Tumor microenvironment and angiogenesis.

The tumor microenvironment is a mixture of extracellular matrix molecules, tumor cells, endothelial cells, fibroblasts and immune cells. Tumor growth and metastasis formation are dependent on the growth of blood vessels into the tumor mass. The tumor microenvironment contributes to this pathological angiogenic process. The extracellular matrix and basement membranes are a source for endogenous angiogenesis inhibitors, such as endostatin. On the other hand, many extracellular matrix molecules can promote angiogenesis by stabilizing blood vessels and sequestering pro-angiogenic growth factors. The majority of stromal cells in carcinomas are fibroblasts. Carcinoma-associated fibroblasts show a distinct phenotype from normal fibroblasts. The mechanisms how the tumor-associated fibroblasts regulate angiogenesis are not fully known, but they are suggested to be an important source for growth factors and cytokines recruiting endothelial cells. The immune cells, particularly macrophages and neutrophils are another source for angiogenesis-regulating chemokines, growth factors and proteases. Taken together, the tumor microenvironment is a complex unorganized tissue of various cell types and extracellular matrix that can regulate the pathological angiogenic switch.