The Physi(ologi)cal Microenvironment and its role in Tumor Invasion and Metastases
Project PI: Robert J. Gillies, Ph.D.
The PI has investigated the physical microenvironment using a wide range of imaging techniques. This work has clearly demonstrated that chronic and acute (often cyclical) hypoxia exists in most tumors in vivo and that the extracellular pH of tumors is highly acidic while the intracellular pH typically remains in the normal range. A number of observations have these changes in the physical microenvironment significant affect tumor growth. For example, tumor cells exposed to hypoxia or acidosis in-vitro or in-vivo are far more invasive and metastatic. Clinical tumors that have high glucose uptake have a poorer prognosis than those with lower uptakes. One reason for this may apparent at the tumor-host interface. Although tumors are often considered as isolated systems, they are in direct contact with adjacent normal tissue. This interface allows interactions of the physical microenvironment so that the acid in tumors can flow down concentration barriers into adjacent normal tissue producing regional acidosis. The acid-mediated invasion model proposes this acidification promotes tumor invasion by inducing proteolysis of the extracellular matrix, inducing death of normal cells, inhibiting immune response, and promoting angiogenesis. A recent test of this hypothesis examined the effects of increasing systemic buffering by adding sodium bicarbonate to the water of tumor bearing mice. Initial analysis with mathematical models suggested that this could reduce the intra- and peri-tumoral pHe sufficiently to reduce tumor invasion. Experiments in tumor-bearing mice demonstrate a significant reduction in tumor metastases in the animals receiving sodium bicarbonate.