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

Abstract

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.

Figure 1

Clonal evolution and hierarchical differentiation. In normal tissues, stem cells give rise to descendent cells including pluripotent progenitor, transit amplifying and ultimately cells with differentiated functions within the organ. In Scheme 1, a transforming mutation (X) is shown to give rise to a similar hierarchy of stem (CSC) and descendent cells, each bearing the mutation. In Scheme 2, we show clonal evolution induced by individual second mutations (Y, Z, A, B) in the CSC that already bear mutation X and that can be the founders of individual clones within the polyclonal tumor population. In addition second mutations in the progenitor and other downstream cell types may also give rise to cells with tumor initiating potential (small arrows). We show in the inset box the potential role of multitargeting Hsp90 drugs (Hsp90i) that can suppress the transforming ability of individual mutated oncoproteins (X, Y, Z, A, B), reduce clonal evolution, and potentially kill the cancer cells.