Aim of the Project
Angiogenesis, the process by which new blood vessels are formed, is an important event in physiologic or pathological conditions. Angiogenesis associated to physiological and pathological conditions recognizes partially overlapping molecular basis. Endothelial cells and pericytes, which form capillaries, carry all genetic information to form the whole capillary network. Angiogenic and antiangiogenic molecules released by accessory cells control neovascularization, notably the migration and proliferation of endothelial cells, their morphogenetic differentiation in capillaries and the concurrent remodelling of extracellular matrix. In physiologic conditions these steps are highly regulated. In contrast, many diseases, including cancer, are driven by persistent unregulated angiogenesis.
In human and experimental cancer, the new vessels are required for a sudden availability of nutrients and are target for invading cells of tumor and many evidences support a key role of angiogenesis in the progression of this disease. At the beginning of the lesion, cancer is not vascularized and it does not grow beyond 2 mm in size unless vascularization has occurred. The appearance of a vascular stage in the natural history of tumor is associated with metastases development.
A modern hypothesis to explain the switch to the angiogenic phenotype of the tumor must take into account at least two factors. First, the formation of capillary network is due to a net balance of positive versus negative angiogenic factors produced by tumor and host infiltrating cells. Second, microvascular and capillary endothelial cells in distinct tissues display different biological properties depending on microenvironmental or genetic backgrounds. Consequently, the different properties of endothelial cells can influence their response to angiogenic and antiangiogenic molecules.
Several clinical studies showed a positive correlation between the number of vessels in the tumor and the metastases formation and the prognosis of the disease. Therefore antiangiogenesis is a major area of therapeutic development for treatment of cancer, since tumor growth and metastasis depends on angiogenesis.
However, the concept that a well established vasculature favours the progression of cancer cannot be so simply considered. There are some conflicting data, such as the observation that not all angiogenic tumors produce metastases, that metastases develop many years after the appearance of a well vascularized tumor, that metastases appear after the excision of primary tumor, or that metastases appear first and the primary cancer remains "occult". These clinical evidences suggest that a simple increase of vessels in the tumor is not always sufficient for the progression of the disease and that phenotypic differences of endothelial cells sustained by different combinations of molecules in the tumoral "milieu" (growth factors and their receptors, cytokines, autacoids, vasodilating agents, matrix components) can influence the process of expansion and metastases formation.
In consequence of these remarks it is necessary a more sophisticated evaluation of angiogenesis in cancer in order to answer the following practical questions:
Are the present tools (antibodies to vascular cells, to angiogenic factors and their receptors, cDNAs) sufficient to discriminate between angiogenesis effective or ineffectual for the progression of cancer disease?
This project is aimed to bring new insights on the angiogenesis mechanisms which favour cancer development and progression, to obtain new tools (diagnostic, therapeutic, experimental) and to reply to the above questions and better engage angiogenesis associated to cancer.
Measurable objectives we propose are distributed according to four main tasks, as following: