Biological implications of macrophage infiltration in human tumor angiogenesis

Tumor angiogenesis is believed to be induced by increased production of ang iogenic factors and decreased production of angiogenic inhibitors by cancer cells, vascular endothelial cells, and other stromal cell types. Most soli d tumor cells are surrounded by stroma comprising interstitial connective t issue, blood vessels, fibroblastic cells, etc. Interaction between the stro ma and malignant cells appears to have a critical role in the development o f tumor neovasculature. We focused on macrophages, which demonstrate wide h eterogeneity in biological function and have an essential role in tumor ang iogenesis. Macrophages are terminally differentiated cells which produce a number of potent angiogenic cytokines and growth factors such as vascular e ndothelial growth factor, tumor necrosis factor-alpha, interleukin-8, and b asic fibroblast growth factor. They also modulate events in the extracellul ar matrix through the secretion of extracellular matrix-degrading enzymes a nd -modulating enzymes. Thus macrophages could influence various stages of angiogenesis either positively or negatively. We found a close correlation between increased macrophage index, malignancy, and high vascular grade in malignant melanoma, and present a model for the possible involvement of act ivated macrophages in neovascularization in human malignant melanoma.