The tumor microenvironment and metastatic disease.

The microenvironment of solid tumors is a heterogeneous, complex milieu for tumor growth and survival that includes features such as acidic pH, low nutrient levels, elevated interstitial fluid pressure (IFP) and chronic and fluctuating levels of oxygenation that relate to the abnormal vascular network that exists in tumors. The metastatic potential of tumor cells is believed to be regulated by interactions between the tumor cells and their extracellular environment (extracellular matrix (ECM)). These interactions can be modified by the accumulation of genetic changes and by the transient alterations in gene expression induced by the local tumor microenvironment. Clinical and experimental evidence suggests that altered gene expression in response to the hypoxic microenvironment is a contributing factor to increased metastatic efficiency. A number of genes that have been implicated in the metastatic process, involving angiogenesis, intra/extravasation, survival and growth, have been found to be hypoxia-responsive. The various metastatic determinants, genetic and epigenetic, somatic and inherited may serve as precedents for the future identification of more genes that are involved in metastasis. Much research has focused on genetic and molecular properties of the tumor cells themselves. In the present review we discuss the epigenetic and physiological regulation of metastasis and emphasize the need for further studies on the interactions between the pathophysiologic tumor microenvironment and the tumor extracellular matrix.