Chemotherapy and Cancer Stem Cells
2007; Elsevier BV; Volume: 1; Issue: 4 Linguagem: Inglês
10.1016/j.stem.2007.09.011
ISSN1934-5909
Autores Tópico(s)Digestive system and related health
ResumoCancer stem cells are subsets of tumor cells defined through the capacity to initiate tumors and have been linked to therapeutic resistance. In this issue of Cell Stem Cell, Todaro et al., 2007Todaro M. Alea M.P. Di Stefano A.B. Cammareri P. Vermeulen L. Iovino F. Tripodo C. Russo A. Gulotta G. Medema J.P. Stassi G. Cell Stem Cell. 2007; 1 (this issue): 389-402Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar demonstrate that targeting tumor IL-4 sensitizes colon cancer stem cells to chemotherapy. Cancer stem cells are subsets of tumor cells defined through the capacity to initiate tumors and have been linked to therapeutic resistance. In this issue of Cell Stem Cell, Todaro et al., 2007Todaro M. Alea M.P. Di Stefano A.B. Cammareri P. Vermeulen L. Iovino F. Tripodo C. Russo A. Gulotta G. Medema J.P. Stassi G. Cell Stem Cell. 2007; 1 (this issue): 389-402Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar demonstrate that targeting tumor IL-4 sensitizes colon cancer stem cells to chemotherapy. Solid tumors consist of not only neoplastic cells but also supporting vasculature, inflammatory cells, and fibroblasts. Essentially, solid tumors mimic aberrantly developed organs or tissues (Reya et al., 2001Reya T. Morrison S.J. Clarke M.F. Weissman I.L. Nature. 2001; 414: 105-111Crossref PubMed Scopus (7388) Google Scholar). Tumor cell populations are commonly heterogeneous with hierarchies of cellular populations that display a range of differentiation phenotypes, including specific morphologies and lineage markers. The majority of cells in bulk tumors may be nontumorigenic end cells derived from stem and progenitor cells, but subsets of tumor cells—called cancer stem cells (CSCs) or tumor-initiating cells—with proposed roles in tumor propagation have been identified in several cancer types. The requirements for identification of a CSC are currently functional: extensive self-renewal and tumor initiation. The laboratories of John Dick and Michael Clarke laid the foundation for the CSC field by applying techniques and differentiation markers developed in normal stem cell biology to derive tumor populations enriched for cancer stem cells in leukemias and solid tumors (reviewed in Dalerba et al., 2007aDalerba P. Cho R.W. Clarke M.F. Annu. Rev. Med. 2007; 58: 267-284Crossref PubMed Scopus (1017) Google Scholar). Two recent reports used the Prominin-1, CD133, cell-surface marker to enrich for CSCs in human colon cancers (O'Brien et al., 2007O'Brien C.A. Pollett A. Gallinger S. Dick J.E. Nature. 2007; 445: 106-110Crossref PubMed Scopus (3302) Google Scholar, Ricci-Vitiani et al., 2007Ricci-Vitiani L. Lombardi D.G. Pilozzi E. Biffoni M. Todaro M. Peschle C. De Maria R. Nature. 2007; 445: 111-115Crossref PubMed Scopus (3245) Google Scholar), whereas the Clarke laboratory used CD44 and epithelial cell adhesion molecule (EpCAM) (Dalerba et al., 2007bDalerba P. Dylla S.J. Park I.K. Liu R. Wang X. Cho R.W. Hoey T. Gurney A. Huang E.H. Simeone D.M. et al.Proc. Natl. Acad. Sci. USA. 2007; 104: 10158-10163Crossref PubMed Scopus (1668) Google Scholar). In this issue of Cell Stem Cell, Todaro et al. employed the CD133 marker to enrich for tumor cells derived from colon cancer surgical specimens that form spheres in serum-free culture and tumors when xenotransplanted into immunocompromised mice (Todaro et al., 2007Todaro M. Alea M.P. Di Stefano A.B. Cammareri P. Vermeulen L. Iovino F. Tripodo C. Russo A. Gulotta G. Medema J.P. Stassi G. Cell Stem Cell. 2007; 1 (this issue): 389-402Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar). Of note, the CD133+ population represented 0.3%–3% of tumor specimens, but only 10 of 21 tumors yielded tumor spheres and secondary tumors, more commonly in tumors with microsatellite instability. Depletion of the CD133-expressing cells attenuated the tumorigenic potential, further implicating the CD133+ fraction in tumor initiation. Despite the development of molecularly targeted therapies, radiation and cytotoxic chemotherapies remain mainstays of cancer treatment. Although unusual cancers like testicular cancers can be cured at advanced stage with conventional therapy, therapeutic resistance is common among most advanced cancers. Many mechanisms may contribute to the development of therapeutic resistance, including the stochastic selection of resistant genetic subclones, microenvironmental factors (hypoxia, acidosis, etc.), and cell extrinsic factors. The development of the CSC hypothesis has led to the expectation that tumor-initiating cells may display resistance to cytotoxic cancer therapies, permitting the repopulation of tumors treated with radiation or chemotherapy. Indeed, several groups, including our own laboratory, have demonstrated that CSCs or cells expressing stem cell markers from multiple cancer types exhibit resistance to conventional cancer therapies. We demonstrated that CSCs derived from human glioblastoma surgical biopsy specimens and xenografts are resistant to the effects of ionizing radiation due to preferential activation of the DNA damage checkpoint response (Bao et al., 2006Bao S. Wu Q. McLendon R.E. Hao Y. Shi Q. Hjelmeland A.B. Dewhirst M.W. Bigner D.D. Rich J.N. Nature. 2006; 444: 756-760Crossref PubMed Scopus (4427) Google Scholar). Additional studies utilizing breast cancer cell lines confirmed that cells expressing CSC markers are resistant to radiation and demonstrated that ectopic expression of Wnt or β-catenin augmented the radioresistance of this subpopulation (Woodward et al., 2007Woodward W.A. Chen M.S. Behbod F. Alfaro M.P. Buchholz T.A. Rosen J.M. Proc. Natl. Acad. Sci. USA. 2007; 104: 618-623Crossref PubMed Scopus (501) Google Scholar, Phillips et al., 2006Phillips T.M. McBride W.H. Pajonk F. J. Natl. Cancer Inst. 2006; 98: 1777-1785Crossref PubMed Scopus (1046) Google Scholar). Studies of tumor cells have also revealed that CSCs are enriched in populations that exclude Hoechset 33342, i.e., the side population (SP). Dye exclusion is mediated by efflux pumps, which may also function to exclude drugs, resulting in the observed chemoresistance of SP cells. Furthermore, leukemic CSCs display chemotherapy resistance relative to the majority of the tumor cells that are more highly differentiated (Wulf et al., 2001Wulf G.G. Wang R.Y. Kuehnle I. Weidner D. Marini F. Brenner M.K. Andreeff M. Goodell M.A. Blood. 2001; 98: 1166-1173Crossref PubMed Scopus (283) Google Scholar). Against this background, Todaro et al., 2007Todaro M. Alea M.P. Di Stefano A.B. Cammareri P. Vermeulen L. Iovino F. Tripodo C. Russo A. Gulotta G. Medema J.P. Stassi G. Cell Stem Cell. 2007; 1 (this issue): 389-402Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar analyzed the chemosensitivity of CD133+ and spheroid-initiating colon cancer cells. Oxaliplatin and 5-fluorouracil, two chemotherapies employed in standard treatment regimens for colon cancer patients, were less effective against CD133+ tumor cells than either bulk cells or CD133− tumor cells. Based on their prior work, they investigated the role of interleukin-4 (IL-4) in mediating chemoresistance. Both adherent cancer cells (enriched for CD133− cells) and tumor spheroids (enriched for CD133+ cells) expressed higher levels of IL-4 ligand and receptor than normal colon. An anti-IL-4 antibody reduced the viability of CD133− and CD133+ cancer cells and increased the efficacy of chemotherapy treatment (Figure 1). The anti-IL-4 antibody induced apoptosis in colon cancer spheres associated with the reduction of prosurvival molecules. These results were validated in animal studies with heterotopic flank tumors with either a mutated, inhibitory form of IL-4 (IL-4DM) or the neutralizing IL-4 antibody. These results support a role of IL-4 in an autocrine survival signal for the entire tumor cell population that contributes to chemoresistance. These results have important implications. First, they validate the observations that have been made in other models that CSCs exhibit therapeutic resistance to cancer treatments currently employed. Second, they identify an additional mechanism of resistance that is shared between heterogeneous tumor cell populations. The expression of IL-4 and its receptor were not specific to the CSC population, so the IL-4 axis does not explain the differential sensitivity of the CSCs. Instead these studies suggest that molecular pathways that contribute to bulk tumor growth can be successfully targeted to sensitize CSCs to cytotoxic therapies. Further, the current availability of anti-IL-4 therapies offers a rapid translation and clinical assessment of an improved therapeutic paradigm. The precise mechanism by which IL-4 mediates chemoresistance in tumor populations remains unclear, but the authors provide strong circumstantial evidence that IL-4 regulates key antiapoptotic mechanisms that may play a functional role. A potential confounding issue is the enrichment of tumor formation in tumors with microsatellite instability. As microsatellite instability also may predict chemosensitivity, the CSC response to chemotherapy and the role of IL-4 in this response may not hold for all cancers. However, the authors did confirm their results in a tumor that was microsatellite stable. If recurrent tumors contain greater numbers of CSCs that are also selected for greater resistance to therapy, the lethality of advanced cancers might be better explained. However, Todaro et al., 2007Todaro M. Alea M.P. Di Stefano A.B. Cammareri P. Vermeulen L. Iovino F. Tripodo C. Russo A. Gulotta G. Medema J.P. Stassi G. Cell Stem Cell. 2007; 1 (this issue): 389-402Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar examine a resistance mechanism (IL-4 expression) that is active in all of the tumor cells and, in some ways, raise as many questions as they answer. In cancers that frequently do not respond to chemotherapy (including colon and other gastrointestinal cancers) is CSC resistance important? Furthermore, how does the CSC hypothesis inform models in which resistant tumor subclones emerge during therapy? Indeed, unpublished data from our own lab suggest that CSCs can give rise to clonal subpopulations in response to selective pressures. Do the models that CSCs reside in hypoxic niches or secrete proteins that may act both in autocrine and paracrine manners impact on traditional hypotheses of cancer therapeutic resistance? Finally, are mechanisms of CSC therapeutic resistance shared across cancer types? If so, the identification of common CSC resistance mechanisms may have broad utility in targeting new therapeutics. In sum, the CSC hypothesis is not a replacement for the large body of work that has defined multiple mechanisms whereby cancers are resistant to conventional therapies, but interpreting prior hypotheses through the prism of cellular heterogeneity within tumors may better model clinical observations in some cancers. In particular, given the poor capacity of current preclinical cancer models to predict therapeutic efficacy in human subject clinical trials, it would be of profound significance should CSC models yield more accurate outcome predictions. Of course, the contribution of CSCs will first require validation in human subjects. Finally, it is important to remember that, although Todaro and coworkers examined the expression of IL-4 in normal colon specimens, specific, noncancerous stem cell populations were not assessed. Future studies will certainly address the role of each resistance mechanism in cancer and normal stem cells as an essential step in the development of targeted therapeutics. Colon Cancer Stem Cells Dictate Tumor Growth and Resist Cell Death by Production of Interleukin-4Todaro et al.Cell Stem CellOctober 11, 2007In BriefA novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The CD133+ cells grow in vitro as undifferentiated tumor spheroids, and they are both necessary and sufficient to initiate tumor growth in immunodeficient mice. Xenografts resemble the original human tumor maintaining the rare subpopulation of tumorigenic CD133+ cells. Full-Text PDF Open Archive
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