Responsabile di unità operativa nel progetto “Characterization of molecules involved in tumor angiogenesis regulation”; Ministero della Salute, Ricerca Finalizzata 2006 – Progetto Oncologico

Angiogenesis plays an important role in tumour growth and metastatization, as the result of a dynamic balance between pro-angiogenic factors and antiangiogenic factors and of neoplastic transendothelial cell migration (TEM). Several soluble factors have been shown to be important regulators of angiogenesis. Tissue factor (TF) is the principal initiator of the extrinsic coagulation cascade. The role for TF, but not yet of alternatively spliced TF isoforms, in angiogenesis is supported by both clinical and experimental work (Belting et al ATVB, 2005). Interestingly, a reciprocal regulation of TF and vascular endothelial growth factor (VEGF) expression/activation has been reported in several tumours, suggesting a close relationship between the two molecules in tumour angiogenesis. Further, it has not been investigated whether low molecular weight heparins (LMWH) may affect TF and TF pathway inhibitor (TFPI) expression by ECs challenged by tumor cells. Extracellular HMGB1 and its receptor RAGE are involved in tumor growth and TEM in vitro, and lung metastases in vivo. A role in FORHMGB1 angiogenesis has been described but poorly characterized. Molecules involved in both neuronal and EC guidance, such as SEMA3, may regulate angiogenesis and are lost during multiple myeloma progression. Further, soluble forms of neurexin and neuroligin may prove to be important regulators of tumor angiogenesis. Tumor microenvironment (hypoxic, acidotic etc.) is known to affect neoplastic growth and metastatization. Chemokines and their receptors, such as CXCR4, are crucial player in this processes and are sensitive to microenvironmental changes. It is yet to be determined whether dendritic (DC) and NK cells, that produce both pro- and anti-angiogenic cytokines (Riboldi et al, J. Immunol, 2005) may contribute to tumor growth also through the effect of microenvironment (hypoxia etc.). Cancer stem cell (CSC) might directly contribute to generate part of the newly-formed endothelial compartment that compose the tumor vessels either through promoting angiogenesis or through directly supporting endothelial wall formation. The embryonic vascular development and tumour vascularization are processes regulated by shared molecular mechanisms. The zebrafish embryo (Stern and Zon, Nature 2003) may thus be regarded as a model for testing angiogenic potential of CSC. The present project is aimed at: 1) Providing insights into a) the role of alternatively-spliced TF in tumor angiogenesis, b) into the mechanisms of thrombosis associated with antiangiogenic treatments, and c) into the modulation of TF expression by LMWH. 2) Demonstrating that tumor progression may involve an extracellular HMGB1-driven autocrine/paracrine loop 3) Modulating tumour angiogenesis by targeting molecular cues, such as SEM3, neurexin and neuroligin, involved in vascular guidance and vascular maturation. 4) Analyzing the effect of microenvironment on tumor angiogenesis, invasion, metastatization either a) directly on neoplastic cells (through CXCR4), or b) indirectly on immune cells, such as NK cells and DC. 5) Studying a) the mechanisms of human cancer stem cells (CSC)-induced angiogenic activity and b) to study CSC plasticity, for the identification of novel microenvironment embryonic cues, genes or pathways, able to inhibit CSC angiogenic activity.