Tumor Stem Cell Niches: A New Functional Framework for the Action of Anticancer Drugs

Newer treatments of advanced human cancer increasingly rely on combinations of drugs that have quite different actions yet unexpectedly potentiate each other's effects. Recent research in stem cell biology suggests a model for tumors in which tumor growth is governed by the generation of cells from tumor cell niches rather than from the population as a whole. Each niche contains a population of tumor stem cells supported by a closely associated vascular bed comprising mesenchyme-derived cells and an extracellular matrix. Division of tumor stem cells is asymmetric in the sense that some daughter cells are always retained within the niche while others leave the niche to proliferate further and eventually die. One important potential difference between normal and tumor stem cell niches is that while most normal stem cells are in a non-proliferating or Go-state, tumor stem cells are continuously in cycle. Combinations of cytotoxic drugs and antagonists of survival factors to reduce the stem cell population may require the addition of vascular disrupting agents to compromise the function of the tumor cell niche. As well as providing opportunities for new drug discovery, this model of tumor growth also presents challenges as to how the contributions of individual drugs in a combination might be assessed in individual patients.