Tumor heterogeneity, clonal evolution, and therapy resistance: an opportunity for multitargeting therapy.

Heterogeneity within the cell population is a feature of many tumors. This lack of cellular homogeneity may originate from a number of sources, including differential nutrient status due to the de novo microcirculations of tumors, to infiltration of normal cells into the tumor, and to the hierarchical natures of the cell populations from which cancers arise. Tumors are thought to arise from one or more tumor initiating cells (TIC) within the population and to found hierarchies of progenitors and more differentiated cancer cells. TIC are often derived from tissue stem cells and these cancer stem cells are characterized by resistance to most cytotoxic treatments and by a high metastatic rate. Many of the properties of tumor populations, including the ability to express mutated oncogenes and to evolve new features such as treatment resistance and invasive and metastatic potential appear to depend on the molecular chaperone Hsp90. We discuss the potential of targeting the heterogeneous cell population with Hsp90 inhibitory drugs and its potential ability to inactivate TIC and to block the evolution of new phenotypes in cancer.