Angiogenesis is an important step in the progression of solid tumors and in the formation of metastasis. The new vessels are required for a sudden availability of nutrients and are target for invading cells of tumor. Several clinical studies showed a positive correlation between the number of vessels in the tumor (breast cancer, lung cancer, prostate carcinoma, melanoma, head-and-neck carcinoma) and the metastatization and the prognosis of the disease. However, there are some conflicting data, such as the observation that not all angiogenic tumors produce metastasis, or that metastases develop many years after the appearance of a well vascularized tumor. Several hypotheses have been proposed to explain these observations, including a change in the cell cycle, the selection of sub-clones, the change of the host immunity, and the modification of microenvironment. Our working hypothesis is that a change in the phenotype of endothelial cells (EC) in the tumor is essential for the progression of the disease, rather than a simple increase of vessels. Indeed, the aim of this project is to demonstrate the existence of a endothelial cell phenotype(s), which favours the tumor progression.

The plan of the research is as follows: 1) cloning of a murine EC line immortalized in our Lab by mT oncogene of polyomavirus (H.End.FB), of EC originated from endothelioma obtained by transplantation of this line in recipient mice. This cell line shows a higher production of nitric oxide (NO) and IL-6 that normal murine endothelial cells, and represents a unique model of tumoral angiogenesis with secondary lesions. We will characterize the clones on the basis of NO and IL-6 production and on the ability to induce the hemangioma; 2) cloning of EC originated from human cerebral vascular tumors; we will characterize the clones on the basis of the ability to form in vitro angiogenesis; 3) we will study the in vitro biological responses of clones to growth factors in order to answer to the following question: Does a soluble factor modify the phenotype of clones?; 4) we will study the ability of clones originated from human tumors to induce in vivo angiogenesis; 5) we will study the adhesion of human cancer cell lines to the clones originated from human tumors; 6) we will study the genetic regulation of the phenotypic differentiation of the angiogenic clones.