Role of "cancer stem cells" and cell survival in tumor development and maintenance.

One critical issue for cancer biology is the nature of the cells that drive the inexorable growth of malignant tumors. Reports that only rare cell populations within human leukemias seeded leukemia in mice stimulated the now widely embraced hypothesis that only such "cancer stem cells" maintain all tumor growth. However, the mouse microenvironment might instead fail to support the dominant human tumor cell populations. Indeed, on syngeneic transplantation of mouse lymphomas and leukemias, we and other investigators have found that a substantial proportion (>10%) of their cells drive tumor growth. Thus, dominant clones rather than rare cancer stem cells appear to sustain many tumors. Another issue is the role of cell survival in tumorigenesis. Because tumor development can be promoted by the overexpression of prosurvival genes such as bcl-2, we are exploring the role of endogenous Bcl-2-like proteins in lymphomagenesis. The absence of endogenous Bcl-2 in mice expressing an Emu-myc transgene reduced mature B-cell numbers and enhanced their apoptosis, but unexpectedly, lymphoma development was undiminished or even delayed. This suggests that these tumors originate in an earlier cell type, such as the pro-B or pre-B cell, and that the nascent neoplastic clones do not require Bcl-2 but may instead be protected by a Bcl-2 relative.