Targeting Cancer Stem Cells, The Major Leap Toward a Cure

The concept of stem cells, cells that can self-renew and differentiate, was initially postulated by Pappenheim in 1917 and their existence has since been shown in many different tissues [1]. The original ideas for cancer stem cells came in remarkable papers by Southham et al and Hamburger et al which showed that cancer cells had varying tumorinitiating capacities [2, 3]. Later, John Dick’s lab isolated acute myeloid leukemia stem cells in 1994 and acute lymphocytic leukemia stem cells soon thereafter [4, 5]. Since then, cancer stem cells have been isolated in many solid tumors; in brain, head and neck, breast and prostate cancer [6-15]. The cancer stem cell model represents a paradigm shift in our understanding of carcinogenesis and tumor cell biology. In this model, tumors originate in either tissue stem cells or their immediate progeny through dysregulation of the normally tightly regulated process of selfrenewal. Consequently, tumors contain a cellular subcomponent that retains key stem cell-like properties. These properties include selfrenewal, tumor regeneration, and differentiation [16]. Despite the mounting evidence in support of the CSC model, there is some controversy regarding the similarities and differences between cancer and somatic stem cells [17]. Significantly, some recent reports have claimed that unlike somatic stem cells, CSCs may not be rare subpopulations within tumors in some cancers [17]. In response, Weinberg comprehensively argues that the CSC model rests on solid experimental foundations and that the differences in the observed frequencies of CSCs within tumors reflects the various cancer types and hosts used to assay these cells and . The existence of CSCs has fundamental implications for cancer risk assessment, early detection, prognostication, and prevention. Control of many stem cell phenotypes depends on epigenetic reprogramming; thus epigenetic transformation of CSCs has become a very promising area of basic and preclinical moleculartargeted prevention science. An important characteristic of these cells is their ability to restrict DNA damage sustained during radiation or chemotherapy [18, 19] and their ability to effectively pump out chemotoxic agents through a wide range of active membrane transporters. As a result, many current therapeutic agents are only able to reduce the bulk of the cancer cells while residual CSCs are able to regenerate the cancer. In addition, cancer stem cells are implicated in developing drug resistant progeny in some cancers such as chronic myeloid leukemia (CML) [20]. Thus, it is imperative that any truly curative treatment of cancer specifically target CSCs. Successful stem cell therapy will have to avoid targeting normal stem cells with phenotype and cell signalling pathways similar to CSCs. There is not enough literature in this field yet but an effective way to contrast somatic and cancer stem cells may be in evaluating protein expression levels and looking for mutant proteins specific to cancerous cells. In addition, prospective therapies like epigenetic modifications using interfering RNA and therapies based on synthetic lethality may achieve exquisite selectivity when aimed at CSCs and represent major improvements in cancer treatment. Effective eradication of CSCs will be the major breakthrough required in the road to finding cures for various cancer types.