IL-4-mediated drug resistance in colon cancer stem cells

Abstract

Cancer stem cells are defined as cells able to both extensively self-renew and differentiate into progenitors. Cancer stem cells are thus likely to be responsible for maintaining or spreading a cancer, and may be the most relevant targets for cancer therapy. The CD133 glycoprotein was recently described as a reliable cancer stem-like cell marker in colon carcinoma. CD133+ cells are both necessary and sufficient to initiate tumour growth in animal models. The CD133+ cell population and spheroid cultures contain cells expressing the stem cell marker Musashi-1 which is involved in maintenance of stem cell fate in several tissues and importantly, this expression is maintained in stem-like cells derived from xenografted tumors. Here we discuss the potential use of the CD133 antigen in concert with Musashi-1 as markers to identify the colon cancer stem cell population. Since the upregulation of IL-4 cytokine was recently demonstrated to constitute an important mechanism that protects the tumorigenic CD133+ cells from apoptosis, the potential benefits of standard chemotherapeutic treatments in combination with IL-4 inhibitors in the context of human colon carcinoma, are also discussed.

Newly characterised ex vivo colospheres as a three-dimensional colon cancer cell model of tumour aggressiveness

“…Furthermore, these two models also differ by the expression profile of putative colon cancer stem cell markers. CD133 has been reported to be a presumed colon cancer stem cell marker (O'Brien et al, 2007;Ricci-Vitiani et al, 2007;Todaro et al, 2008), even if this function is now challenged (LaBarge and Bissell, 2008;Shmelkov et al, 2008), and CD44 has been more convincingly described as an informative marker of colon cancer stem cells in both primary tumours and xenografts (Dalerba et al, 2007;Subramaniam et al, 2007;Du et al, 2008). Although cells grown as undifferentiated colon cancer spheres have been reported to be exclusively CD133 þ (Ricci-Vitiani et al, 2007), a large number of cells from colospheres expressed CD133, but a negative population was also present.…”

“…The impact of the microenvironment -such as cell -cell interactions and extracellular matrix -on cell phenotype is indeed well described (Santini and Rainaldi, 1999;Jacks and Weinberg, 2002;O'Brien et al, 2002;Smalley et al, 2006;Friedrich et al, 2007). Owing to their round compact architecture and their direct CRC tissue origin, colospheres can be compared with colon cancer spheres, a model previously described for colon cancer stem cell expansion cultures (Ricci-Vitiani et al, 2007;Todaro et al, 2008;Vermeulen et al, 2008 Figure 6 Tumorigenic and metastatic phenotype of XenoCT320 colospheres. (A) Injections of a quantity equivalent to 4 Â 10 4 cells as colospheres, spheroids or single-cell suspension were administered in a subrenal capsule assay in nude mice.…”

Crucial Role of Interleukin-4 in the Survival of Colon Cancer Stem Cells

“…Specifically, the mammalian RNA-binding protein Musashi-1 (Msi-1) and the macromolecule Lgr5 (GPR49), have been highlighted as potential stem cell markers in the intestinal epithelium. Our more current data show that Msi-1 is abundantly expressed in colon CSCs, which suggests that it could play an active role in driving tumorigenesis as well (12). Similarly, Lgr5 protein expression has been shown to be highly restricted to the cycling columnar cells at the crypt base, and because these cells have the ability to generate all the epithelial lineages, they represent, with high probability, the adult stem cells (6).…”

Cytokine regulation of stem cells

“…CSCs are often resistant to chemotherapy and some reports suggests that IL-4 might be contributing to this phenomenon ,as, abrogation of IL-4 signaling causes apoptosis in CSCs, and, IL-4 mediated STAT-6 expression enhances cancer-promoting survivin expression [47]. IL-8 is often found upregulated in certain types of cancers and has been suspected to promote CSC's growth.…”