**3. Risk factors for pancreatic cancer**

There are several factors that pose high risk for PC, such as obesity, chronic pancreatitis, diabetes, tobacco, and alcohol usage, exposure to chemicals, such as dyes and pesticides, age, and epigenetic changes. High-fat diets activate oncogenic Kras and Cox-2, causing inflammation and fibrosis in the pancreas, leading to PanINs and PC onset. Fat diet that induces pancreatic fatty infiltration could play an important role in PC. Moreover, the presence of PanINs was associated with intralobular fat accumulations [19]. The risk of PC increases with age, more than half of new cases occur in patients over 70 years old. ABO blood types and genetic variants may also influence PC risk [20]. Cigarette smoking increases the risk for PC by 75% when compared with nonsmoking individuals, and the risk persists for 10 years after smoking cessation [7]. Although several risk factors have been identified, the causes of PC are not well known. Understanding the mechanisms through which the risk factors might affect PC progression and survival is the key to develop a prevention strategy for this disease.

#### **3.1. Obesity**

Obesity is pandemic in the USA and has been associated with poor prognosis of several malignancies, including prostate, colon, breast, endometrial cancer, and PC. Both general and abdominal obesity are associated with increased PC risk. Moreover, physical inactivity has been linked with increased PC risk [7]. Obesity was linked with increased mortality from PC [21] and the promotion of stromal desmoplasia [22].

The most common method for obesity detection is the determination of the body mass index (BMI) that is calculated based on the relationship between body height and weight (BMI 18.5–24.9, normal; 25.0–29.9, overweight; ≥30, obese). Obesity strongly correlates with body fat levels. Adipose tissue has a very strong endocrine function, secreting various adipokines that are involved in cancer development and progression, and insulin resistance. Leptin, IL-6, and tumor necrosis factor-alpha (TNF-α) are inflammatory factors increased in cancers, but adiponectin is protective against tumorigenesis, and its serum levels are usually decreased. Cancer patients show higher baseline levels of C-reactive protein and soluble TNFα receptor 2. Lipocalin 2 was associated with tumor invasiveness. Resistin, another proinflammatory adipokine, was increased in colon, breast, and prostate cancer. To date, many adipokines have been associated with cancer, contributing to enhanced inflammation, angiogenesis, cellular proliferation, and tumorigenesis [23].

#### *3.1.1. Leptin*

Pancreatic neuroendocrine tumors (PNETs), representing 1–2% of PC, are commonly called islet cell carcinomas. Functional PNET secretes biologically active hormones (insulin, glucagon, somatostatin, or vasoactive intestinal peptide), causing a clinical syndrome. Nonfunctioning PNET does not cause clinical symptoms [14]. Other types of exocrine PC include acinar cell carcinomas, adenosquamous carcinomas, colloid carcinomas, hepatoid

The majority of PC develops silently from pancreatic intraepithelial neoplasia (PanIN) over a long period of time that highlights the importance and the challenge for early diagnosis [16]. Survival of patients with PC depends on the tumor stage at the time of diagnosis. The American Joint Committee on Cancer staging system has defined the relationship of pancreatic tumor with surrounding tissues, lymph nodes, vessels, and distant organs [17]. The first clinical stage of PC refers to tumors that are confined within the pancreas. The second stage involves PC that is spread to the adjacent tissues, especially to the lymph nodes. In Stage 3, the disease has already spread to the blood vessels, while in Stage 4, the metastasis has occurred in distant organs. Unfortunately, at the time of diagnosis, most of the patients have already invasion of vascular, lymphatic, and perineural tissue. The most common sites for distant metastasis are the liver, lung, pleura, peritoneum, and adrenal glands. Surgery may be offered to <20% of patients with PC. An additional challenge is that surgery success rate is gravely

There are several factors that pose high risk for PC, such as obesity, chronic pancreatitis, diabetes, tobacco, and alcohol usage, exposure to chemicals, such as dyes and pesticides, age, and epigenetic changes. High-fat diets activate oncogenic Kras and Cox-2, causing inflammation and fibrosis in the pancreas, leading to PanINs and PC onset. Fat diet that induces pancreatic fatty infiltration could play an important role in PC. Moreover, the presence of PanINs was associated with intralobular fat accumulations [19]. The risk of PC increases with age, more than half of new cases occur in patients over 70 years old. ABO blood types and genetic variants may also influence PC risk [20]. Cigarette smoking increases the risk for PC by 75% when compared with nonsmoking individuals, and the risk persists for 10 years after smoking cessation [7]. Although several risk factors have been identified, the causes of PC are not well known. Understanding the mechanisms through which the risk factors might affect PC progression and survival is the key to develop a prevention strategy for this disease.

Obesity is pandemic in the USA and has been associated with poor prognosis of several malignancies, including prostate, colon, breast, endometrial cancer, and PC. Both general and abdominal obesity are associated with increased PC risk. Moreover, physical inactivity has been linked with increased PC risk [7]. Obesity was linked with increased mortality from PC [21] and the

carcinomas, intraductal papillary mucinous neoplasms and pancreatoblastomas [15].

limited by the extent of early or occult micro metastases [18].

**3. Risk factors for pancreatic cancer**

34 Advances in Pancreatic Cancer

promotion of stromal desmoplasia [22].

**3.1. Obesity**

One of the main adipokines is leptin, a small protein (16 kDa), which is secreted by white, brown adipose tissue and cancer cells [24]. Leptin binding to its receptor, Ob-R, in the hypothalamus controls food intake and energy expenditure. Leptin also influences the reproductive function and is a long-term regulator of body weight. Leptin is also expressed in placenta, ovaries, skeletal muscle, stomach, and mammary epithelial cells. Leptin can inhibit bone formation. It regulates the ovulatory cycle and plays an important role in embryo implantation [25]. Obese and overweight individuals have high levels of leptin in blood but exhibit leptin resistance, failing to control food intake. Leptin blood levels in obese patients are 10 times higher (40 ng/ml) than in normal individuals (4 ng/ml). The underlying mechanism of leptin resistance in obese individuals is multifactorial that includes impairment of Ob-Rb signaling, hypothalamic neuronal wiring, leptin transport into the brain and Ob-R trafficking, endoplasmic reticulum (ER) stress, and inflammation [26]. High-leptin levels can induce cancer cell proliferation and thus can provide a link between obesity and cancer progression.

Several cancer cell types express leptin [25, 27, 28]. Both in vitro preclinical studies and patient, data suggest that leptin signaling is linked to the development of PC, breast, endometrial, colon, esophagus, stomach, thyroid gland, prostatic, hepatic, skin, brain, ovarian, lung and colon cancers, and leukemia [28–32]. Leptin can induce the development of nonalcoholic fatty liver disease, one of the major causes of hepatocellular carcinoma [33]. Leptin increases the proliferation of human myeloid leukemia cell lines and prostate cancer [34, 35]. In breast cancer, leptin increases the cancer cell proliferation and the expression of antiapoptosis-related proteins like Bcl-2 [36, 37]. Moreover, leptin induces the tumor angiogenesis, by promoting the expression of angiogenic factors, such as vascular endothelial-growth factor (VEGF) and fibroblast-growth factor 2 (FGF-2) [38]. Leptin has a direct effect on the proliferation of endothelial cells that were similar to VEGF [39]. Overall, leptin induces the production of inflammatory cytokines (IL-1, IL-6, and TNF-α), which can promote tumor invasion and metastasis [40].

There is a correlation between increased leptin levels and PC. Overexpression of leptin promotes the growth of human PC xenografts and lymph node metastasis in mice [41]. Ob-R is expressed by pancreatic cells, but its expression is increased in PC cells. Leptin binding to Ob-R induces proliferation, migration, angiogenesis and reduces PC cell apoptosis. The receptor long isoform, Ob-Rb, is found more often in cancer cells and has full signaling capabilities, in contrast to the short isoform. Leptin and Ob-R have absolute affinity for binding. Leptin binding to Ob-R activates canonical (JAK2/STAT3, MAPK, PI-3 K/AKT1) and noncanonical signaling pathways (p38MAK, JNK, AMPK). The first leptin signaling event is the activation of JAK2, which phosphorylates Ob-R intracytoplasmic tail, leading to the phosphorylation of a tyrosine residue of STAT3 (pSTAT3). pSTAT3 forms a dimer that is translocated to the nucleus, inducing the transcription of specific genes, such as SOCS3, which acts as a potent negative feedback regulator of the JAK/STAT pathway [26]. Recently, it was reported that the central or peripheral administration of an Ob-R antagonist induced comparable changes in food intake, body weight, and hypothalamic SOCS3 expression in lean and diet-induced obesity (DIO) mice. These results suggest that endogenous Ob-R signaling may not be reduced in the context of DIO, thus challenging the established concept of leptin resistance under dietary-induced conditions [42].

Gemcitabine in PC. TGF-β negatively regulates ALDH1 in PC in a SMAD-dependent manner. That can be disrupted by SMAD4 mutations and deletions. Therefore, targeting PCSC could

Pancreatic Cancer, Leptin, and Chemoresistance: Current Challenges

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Chemotherapeutic agents target the bulk of the tumor but unfortunately allow the proliferation of CSC that exhibits chemoresistance. Gemcitabine kills tumor cells but increases PCSC (CD24+ and CD133+) that expresses stemness-associated genes, such as Bmi1, Sox2, and Nanog. PCSC expansion increased cell migration, chemoresistance, and tumorigenesis [47]. Drug resistant cells showed activated c-Met and increased expression of CD24, CD44, and ESA. The use of a c-Met+ cell inhibitor (Cabozantinib) abrogated Gemcitabine resistance in PC patients [48]. Administration of anti-CD44 monoclonal antibody to a human PC xenograft mouse model increased Gemcitabine sensitivity [49]. Similarly, Metformin enhanced the antiproliferation effects of Gemcitabine by inhibiting the proliferation of CD133+ cells in PC [50].

Another PCSC marker, Dclk1, was found in PanIN lesions, and PC at invasive stages [51], suggesting that PCSC may be used as diagnosis biomarkers. PCSCs show transcription factors found on embryonic stem cells (Oct-4, Sox-2, and Nanog). Increased levels of Oct-4 and Nanog correlate with early stages of carcinogenesis and worse prognosis. Oct-4 contributes to metastasis and cancer multidrug resistance. Sox-2 expression alone in PC could induce self-

PCSC marker expression correlates with lymph node metastasis and poor survival. There are several factors that could affect PCSC maintenance and proliferation. For example, PCSC maintenance and survival are affected by miRNA34. In addition, stem cell factor (SCF) binding to its receptor, c-Kit, induces an increase in HIF-1α synthesis, which is involved in PC

Our data suggest that 5-FU (a common chemotherapeutic used in PC treatment) decreased PC tumorsphere formation. PC cells that expressed CD24 + CD44+, CD24 + CD44 + ESA+, and pluripotency (Oct-4, Sox-2, Nanog) markers were spared by the 5-FU treatment [30].

Overexpression of drug efflux proteins (ATP-binding cassette proteins and ABC family of proteins) increases the elimination of anticancer drugs and decreases their accumulation inside the cancer cells. ABC proteins (ABCB1, ABCC1, and ABCG2) are found in PCSC and contribute to their resistance to Gemcitabine [52]. Indeed, ABCB1 was significantly increased in CD44+ PC cells during the acquisition of resistance to Gemcitabine [53]. PC chemoresistance correlated with increased expression of CXCR4, CD133, and ABCB1 by PCSC [54]. Interestingly, ABCG2 localization and activity were not confined only to the plasma membrane, as intracellular vesicles containing ABCG2 were detected within CSC in PC, colorectal, and hepatocellular cancers. Moreover, a direct relationship between the presence of these vesicles in CSCs and the maintenance of their stem-like properties, including chemoresistance, was found. Furthermore, the vesicles accumulated ABCG2-dependent substrates, such as the fluorescent vitamin riboflavin (vitamin B2). In addition, the vesicles could accumulate

Therefore, the development of specific treatments against PCSC remains a challenge.

induce sensitization of PC to chemotherapeutic treatment [46].

renewal and differentiation [24].

progression and chemoresistance [26].

**4.2. ATP-binding cassette proteins**
