*Stem Cell Markers in Colon Cancer DOI: http://dx.doi.org/10.5772/intechopen.84315*

*Basic Principles and Practice in Surgery*

**4. CD24 in colon cancer**

expression and poor overall survival only for a specific variant of CD44 and, respectively, Cd44v2 [35]. The association between upregulation of CD44 in colon cancer and worse overall survival was not confirmed by other study groups [24, 36], but the analysis was completed based on standard isoform of CD44 (CD44s). CD44 usage as an independent prognostic factor in colon cancer patients is not currently recommended [17], but further studies need to concentrate on specific isoforms, like the one abovementioned, in order to correctly identify its value as a prognostic marker. CD44 targeting is currently being tested in various digestive (stomach, colon cancer) [31, 37] and non-digestive cancer (lung, breast cancer) [38]. The results in terms of cancer stem cell apoptosis for in vitro and preclinical animal models are promising. In pancreatic cancer the anti-CD44 antibody tested against CD44v6 isoforms with promising antitumor results was bivatuzumab [37], while the first humanized antibody directed toward solid tumors expressing CD44 approved for clinical research is

RO5429083 (NCT01358903), and the publication of results is in progress.

malignant polyps than CD24 expression in colon adenomatous lesions.

chemotherapeutic regiments based on 5-FU [47].

**5. Epithelial cell adhesion molecule (EpCAM)**

type or degree of differentiation (G) [5, 44]; other authors have highlighted, however, an inverse relation between CD24 expression and tumor size, poor differentiated cancers, and advanced TNM stages [39]. Regarding lymph node involvement and CD24 expression, as association between high CD24 expression and a larger number of lymph nodes involved was reported in some research papers [45] but not in others [5, 24]. In terms of overall survival, CD24 expression was in general associated with worse survival rates [16, 26]; results were not confirmed by other recent research papers [5, 24, 44]. Resistance to chemotherapeutic treatment was also objective by Nosrati et al. [5] probably due to their capacity to induce the epithelial-mesenchymal transition (EMT) mechanism [46]. Moreover, colon cancer stem cells expressing both CD133 and CD24 markers were found to be resistant to

CD24 is a glycoprotein located on the external surface of the cellular membrane [16]. It is formed of 27 amino acids, and it has a molecular weight of 24–70 kDa [5, 26]. Its expression was confirmed in normal nervous tissue [16] and in cancers of the colon [5], pancreas [24], breast, and prostate [26]. CD24 is involved in cellular signaling processes, in cellular differentiation, and in proliferation and is being considered a significant marker of cancer stem cells (CSCs) [4, 16, 39]. The mechanism by which CD24 participates in signaling processes seems to be related to mitogen-activated protein kinase (MAPK) and serine/threonine pathway [26]. In colon cancer, CD24 was found to be expressed in a percentage of 50–68% [24, 40]. CD44 is involved in first steps of carcinogenesis and plays an important role in liver metastasis formation [4, 9, 41–43]. Yeo et al. found CD24 a useful diagnostic marker of early colon cancer [39], whereas its expression was higher in

No correlation was found between CD24 expression in colon cancer and tumor

CD24 was highly studied in colon cancer samples, but consistent results have failed to establish its precise role in colon cancer, considering the heterogeneous

Epithelial cell adhesion molecule (EpCAM) is a Ca2+ independent, type I transmembrane glycoprotein with a molecular weight of 40 kDa [48] located on

**12**

results observed.

the basolateral surface of epithelial tissues [49]. EpCAM expression was not seen in mesenchymal or lymphoid tissues [50]. EpCAM presents with two main domains: EpICD, an intracellular domain, and EpEx, an extracellular domain of 26, respectively, and 242 amino acids [48, 51].

EpCAM was found to be overexpressed in various digestive (stomach, colon, pancreas, and esophagus) and non-digestive (prostate, ovary, breast) cancers [49]. EpCAM is principally involved in adhesion processes, but its role in cellular differentiation and progression was also confirmed [50].

A high percentage of colon cancer cases (79–99.7%) is characterized by overexpression of EpCAM molecule at tumor level [52, 53]. Moreover, EpCAM was found to be expressed also in liver metastases secondary to colon cancer, a situation that confirmed its involvement in cancer progression as well [50, 52]. Normal liver parenchyma does not express EpCAM [54].

Overexpression of EpCAM in colon cancer correlates in some studies with advanced stages of the disease [50, 55, 56], with a higher risk of metastases [55, 56], with poor differentiated (G3) patterns [54–57], with the number of lymph nodes involved (N) [48, 54], and with perilymphatic (L) and perivenous (V) invasion [54, 57] but also with worse overall survival [55, 56]. The results were not, however, confirmed by other study groups, so the predictive value of EpCAM in colon cancer patients was difficult to establish [58].

EpCAM is also involved in epithelial-mesenchymal transition (EMT) process [56]. During EMT, neoplastic cell detaches from the primary tumor (due to loss of EpCAM expression and less intercellular adhesions) to enter the lymphatic and vascular system and initiate the carcinogenesis process [56]. Detached cells, also called circulating tumor cells (CTCs), can be identified from blood samples through "liquid biopsy" technique that is based also on EpCAM detection using specific anti-EpCAM antibodies [59, 60].

In order to achieve distant metastasis formation, circulating tumor cells have to undergo a second, reversed process called mesenchymal-epithelial transition (MET) during which an upregulation of EpCAM expression at the cellular surface has been observed [59]. Secondary to it, cells acquire adhesion properties that allow them to form a solid metastatic mass [59].

Despite constant research in the field of cancer stem cell biomarkers in colon cancer, specific factors or local conditions that initiate and promote EMT or MET are insufficiently known, and further research have to be performed.
