumor cells with BRAF genetic variants may have higher uptake of 18F-FDG.

It has been recognized that there is a link between mutant BRAF and downstream stimulation of MAPK. The c-Myc linkage targets HIF-1a that resulted to high glucose metabolism [88]. The incidence of BRAF V600E mutations may participate in glycolytic phenotypes associated with overexpression of GLUT1. In this case, GLUT1 is the target of the RAF / MEK / ERK activated pathway. This contribution leads to cancer cells growth [89, 90]. BRAF and MAP/ERK kinase inhibitors give the assurance in cancer therapy linked with BRAF mutations [91].

**Figure 3.** *Molecular basis of flipflop phenomenon.*

#### **4. Positive regulation of glucose uptake**

#### **4.1 HIF-1**

Hypoxia is an important feature of invasive malignancies that causes malignant phenotypes and activates the physiological adaptation of cancer cells. This helps the tumor to survive and also to progress the diseases. Examples of this adaptation for cancer cells include the glucose transporter 1 gene (GLUT1), which increases glucose uptake for glycolysis [92]. Evidences suggest that the high rate of HIF-1a signaling observed in many tumors can lead to tumor metastasis, poor prognosis, or therapy. It is important to note that HIF-1a signaling is induced by low oxygen uptake as well as by oncogenic stimulation through abnormal growth mediators or lack of tumor suppressors [93]. The level of HIF-1a protein and the upregulation of reporter gene activity is equal to the increase in GLUT1 levels. HIF-1a expression is increased in FTC-133 cells with PTEN mutation. There is an important correlation between PI3K/AKT and HIF-1a that may be particularly associated with disease progression in thyroid cancer [86].

There is no sign of HIF-1α expression in normal thyroid tissue, but it is highly expressed in the most invasive differential thyroid cancers. In PTC, MTC, and FTC, overexpression of HIF-1 is associated with poor prognosis and distant metastasis [15, 93]. Thyroid hormones can activate the PI3K and MAPK signal cascades. In addition, thyroid hormones have the task of directly regulating HIF-1α expression by stimulating these signal transduction pathways. A TRβ mutation binds to the PI3K-regulatory subunit p85α following high signaling of PI3K and causes thyroid tumorigenesis, which may result in high HIF-1α expression [93].

*Molecular Mechanisms of Glucose Uptake Regulation in Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.101937*

HIF-1 contributes to the Warburg effect by increasing glycolysis. It is performed through the stimulation of all glycolytic enzymes, as well as increasing their substrates affinity [83]. HIF-1 also can increase the GLUTs level and decrease mitochondrial metabolism, which may be important in inhibiting ROS production and protecting cancer cells from death [94, 95]. HIF-1 has been suggested to help the Warburg effect by stimulating a number of glycolysis-mediated genes [96, 97], including GLUT1 and GLUT3, which contain hypoxia-reactive elements (HRE) in their promoters [98, 99].

In addition, HIF-1 can show a direct effect on the expression of all 12 enzymes required for glycolysis, or glucose and lactate transporters. These factors showed high expression in TC. In general, these results suggest that TC cells showed the Warburg effect by altering the energy supply by increasing the glycolysis pathway and decreasing mitochondrial function [100]. The close association of HIF-1α with metabolic pathways may be a welcome goal for better treatment of thyroid cancer [92].

#### **4.2 PI3K/AKT**

The phosphatidylinositol 3-kinase (PI3K)-Akt pathway is a family of growth factor-activated lipid and protein kinases that are involved in the regulation of growth and survival processes [101]. The PI3K/Akt pathway was initially associated with thyroid cancer due to the proclivity of patients with Cowden's syndrome to develop thyroid cancer. Due to the fact that Akt phosphorylates a vast number of downstream cytoplasmic and nuclear mediators, it is involved in the regulation of a variety of activities, including glucose metabolism. Increased PI3K/Akt expression appears to be connected with a poor prognosis in a variety of malignancies. Although the PI3K/Akt pathway plays a crucial role in endocrine malignancies, it has received less attention than other types of tumors [102].

The PI3K/Akt pathway mediates increased glucose uptake and overexpression of GLUT in cancers and is also involved in stimulating glucose transport in normal insulin-responsive tissues to increase glucose uptake [103]. PTEN functions as a tumor suppressor by blocking the PI3K/AKT pathway. The absence of this inhibitor can result in enhanced PI3K signaling, which can result in carcinogenesis. In malignancies, overactivation of Akt in the absence of a suppressor may result in enhanced glucose absorption. The serine/threonine kinase Akt, which is downstream of PI3K, is implicated in mediating the Warburg effect and triggering the expression of GLUTs such as GLUT1, GLUT3, and GLUT5 [101, 103–105]. It also acts as a regulator of GLUT4 transport around the plasma membrane, which facilitates glucose transport [103].

The effect of oncogenes on the metabolic change of cells to maintain cell proliferation is a major aspect of thyroid tumors [106]. In many tumors, activation of the PI3K / AKT pathway may be associated with mutations in RAS [107] leading to increased glycolysis flux [108, 109]. The PI3K / AKT pathway in the transfer of the GLUT1 cytoplasm to the plasma membrane in thyroid cells is very significant [15, 32]. According to the list of somatic mutations in cancer, PI3K/Akt pathway mutations are more prevalent in follicular and anaplastic thyroid tumors but are less prevalent in papillary thyroid cancer.

PI3K/Akt signaling has been implicated in thyroid carcinogenesis in animal studies. Thyroid cancer incidence is dramatically reduced in patients with Akt deficiency. Additionally, there is considerable evidence that AKT activation occurs in human thyroid cancer [96, 110, 111]. Numerous medicines targeting the PI3K/ Akt signaling pathways are now being explored in phase I to III clinical studies. Temsirolimus and everolimus have been discovered to be very effective in the treatment of thyroid cancer [112].

#### **4.3 TSH**

TSH is an abbreviation for Thyroid Stimulating Hormone, a hormone that plays a critical role in the regulation of the activity and metabolism of normal thyroid cells. Its stimulation increases glucose metabolism to enhance iodide transport and thyroid hormone synthesis (T3 and T4) [15]. Increased glucose uptake in tumor cells may reflect changes in gene expression or increased transmission to the cell surface. According to study, thyroid cells enhance their glucose absorption in response to thyroid-stimulating hormone activity. TSH, on the other hand, does not appear to have a substantial effect on GLUT gene expression, indicating that TSH alters glucose uptake through shifting/transferring GLUT rather than boosting GLUT gene expression [27]. TSH significantly increased the cellular absorption of 2-deoxy-D-glucose and the glucose transport tracer 3-O-methyl-D-glucose, both of which were labeled with carbon-14. Additionally, it has been demonstrated that enhanced glucose transfer may be a factor in increased GLUT1 transfer to the thyroid cell surface. These findings may help for explanation of the increased absorption of FDG with high TSH [113].

TSH can promote glucose absorption in normal thyroid tissue. TSH stimulation has an effect on adenylate cyclase, increasing the levels of cAMP. The results indicated an increase in glucose metabolism in a well-differentiated rat cell line FRTL-5. TSH-induced increase in 18F-FDG accumulation is dependent on phosphatidylinositol-3-kinase (PI3-kinase) in FRTL-5 cells. TSH or cAMP influence glucose absorption in thyroid cancer cells. This is depending on the activity of the PI3-kinase triggered by the mutant K-ras oncogene. TSH-induced glucose uptake was studied in ML-1 and FRTL-5 cell lines. This diversity is due to the clinical heterogeneity of various tumor morphologies and the degree of differentiation of tumor cells. Increased PI3-kinase activity, which may be induced by oncogenes such as mutant Ras, is responsible for glucose uptake in dedifferentiated thyroid cancer, indicating possible pathogenesis for thyroid malignancies (**Figure 4**) [107, 108, 114].

TSH affects FDG absorption in a time and concentration-dependent manner through TSH receptors. At high TSH levels, glucose absorption is enhanced in welldifferentiated thyroid carcinomas, which are typically still sensitive to TSH. TSH receptor messenger RNA expression in thyroid malignancies has been linked to the degree of differentiation, and poorly differentiated thyroid carcinomas may lack TSH receptors [115, 116]. Thyroid malignancies have been shown to contain somatic mutations in the TSH receptor gene as well as other CAMP cascade alterations, thus even when the TSH receptor is expressed, malignant tissue may respond to TSH stimulation differently than normal tissue. As a result, not all thyroid tumors are likely to accumulate FDG in TSH stimulation to the same degree as normal thyroid tissue [113]. The link between FDG uptake and TSH levels is of therapeutic relevance and might lead to new treatments. The link between FDG uptake and TSH levels is clinically significant and may result in significant misinterpretations in therapeutic studies [114].

#### **4.4 c-Myc**

c-MYC, a proto-oncogene, is a known cause of cancer. Myc has been demonstrated to directly influence glucose metabolism genes. The glucose transporter GLUT1, hexokinase 2 (HK2), phosphofructokinase (PFKM), and enolase 1 are the most essential of these [117–119]. Recently, it was demonstrated that glucose metabolism inhibitors targeting MYC inhibited the expression of GLUT-1, LDH-A, and MCT1 in cancer cell lines, coupled with lower MYC activity, hence inhibiting cell proliferation and tumor formation. Is it [120]. Myc controls the expression of genes involved in the

*Molecular Mechanisms of Glucose Uptake Regulation in Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.101937*

#### **Figure 4.**

*According to Riesco-Eizaguirre and Santisteban, and Rivas and Santisteban, a proposed signal transduction pathway in the thyreocyte exist [36, 43]. The absorption of 18F-FDG triggered by TSH is mediated via adenylate cyclase (AC) and cAMP, as well as Ras, PI3K, and Akt. PKA regulates iodide absorption. The mitogen-activated protein (MAP) kinase pathway is hypothesized to control cell proliferation by involving B-type Raf (BRAF), extracellular signal-regulated kinase, and mitogen-activated protein kinase.*

transfer of glucose, its catabolism to triose and pyruvate, and lastly to lactate. Due to the fact that glycolytic genes also respond directly to HIF-1, a collaboration between Myc and HIF has been seen in a number of cancers with genetic abnormalities [16, 120, 121]. In normoxia, Myc can accelerate glucose oxidation and lactate generation. Myc inhibits mitochondrial respiration with HIF-1 in order to create phosphoinositide-dependent kinase-1 and eventually favors anaerobic glycolysis (**Figure 5**) [122].

In addition to thyroid cancer, overexpression of c-Myc has been detected in a variety of other malignancies, where it promotes the expression of glucose metabolism genes. The c-Myc gene is a transcription factor that is associated with alterations in cellular metabolism and cancer. The initial connection between c-Myc and glycolysis was its influence on the positive regulation of an enzyme involved in the conversion of pyruvate from glycolysis to lactate. Additionally, c-Myc targets included glucose transporter-1, hexokinase 2, phosphofructokinase, and enolase 1 (**Figure 5**) [122].

#### **Figure 5.**

*Myc and HIF-1 are involved in the regulation of glucose metabolism and the Warburg effect. Myc and HIF-1 are shown to influence (dotted lines) glucose metabolism genes (glucose transporter Glut1, HK2, PKM2, LDHA, and PDK1), preferring glucose to lactate conversion (glycolysis). Myc is also shown to increase glutamine metabolism via the modulation of glutaminase and transporters (SLC1A5) (GLS).*

#### **4.5 AMPK**

The reactive oxygen species (ROS) as upstream signals of AMP kinase (AMPK) can alter cellular metabolism and increase the Warburg effect by upregulation of AMPK. AMPK is a metabolic cytosolic enzyme that senses stress and is activated by a lack of energy for the regulation of metabolism and cell growth [123]. In contrast, ROS production is not controlled by AMPK. This is proven by inhibiting AMPK phosphorylation and evaluating ROS production under these conditions. AMPK plays an essential role in cell cycle arrest and has a strong anti-growth effect in various cancer cell lines.

In the thyroid gland, it plays a serious physiological role in the absorption of thyroid iodide in vitro and in vivo and can play a role in severe invasive thyroid cancer. When activated, AMPK promotes energy generation pathways and restores intracellular ATP levels, while simultaneously inhibiting energy consumption processes. AMPK activation also enhances glucose absorption in non-cancerous cells and papillary thyroid cancer cells, mostly in the first step of the glycolysis process. AMPK has been shown to increase glucose absorption in thyroid cells without requiring TSH by increasing both GLUT 1 expression and hexokinase (HK) activity.

This definitely suggests that AMPK regulates glucose absorption by thyrocytes via a different pathway. Two mechanisms that influence glucose metabolism include enhanced glucose transport to cells and increased glucose phosphorylation. Three kinases, including the liver kinase B1 homolog (serine/threonine protein kinase LKB1), calcium/calmodulin-dependent protein kinase kinase (CaMKK), and TGFbeta-activated kinase 1 (TAK1), may be involved in the control of thyrocyte glucose absorption. The capacity of AMPK to influence glucose metabolism may be valuable in discovering novel pathways involved in thyroid function regulation in the future [34, 124]. Inhibiting AMPK activation in tumor cells can enhance the Warburg

*Molecular Mechanisms of Glucose Uptake Regulation in Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.101937*

effect. mTOR is significantly elevated in AMPK deficient models. Additionally, HIF-1 promotes the expression of HK2 and GLUT1, as well as glucose absorption by tumor cells. AMPK activation appears to contribute to the glucose metabolism seen in certain PTC cells. The active phosphorylated form of AMPK is expressed at a greater level in PTC tumor cell samples than in non-tumor tissue samples. Finally, more studies are necessary to clarify the role of AMPK in human thyroid cancer, particularly in metabolic regulation mechanisms such as cell proliferation, apoptosis, and survival [125–127].

#### **5. Conclusion**

While cancer was generally defined as aberrant cell growth, emerging data indicate that cancer is also a metabolic disorder. Metabolomics investigations, in addition to conventional approaches, are likely to be employed in the near future for the detection and classification of various forms of thyroid malignancies, most likely introducing altered metabolic pathways as treatment targets [128]. Thyroid cancer has a greater quick prevalence grade than any other kind of cancer in several countries [129]. Thyroid cancer cells have a high degree of metabolic complexity, indicating that they are capable of reprogramming glucose metabolism in response to nutritional restriction circumstances in the hypoxic tumor microenvironment. Malignant cells undergo metabolic alterations in order to get sufficient energy to continue growth signaling. Metabolic alterations such as increased glucose uptake are reported in invasive thyroid carcinoma for this purpose. Understanding the mechanisms of glucose transport to normal and pathological tissues of the thyroid can provide effective insights into the diagnosis and treatment of thyroid cancer treatments [27, 130].

Anticancer treatment is based on two main aspects. One is the traditional aspect of conventional chemotherapy, which is examined non-specifically against general cell processes. Another method is targeted molecular therapies, which include drugs designed to inhibit specific components of deregulated signaling pathways in cancer [131]. Deregulation of cellular metabolism as a hallmark of cancer may indicate changes in different signaling pathways. The metabolic change suggests a survival score for tumor cells [132]. Despite the number of various thyroid cancer biomarkers, only a few of them are clinically useful. Because one of these molecules may be ineffective on its own in many circumstances, the combination of two or more biomarkers can be quite helpful in detecting and predicting thyroid cancer [133]. The regulation of GLUTs is reviewed in this article in relation to critical amplification and survival pathways including as PI3K-Akt, HIF-1, MicroRNA, PTEN, AMPK, BRAF, c-Myc, and p53. Combination therapy is promising to enhance the efficacy of cancer treatment and cope with the multiple genetic alterations in different cancer cells. It involves simultaneous administration of more than one type of treatment such as two or more chemotherapies or merging chemotherapy with radiation/ adjuvant therapy.

Because glucose uptake into cancer cells is a limiting step in glycolysis, nutritional restriction in tumors through targeting GLUTs by inhibiting their glucose transport channel with small molecules might be an acceptable approach [134]. Recently, the concept of cancer chemotherapy targeting glucose transporters has been highlighted [1]. Glucose transport inhibitors have been demonstrated to be potential anticancer medicines that need more investigation and clinical trials. As more information on cancer metabolism becomes available, we will be able to produce more effective anti-cancer treatments [39]. The discovery of the method of impaired glucose uptake through glucose-transporting proteins may alter the

metabolism of malignant cells and thus disrupt tumor growth. If this hypothesis is confirmed, glucose-transporting proteins could become significant targets for cancer treatment [127]. Shifting the balance between cancer and stromal cells or the metabolic cooperation between different TC cell populations is a promising therapeutic strategy, but still needs further study. Finally, a better description of the metabolic phenotype under TC subtypes is clearly needed to provide a treatment option for poorly differentiated and refractory TC [130].

While conventional treatments such as surgical thyroidectomy and radioiodine therapy have been the main aspect of thyroid cancer treatment, they are frequently ineffective. As a result, treatment approaches against these sorts of malignancies must be recast in order to achieve modern drugs. Currently, the levels of GLUT1 or GLUT3 expression may give crucial information about the aggressiveness and growth of a tumor, as well as patient survival. The potential use of GLUTs as therapeutic targets is an exciting topic for future research in combination therapy.

### **Author details**

Shabnam Heydarzadeh1,2, Ali Asghar Moshtaghie1 , Maryam Daneshpour2 and Mehdi Hedayati2 \*

1 Department of Biochemistry, School of Biological Sciences, Falavarjan Branch Islamic Azad University, Isfahan, Iran

2 Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

\*Address all correspondence to: hedayati@endocrine.ac.ir

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Molecular Mechanisms of Glucose Uptake Regulation in Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.101937*

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### *Edited by Ifigenia Kostoglou-Athanassiou*

Hypothyroidism is an endocrine disorder commonly caused by Hashimoto's disease. Nowadays, autoimmune diseases appear to be on the rise. As such, there is renewed interest in hypothyroidism. This book presents a comprehensive overview of the disorder with chapters on etiology and pathogenesis, precision medicine tools for detection, diagnosis and treatment, the morphology of the thyroid gland, the effect of hypothyroidism on various organ systems, and much more.

Published in London, UK © 2022 IntechOpen © AlexLMX / iStock

Hypothyroidism - New Aspects of an Old Disease

Hypothyroidism

New Aspects of an Old Disease

*Edited by Ifigenia Kostoglou-Athanassiou*