Search

Tumors derived from rat LA7 cancer stem cells (CSCs) contain a hierarchy of cells with different capacities to generate self-renew- ing spheres and tubules serially ex vivo and to evoke tumors in vivo. We isolated two morphologically distinct cell types with distinct tumorigenic potential from LA7-evoked tumors: cells with polygonal morphology that are characterized by expression of p21/[supWAF1] and p63 and display hallmarks of CSC5 and elongated epithelial cells, which generate tumors with far less heterogeneity than LA7 CSC5. Serial transplantation of elongated epithelial cells results in progressive loss of tumorigenic potential; tumor heter- ogeneity; CD44, E-cadherin, and epithelial cytokeratin expression and increased a-smooth muscle actin I and vimentin expression. In contrast, serial transplantation of 1A7 CSCs can be performed indefinitely and results in tumors that maintain their heterogene- ity, consistent with self-renewal and multilineage differentiation potential. Collectively, our data show that polygonal cells are CSCs, whereas epithelial elongated cells are lineage-committed progen- itors with tumorigenic potential, and suggest that tumor progen- itors, although lacking indefinite self-renewal potential, neverthe- less may make a substantial contribution to tumor development. Because LA7 cells can switch between conditions that favor main- tenance of pure CSC5 vs. differentiation into other tumor cell types, this cell system provides the opportunity to study factors that influence CSC self-renewal and differentiation. One factor, p63, was identified as a key gene regulating the transition between CSC5 and early progenitor cells. [ABSTRACT FROM AUTHOR]