**3. CD44 in colon cancer**

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

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

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.
