**4.1. Adenocarcinoma**

12 Dehydrogenases

*3.1.4. ALDH2* 

*3.1.5. ALDH7A1* 

spleen, muscle, lung and brain.

It's been shown that ALDH1A3 takes part in the development of the eye, nucleus

ALDH1A3 deficiency has been shown to play a critical role in cancer by a number of studies. For instance, in human breast cancer MCF-7 cells, ALDH1A3 expression is downregulated, whereas in cultured human colon cancer cells, *ALDH1A3* is one of two genes that are upregulated by induction of wild type *p*53. In mammary tumor-susceptible BALB/cJ mice that are heterozygous for *p*53, *Aldh1a3* is one of five candidate genes located within a region determined for its linkage to mammary tumorigenesis. In mice resistant to induced mammary tumors, (C57BL/6J), *Aldh1a3* is one of the two upregulated genes. *ALDH1A3* is silenced by methylation in gastric cancer cells, whereas in glioblastoma

ALDH2 is a tetrameric enzyme expressed profusely in lungs and liver; it is also present in organs that obligate high mitochondrial capacity for oxidative ATP generation including heart and brain. Apart from that, ALDH2 is also important in the aldehydic substrate oxidation such as 4-HNE, acrolein, and short-chain, aromatic or polycyclic carbons. To add to its dehydrogenase activity, depending on the substrates, ALDH2 can function as an esterase and reductase. More recent attention has also been focused on ALDH2 in regards to its function in the biotransformation of nitroglycerin, reducing it to 1,2-glyceryl dinitrate for

ALDH7A1 is a homotetramer that's expressed in a large number of tissues; in rat heart, liver and kidney, increased levels of ALDH7A1 are noted, whereas in black seabream fish (sbALDH7A1), ALDH7A1 is significantly formed in the liver and the kidney, excluding the heart. In human fetal tissues, ALDH7A1 has been encountered at elevated levels in the cochlea, eye, ovary, heart and kidney. In contrast, balanced levels are detected in the liver,

Human ALDH7A1's primary role happens in the pipecolic acid pathway of lysine catabolism, in which it catalyzes the oxidation reaction of alpha-aminoadipic semialdehyde (AASA) (*K*m180 μM) to alpha-aminoadipate. *ALDH7A1* mutations form the molecular basis for pyridoxine-dependent epilepsy (PDE), an autosomal recessive disorder characterized by the aggression of tenacious seizures during infancy and early childhood and are avoidable

Remarkably, ADH7A1 expression in the cochlea of the ear, the region dependent on the healthy upkeep of internal hydrostatic pressure, clarifies that mammalian ALDH7A1 might have an accomplishable function in osmotic regulation and in hearing disorders. However, no connection has been revealed yet, including patients with the inner-ear disorder

accumbens and olfactory bulbs, the forebrain, hair follicles and the cerebral cortex.

cells, it is triggered by the antitumor agent IL-13 cytotoxin (Marchitti*, et al.*, 2008).

the production of nitric oxide, which is a critical vasodilator (Chen*, et al.*, 2010).

by daily use of high-dose pyridoxine (Vitamin B6) supplementation.

Ménière's disease, which effects hearing and balance.

Adenocarcinoma is an epithelium cancer that is generated from glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissues that line the cavities and organs of the body. Epithelium can be derived from the three germ layers ectoderm, mesoderm and endoderm during embryologic period. Adenocarcinoma classification depends on not only being a part of the gland, but also depends on having the same secretory characteristics. But, this form of carcinoma can occur in some higher mammals, including humans (Fauquier*, et al.*, 2003).

Adenocarcinomas can arise in many tissues of the body due to the ubiquitous nature of glands within the body. While each gland may not be secreting the same substance, as long as there is an exocrine function to the cell, it is considered glandular and its malignant form is therefore named adenocarcinoma. Endocrine gland tumors, such as a VIPoma, an insulinoma, a pheochromocytoma, etc. are typically not referred to as adenocarcinomas, but rather, are often called neuroendocrine tumors. If the glandular tissue is abnormal, but benign, it is called an adenoma. Benign adenomas typically do not invade other tissues and rarely metastasize, whereas malignant adenocarcinomas do both. Colon, urogenital (cervical (Tewari*, et al.*, 2002), prostate, urachus and vagina), breast (Buchholz, 2009), esophagus, pancreas, stomach and throat are several examples of adenocarcinoma (Subramanian & Govindan, 2007).

It is reported that ALDH expression marks pancreatic cancer stem cells. Also, they have mentioned that the enhanced clonogenic growth and migratory properties of ALDHpositive pancreatic cancer cells suggest a key role in the development of metastatic disease that negatively affects the overall survival of patients with pancreatic adenocarcinoma (Rasheed*, et al.*, 2010).

### **4.2. Breast cancer**

From high-grade, absence of hormone receptor expression to positive HER2 status and the basal-like molecular subtype, the expression of ALDH1 is in direct relation with undesired tumor characteristics in breast cancer (Mieog*, et al.*, 2012).

Breast cancer cells with stem-cell-like properties are suggested to be responsible for metastatic spread. Aldehyde dehydrogenase 1 (ALDH1) and cluster of differentiation 44 (CD44) in addition to RhoC GTPase are among the stem cell markers that are expressed by these cells (Chaterjee & van Golen, 2011).

Breast CSCs were initially isolated, established on cell surface marker with CD24/lowCD44 expression. More currently, ''functional'' markers depending on stem cell properties are investigated for their plausible applications in the breast CSCs isolation. By this method, applying the aldefluor assay (Stemcell Technologies), originally designed to isolate viable HSCs and is an enzyme-based assay that recognizes ALDH activity, Ginestier et al. isolated breast CSCs. The assay is thought to precisely recognize ALDH isoform ALDH1A1 activity degree. Besides its application as a prognostic and CSC marker, ALDH activity that is primarily carried out by ALDH1A3 might be functional in breast cancer progression.

Aldehyde Dehydrogenase: Cancer and Stem Cells 15

ALDH1-positive, in contrast to CD44+/CD24-, was tremendously related to sequential paclitaxel- and epirubicin-based chemotherapy resistance, and the expression of ALDH1 increased after neoadjuvant chemotherapy, which stands for an indication of BCSCs, determined by ALDH1, indeed having played a significant role in chemotherapy resistance. This means that ALDH1-positive appears to be a better marker than CD44+/CD24- in identifying BCSCs, at least for the prediction of resistance to chemotherapy (Tanei*, et al.*,

Each year, approximately 171,000 new cases of lung cancer are diagnosed, and 160,000 individuals do not survive from the disease in the United States. This high incidence and mortality makes lung cancer one of the most common cancers and the leading cause of cancer death in men. Lung cancer is still the leading cause of death from malignant diseases worldwide in spite of the advances in surgical treatment and multimodality treatments

Cancer stem cells have attributed resistance of a smaller fraction of cells in the tumor bulk against chemotherapeutics. The isolation of CSCs is important for these reasons and have been isolated using a variety of stem cell markers and phenotypes. CD133 has recently been reported to identify tumor-initiating cells in non-small cell lung cancer (NSCLC). ABCG2 is also a stem cell marker of a variety of tissues and transporter responsible for the multidrugresistance phenotype. However, it was demonstrated that many cells in NSCLC and SCLC cell lines show tumorigenic potential, regardless of ABCG2 and CD133 expression. Recently, ALDH activity has been used for isolation of these kinds of cells. Normal SCs were shown to contain higher levels of ALDH activity than their more differentiated progeny. ALDHpositive cells of tumors have higher proliferation rates, migration and adhesion ability, and metastatic potential than ALDH-negative cells. This may occur because that RA product of ALDHs is thought to participate in cellular differentiation and stem cell self-protection

Epithelial ovarian cancer is the sixth most common cancer in women worldwide and it is still the most lethal gynecologic malignancy (Iorio*, et al.*, 2007)**.** Application of new technologies for detection of ovarian cancer could have an important effect on public health, but to achieve this goal, specific and sensitive molecular markers are essential (Petricoin*, et al.*, 2002)**.** Aldehyde dehydrogenase-1A1 (ALDH1A1) has been a valid marker among several malignant and non-malignant tissues in spite of several stem cell markers to identify CSCs. ALDH plays a role in the biology of TICs as well as being a stem cell marker. Because ALDH1A1 is implicated in chemo resistance pathways, it is questioned that targeting ALDH1A1 can effect cells resistant to chemotherapy and represent a potential target for cancer stem-cell-directed therapy. In a study, ALDH1A1 was investigated in ovarian cancer cell lines and patient samples and examined whether targeting ALDH1A1 sensitizes cells to

2009).

**4.3. Lung cancer** 

(Hibi*, et al.*, 1998).

(Serrano*, et al.*, 2011).

**4.4. Ovarian cancer** 

Expression of genes and tumor sphere formation in self-renewal and differentiation could be changed by adding chemical RA signaling inducers or inhibitors in breast cancer cell lines (Marcato*, et al.*, 2011).

ALDH1 could work as a marker of breast CSCs better than CD44+/CD24-. Though we could not maintain a conclusion that ALDH1 expression was significantly related with any conventional clinicopathologic attributes, nevertheless, there is a compelling relation between ALDH1-positive breast tumors and resistance to neoadjuvant chemotherapy, because of the pCR rates being obtained, which are lower in ALDH1-positive tumors (9.5%) than ALDH1-negative tumors (32.2%). Moreover, after neoadjuvant chemotherapy, a considerable increase in the proportion of ALDH1-positive tumor cells was observed. These results are an indication of ALDH1-positive tumor cells playing an important role in resistance to chemotherapy. Because of tumor cells being more tumorigenic than CD44+/CD24-, tumor cells of breast CSCs are thought to be richer in ALDH1-positive tumor cells than in CD44+/CD24- tumor cells. As a matter of course, we have shown that ALDH1 positive, in contrast with CD44+/CD24-, is closely associated with colony formation in the collagen gel as well. The subset of ALDH1-positive and CD44+/CD24- tumor cells has been reported to contain the largest proportion of breast cancer stem cells (BCSCs); consequently, it is speculated to have the strongest resistantance to chemotherapy. However, in our current study, pCR rates in the ALDH1-positive and CD44+/CD24- high subset (20%, 2 of 10), are not the lowest among all the subsets consisting of the ALDH1-positive and CD44+/CD24- low subset (0%, 0 of 11), the ALDH1-negative and CD44+/CD24- high subset (34.1%, 15 of 44), and the ALDH1-negative and CD44+/CD24- low subset (30.2%, 13 of 43). Adding CD44/CD24 status to ALDH1 status does not seem to positively improve the prediction of response to chemotherapy. Together, these results direct us to assume that, at least for the prediction of resistance to chemotherapy, ALDH1-positive tumor cells serve as a better marker for BCSCs than CD44+/CD24- tumor cells. Because such tumors contain a higher proportion of CSCs, we suppose that ALDH1- positive tumors are resistant to chemotherapy. However, because ALDH1 has been shown to play an important role in the resistance to chemotherapy in hematopoietic cells, ALDH1-positive tumor cells might be involved in resistance to chemotherapy, regardless of whether they are CSCs or not. In addition to deeper illumination of ALDH1's function in chemotherapy resistance in breast cancers, obtaining a significantly specific marker for BCSCs is necessary to enlighten an authentic role of BCSCs' chemotherapy resistance.

ALDH1-positive, in contrast to CD44+/CD24-, was tremendously related to sequential paclitaxel- and epirubicin-based chemotherapy resistance, and the expression of ALDH1 increased after neoadjuvant chemotherapy, which stands for an indication of BCSCs, determined by ALDH1, indeed having played a significant role in chemotherapy resistance. This means that ALDH1-positive appears to be a better marker than CD44+/CD24- in identifying BCSCs, at least for the prediction of resistance to chemotherapy (Tanei*, et al.*, 2009).
