**2. CD133/prominin-1**

CD133 was first described in 1997 by Yin et al. on the cellular surface of hematopoietic cells [6]. Also called prominin-1, CD133 is a 5-transmembranaire glycoprotein of 120 kDa which can be found in two isoforms: CD133-1 and CD133-2 [5–7]. CD133 is found on the short arm of chromosome 4 [5]. Its cellular function is unclear [5–7], but its involvement in cell-cell and cell-matrix interactions was described [5]. According to some recent studies, CD133 expression is an important tool in cancer stem cells (CSCs) identification and characterization [7]. CD133 was found to be expressed in various digestive (pancreatic, liver, colorectal) and nondigestive tumors (brain, kidney, prostate, ovary cancer) [7–9]. CD133 expression promotes cancer cell proliferation through activation of Wnt/beta-catenin pathway [10, 11]. Moreover, in highly expression CD133 cancer stem cells, the development of solid tumor mass is assured by the anti-apoptotic factors BCL-2, BCL-XL, and MCL-1 that are stimulated through PI3K pathway, with subsequent activation of Akt [11]. Even if various studies focused on targeting CSCs and especially CD133 due to its overexpression, most of the results arise from in vitro research and not from clinical experience. Targeted therapy was tested using Anti-CD133 scFv immunotoxins by Waldron et al. that found an interruption of the protein synthesis secondary to this process [12].

CD133 expression in colon cancer was confirmed 10 years after its initial description in 2007 [13, 14], when Obrien et al. proved that neoplastic cells expressing CD133 have the ability to form solid colon cancer masses in immunodeficient mice. From that point, many studies focused on CD133 expression in colon cancer carcinogenesis. Various studies analyzed CD133 expression in relation to clinical and pathological characteristics of the neoplastic patients, but result were inconsistent. CD133 expression correlates with the degree of tumor wall involvement (T) [15], with distant metastasis formation (M) [5, 16], with venous (V) and lymphatic (L) invasion [15]. A relation between CD133 expression and tumor recurrence was also noticed in one study [5], while other research groups found a significant association between CD133 expression and tumor size [7]. CD133 expression was correlated in some studies with a poor degree of tumor differentiation (G) [7], but the result was not confirmed by other studies where CD133 expression was found more frequent in moderate (G2) and well differentiated (G1) colon tumor tissues [17].

Chemoresistance was also found to be influenced by CD133 expression in colon cancer especially due to upregulation of FLICE-like inhibitory protein (FLIP), a ligand that inhibits tumor necrosis factors (TNF)-mediated apoptosis [11]. According to some studies, tumors expressing CD133 are more likely to be resistant to chemotherapy [5, 7, 18]. Moreover, tumors expressing high CD133 and CD44 biomarkers on the cellular surface are expected to be unresponsive to chemotherapy when compared to tumors where the expression of the two molecules is low or absent [16].

**11**

*Stem Cell Markers in Colon Cancer*

recurrent liver metastases [20].

colon cancer patients [23, 26].

**3. CD44 in colon cancer**

*DOI: http://dx.doi.org/10.5772/intechopen.84315*

Results are contradictory in terms of CD133 expression in liver metastases secondary to colon cancer. While CD133 expression in liver metastases was thought to predict a better overall survival (OS) in colon cancer patients [19], Spelt et al. found, in a recent study, different results [4]. According to them, CD133 expression in liver metastases is associated with worse overall survival (OS). Results in favor of a worse prognostic impact of CD133 expression in liver metastases are suggested also by Narita et al. which demonstrated an increased CD133 expression in cases of early recurrence of liver metastases compared with a low CD133 expression in late

In terms of survival, overexpression of CD133 was associated with worse overall survival in some studies [16, 21–23] and also with low disease-free survival interval [23], but the relation was not found by others [4, 5, 17, 24, 25]. According to two recent meta-analyses, CD133 expression represents a negative prognostic factor in

Heterogeneous results exist in literature considering CD133 role in colon cancer. Its involvement in tumor progression and metastasis formation is suggested, but its precise role remains unclear. CD133 represents a useful tool for CSCs identification and characterization in colon cancer samples. Various studies analyzed the correlation between CD133 expression and clinical and pathological characteristic of the patient, but a direct association between its degree of expression and advanced tumor stages was not confirmed. Moreover, its prognostic role regarding overall survival in colon cancer is still debated, and further studies are needed for a better

CD44 is a type 1, 85–200 kDa transmembrane glycoprotein expressed in both normal and tumor tissues [16, 27, 28]. Discovered initially as a receptor for hyaluronic acid, the molecule has retained its affinity for it and for other components like collagens, osteopontin, or type I metalloproteinase [3, 27]. Supplementary, an adhesion function was highlighted for CD44 that was found to intervene in both cell-cell and cell-matrix interactions [4, 16]. From a structural point of view, CD44 has three main domains: an extracellular one, a transmembrane, and, respectively, an intracellular domain [27]. CD44 has the capacity to present in various isoform, depending on the exons that attach to the extracellular part (CD44v) [27]. Its

CD44 is expressed ubiquitary in normal tissue and participates, through lymphocytes activation, in various inflammatory processes [3, 27]; its involvement in wound healing processes was also described by some authors [3]. In neoplastic lesions, CD44 is expressed, in different isoforms, in pancreatic (CD44v8–10) and colon cancer (CD44v6) [27], in prostatic tumors (CD44s—standard isoform), in breast cancer [27], and also in epithelial ovarian cancers [30]. Through its adhesiveness properties, CD44 was found to intervene in tumor growth [16, 17]. Additionally, tumor cells expressing CD44 present with invasiveness properties and are also characterized by the capacity to initiate the metastatic process [28, 31] intervening thus in cell differentiation, proliferation, and migration [32]. The mechanisms by which the molecule intervenes in these processes remain, however, unknown, and further studies have to be performed. Assessment of the prognostic value of CD44 was analyzed in recent papers that highlighted an association between CD44 expression and both advanced tumor stages and liver metastasis formation [27, 31]. Overexpression of CD44 in colon cancer samples was found to negatively influence overall survival of colon cancer patients [33, 34]; one study group found a negative association between CD44

characterization of the molecule in relation to colon cancer patients.

encoded gene is located on the short arm of chromosome 13 [29].

*Basic Principles and Practice in Surgery*

ALDH1A1, and ALDH1B1 [3, 4].

**2. CD133/prominin-1**

secondary to this process [12].

biomarkers for advanced stages of the disease.

Detection of cancer stem cells (CSCs) in various digestive and extra-digestive cancers has been a topic of great interest in the literature of recent years and was frequently done using cluster of differentiation (CD) markers. In colon cancer, various biomarkers have been identified at the surface of CSCs, and their role in colon cancer is currently being tested: EpCAM, CD133, CD29, CD24, CD44, CD166,

The aim of this paper is to review the most important biomarkers which have been identified in colon cancer, to expose current information regarding their role in colon cancer development and progression and to identify possible predictive

CD133 was first described in 1997 by Yin et al. on the cellular surface of hematopoietic cells [6]. Also called prominin-1, CD133 is a 5-transmembranaire glycoprotein of 120 kDa which can be found in two isoforms: CD133-1 and CD133-2 [5–7]. CD133 is found on the short arm of chromosome 4 [5]. Its cellular function is unclear [5–7], but its involvement in cell-cell and cell-matrix interactions was described [5]. According to some recent studies, CD133 expression is an important tool in cancer stem cells (CSCs) identification and characterization [7]. CD133 was found to be expressed in various digestive (pancreatic, liver, colorectal) and nondigestive tumors (brain, kidney, prostate, ovary cancer) [7–9]. CD133 expression promotes cancer cell proliferation through activation of Wnt/beta-catenin pathway [10, 11]. Moreover, in highly expression CD133 cancer stem cells, the development of solid tumor mass is assured by the anti-apoptotic factors BCL-2, BCL-XL, and MCL-1 that are stimulated through PI3K pathway, with subsequent activation of Akt [11]. Even if various studies focused on targeting CSCs and especially CD133 due to its overexpression, most of the results arise from in vitro research and not from clinical experience. Targeted therapy was tested using Anti-CD133 scFv immunotoxins by Waldron et al. that found an interruption of the protein synthesis

CD133 expression in colon cancer was confirmed 10 years after its initial descrip-

tion in 2007 [13, 14], when Obrien et al. proved that neoplastic cells expressing CD133 have the ability to form solid colon cancer masses in immunodeficient mice. From that point, many studies focused on CD133 expression in colon cancer carcinogenesis. Various studies analyzed CD133 expression in relation to clinical and pathological characteristics of the neoplastic patients, but result were inconsistent. CD133 expression correlates with the degree of tumor wall involvement (T) [15], with distant metastasis formation (M) [5, 16], with venous (V) and lymphatic (L) invasion [15]. A relation between CD133 expression and tumor recurrence was also noticed in one study [5], while other research groups found a significant association between CD133 expression and tumor size [7]. CD133 expression was correlated in some studies with a poor degree of tumor differentiation (G) [7], but the result was not confirmed by other studies where CD133 expression was found more frequent in

moderate (G2) and well differentiated (G1) colon tumor tissues [17].

to tumors where the expression of the two molecules is low or absent [16].

Chemoresistance was also found to be influenced by CD133 expression in colon cancer especially due to upregulation of FLICE-like inhibitory protein (FLIP), a ligand that inhibits tumor necrosis factors (TNF)-mediated apoptosis [11]. According to some studies, tumors expressing CD133 are more likely to be resistant to chemotherapy [5, 7, 18]. Moreover, tumors expressing high CD133 and CD44 biomarkers on the cellular surface are expected to be unresponsive to chemotherapy when compared

**10**

Results are contradictory in terms of CD133 expression in liver metastases secondary to colon cancer. While CD133 expression in liver metastases was thought to predict a better overall survival (OS) in colon cancer patients [19], Spelt et al. found, in a recent study, different results [4]. According to them, CD133 expression in liver metastases is associated with worse overall survival (OS). Results in favor of a worse prognostic impact of CD133 expression in liver metastases are suggested also by Narita et al. which demonstrated an increased CD133 expression in cases of early recurrence of liver metastases compared with a low CD133 expression in late recurrent liver metastases [20].

In terms of survival, overexpression of CD133 was associated with worse overall survival in some studies [16, 21–23] and also with low disease-free survival interval [23], but the relation was not found by others [4, 5, 17, 24, 25]. According to two recent meta-analyses, CD133 expression represents a negative prognostic factor in colon cancer patients [23, 26].

Heterogeneous results exist in literature considering CD133 role in colon cancer. Its involvement in tumor progression and metastasis formation is suggested, but its precise role remains unclear. CD133 represents a useful tool for CSCs identification and characterization in colon cancer samples. Various studies analyzed the correlation between CD133 expression and clinical and pathological characteristic of the patient, but a direct association between its degree of expression and advanced tumor stages was not confirmed. Moreover, its prognostic role regarding overall survival in colon cancer is still debated, and further studies are needed for a better characterization of the molecule in relation to colon cancer patients.
