Tumors are complex structures that contain many different kinds of cells and extracellular matrix components. Besides transformed cells, tumors contain cells of the immune system, fibroblasts, blood vessels and many other elements that form the tumor stroma or microenvironment. We are interested in investigating the role of tumor microenvironment in cancer development and progression. In particular, our studies focus on the role of Tumor Necrosis Factor-alpha (TNF) and of other proteins of the extracellular matrix (in particular those containing NGR, isoDGR and RGD motives) in tumor vascular biology and angiogenesis. In addition, we are interested in developing new strategies for cancer therapy based on the manipulation of the tumor microenvironment. We have discovered that chromogranin A, a protein secreted by neuroendocrine cells and neurons, can affect the tumor vascular physiology and growth. Moreover, we have found that peptides containing the NGR and isoDGR motives can be exploited for delivering TNF and other cytokines to tumors vessels. One of these compounds, called NGR-TNF, can induce vascular damage and can increase the penetration of chemotherapeutic drugs in tumors. Because of these properties, NGR-TNF is currently tested in Phase I and II clinical studies, alone and in combination with chemotherapy.