**2.1. Cancer stem cells**

6 Dehydrogenases

formation. Furthermore, ALDHs also have several non-enzymic functions such as binding to some hormones and other small molecules and decreasing the effects of ultraviolet irradiation in the cornea (Pappa*, et al.*, 2003, Wymore*, et al.*, 2004). The most important role of ALDHs is detoxication of aldehydes, which caused cytotoxicity, mutagenicity, genotoxicity, and carcinogenesis in healthy cells. Mutations in ALDH genes cause severe diseases including Sjögren-Larsson syndrome, pyridoxine-dependent seizures, and type II hyperprolinemia, and also plays a role in cancer and Alzheimer's disease (Black*, et al.*, 2009). Functions of some of these ALDHs in endobiotic and xenobiotic metabolisms have been highly reviewed before and the distinctive metabolic pathways' influences have been depicted. Because of their chemical reactivity, many distinct aldehydes are pervasive in nature and are toxic at low levels. Hence, levels of metabolic-intermediate aldehydes should be cautiously regulated. The presence of several distinct ALDH families in most studied organisms seem to have wide fundamental tissue distribution. A wide range of allelic variants within the ALDH gene family have been identified, leading to heterogeneity in pharmacogenetic characteristics between individuals, resulting distinctive phenotypes including intolerance to alcohol and increased risk of ethanol-induced cancers in most cases (ALDH2 and ALDH1A1), Sjogren-Larson Syndrome (ALDH3A1), type II hyperprolinemia (ALDH4A1), 4-hydroxybutyric aciduria, mental retardation and seizures (ALDH5A1), developmental delay (ALDH6A1), hyperammonemia (ALDH18A1), Pyridoxine-dependent

ALDH dysfunction could also be caused by drugs and environmental substances, substrate inhibition, as well as oxidative and metabolic stress. ALDH activity in drug resistance to oxazaphosphorines is one of the most vigorously studied pathways. The role of ALDH1A1 in drug resistance has been studied first in hematopoietic progenitors and more recently in

During early life and growth, SCs have a spectacular potential to develop into several cell types in the body. In many tissues, SCs behave as a kind of internal repair system, dividing essentially without limit to replenish other cells (Weissman, 2000). Stem cells are distinguished from other cell types by two important characteristics: First, they are unspecialized cells and, sometimes after long periods of inactivity, they can renew themselves through cell division; second, under certain physiologic or experimental conditions, they are naturally sensitive to their environment, responding to chemical, physical, and mechanical features of their matrices or substrates (Discher*, et al.*, 2009, Solis*,* 

Until recently, scientists primarily worked with two kinds of SCs from animals and humans: embryonic SCs and non-embryonic "somatic" or "adult" SCs (Feng*, et al.*, 2009).

In 1981, scientists discovered ways to derive embryonic SCs from mouse embryos. In 1998, a detailed study of the biology of mouse SCs led to the discovery of a method to derive SCs

epilepsy (ALDH7A1), and late-onset Alzheimer's disease (ALDH2).

lung cancer (Marchitti*, et al.*, 2008).

**2. Stem cells** 

*et al.*, 2012).

Cancer is a class of diseases characterized by unregulated cell growth(Deisboeck*, et al.*, 2011). Cancer initiation depends on genetic mutations in series that affects cellular programming. Many cancer researches have focused on the identification and characterization of these genetic and molecular properties of cancer cells (Balmain*, et al.*, 2003). Tumors are also heterogeneous cellular entities whose growth is dependent upon dynamic interactions among the cancer cells themselves, and between cells and the constantly changing microenvironment (Bissell & Radisky, 2001). That kind of interaction is depent on signaling through cell adhesion molecules and different cell responses to growth factors and other external signals. All of these interactive processes act together to control cell phenotypic behaviors such as proliferation, apoptosis, and migration. There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected (Lakshmi Prasanna & Sathish Kumar, 2011).

According to recent statistics, cancer accounts for about 23% of the total deaths in the USA and is the second most common cause of death after heart disease (Jemal*, et al.*, 2007).

Cancer is caused by many internal and external factors. Inherited mutations, hormones, and immune conditions are internal factors while tobacco, diet, radiation, and infectious organisms are environmental/acquired factors (Kalluri & Weinberg, 2009, Nagy*, et al.*, 2010, Langley & Fidler, 2011, Mantel & Schmidt-Weber, 2011, Noman*, et al.*, 2011). In recent years, a particular sub-population of tumor cells are said to have a critical role in cancer; these cells are commonly called **CSCs** or **tumor initiating cells (TICs).** In most cancer types, CScs have been identified. CSCs are characterised by their two important properties: (1) Enhanced tumorigenicity; and (2) the capacity for selfrenewal/differentiation (Bonnet & Dick, 1997, Al-Hajj*, et al.*, 2003). Thus, isolating CSCs is important in analyzing their characteristics *in vitro*. The isolated CSC population will not only give rise to de novo tumors with high efficiency, but will also recapitulate the tumor with both CSC and non-CSC populations.

One potential human CSC marker is the membrane antigen CD133 (Prominin) identified in subpopulations of cells in brain, colon and lung tumors (Singh*, et al.*, 2004, Ricci-Vitiani*, et al.*, 2007, Eramo*, et al.*, 2008). CD133+ tumor cells are also a marker identifying lung CSCs (Wang*, et al.*, 2008, Salnikov*, et al.*, 2010).

The expression and activity of ALDHs is determined as another potential CSC marker (Ginestier*, et al.*, 2007). ALDH1 is a marker of normal and malignant human mammary SCs and a predictor of poor clinical outcome (Huang*, et al.*, 2009). Aldehyde dehydrogenase enzymes participate in cellular detoxification, differentiation and drug resistance through the oxidation of cellular aldehydes (Moreb*, et al.*, 1996).

Aldehyde Dehydrogenase: Cancer and Stem Cells 9

granulocytes, these 2 enzymes' expressions are necessary, however their expressions are lost once the differentiation is complete. The *in vitro* disulfiram treatment in which disulfiram acts as an ALDH inhibitor may inhibit granulocytic differentiation. ALDH1A1 is found in erythrocytes and has been pointed to contribute to the aldophosphamide detoxification. A study that inhibited ALDH and retinoid signaling with diethylamino-benzaldehyde (DEAB) that reported the expansion of human HSCs probably by blocking differentiation and

The cancer stem cell theory is supported by current evidence in tumor biology, which may also provide a biological reason for the age-related survival difference. The theory demonstrates that CSCs, a small subset of tumor cells with stem cell-like properties such as epithelial-to-mesenchymal progression, are capable of differentiation and self-renewal, after which leads to formation of a heterogeneous tumor cell population. Including aldehyde dehydrogenase-1 (ALDH1) activity, CD44+/CD24-, CD133, and ITGA6, a wide range of putative breast cancer stem cell markers have been proposed. ALDH1 expression has especially demonstrated an assurance of a clinically relevant prognostic marker. In addition, the subset of CSCs is shown to be relatively insusceptible to chemo and radiotherapy by various studies. For this reason, the subpopulation of CSCs can present a statement and a therapeutic target for poor-prognostic, treatment-resistant and recurrent breast cancer. Through its role in oxidizing retinol to RA, which is a modulator of cell proliferation, ALDH1 might have a role in early differentiation of SCs and stem cell proliferation (Mieog*,* 

It is possible to isolate leukemia SCs depending on the elevated ALDH activity by using the aldefluor assay. In patient samples, the researchers encountered a population of ALDH+ acute myeloid leukemia (AML) cells (Rollins-Raval*, et al.*, 2012). In most cases, the ALDH+ AML cells coexpressed CD34+ (formerly determined leukemia stem cell marker), and were introduced considerably better than the ALDH- AML cells in immunocompromised mice. In the same year, ALDH+ cells from breast cancers, which had the tumorigenic and selfrenewal features of CSCs, were shown to be possibly isolated. This innovative study displayed the potential applicability of quantifying ALDH activity in solid tumors. ALDH activity would be used successfully as a CSC marker for abundant cancers including liver, colon, lung, bone, prostate, pancreatic, head and neck, thyroid, bladder, brain, cervical and melanoma in the proceeding years. With one exception of a current study for melanoma, 35 demonstrate growing evidence recommending ALDH's activity to be a universal CSC marker. Nonetheless, as amounted by the aldefluor assay in various tissues and cancers, the cause of ALDH activity may differ. Essentially, determination of specific ALDH isoforms carried out commonly in certain cancers might have prognostic suitability. Besides their valuable function in detoxification of aldehydes, ALDHs carry out other functions such as serving as binding proteins for various molecules (e.g., androgens and cholestorol), potentially act as antioxidants by NAD(P)H production, ultraviolet light absorption and/or

Lastly, several isoforms (ALDH1A1, ALDH1A2, ALDH1A3 and ALDH8A1), take place via RA formation by oxidation of all-trans-retinal and 9-cis-retinal in RA cell signaling, which

assisting self-renewal and HSC expansion (Marchitti*, et al.*, 2008).

hydroxyl radical scavenging and ester hydrolysis.

*et al.*, 2012).

The functional activity of ALDH has been widely used to identify and isolate CSCs found in the bone marrow (Ran*, et al.*, 2009), breast (Ginestier*, et al.*, 2007), lung (Ucar*, et al.*, 2009), ovary (Deng*, et al.*, 2010), colon (Huang*, et al.*, 2009), prostate (van den Hoogen*, et al.*, 2010), and pancreas (Dembinski & Krauss, 2009).
