Some potential mechanisms by which tissue stem cells generate cancer. Several potential routes by which mutations can accumulate in stem cells to generate cancer, based on data presented at the AACR Cancer Stem Cell Workshop. A, normal cells divide within a niche (green) and can accumulate mutations over time. B, stem cells may have acquired mutations that enable them to survive and self-renew within an alternative niche. This may enable a population of mutant stem cells to expand in a new region and/or in the environment of different supporting cells (i.e., an alternate niche). Alternatively, mutant stem cells may have acquired the ability to induce the proliferation of niche cells to allow for expansion of the niche to accommodate the mutant stem cells. C, mutations within the stem cells may enable them to proliferate in the absence of a niche, but they would require additional mutations to undergo self-renewal (D). A related possibility is that mutated stem cells undergo a differentiation program but retain proliferative potential. Acquisition of additional mutations in the proliferative progenitors would then be required to enable them to self-renew. E, normal stem cells may be exposed to a niche that has itself undergone modifications. Self-renewing divisions in the aberrant niche may then select for specific types of mutations within the stem cells, which are the precursors of cancer. The cancer shown is composed of a heterogeneous cell population that could be generated by the self-renewing divisions of the mutated cancer stem cell along with its “differentiated” cell types that comprise the tumor. Various mutated proliferative progenitors could also contribute to the tumor along with the self-renewing, differentiation competent progenitor that is the cancer stem cell. Both models are compatible with clonal origin of most tumors as all cells shown derive from a common stem cell ancestor.