Neoangiogénese

Interesse da Investigação

We are interested in several aspects of vascular biology, namely the role and regulation of Vascular Endothelial Growth Factor (VEGF) and its receptors in normalcy and in disease. Our focused research areas are: 1) Endothelial cell biology and the molecular basis of endothelial differentiation; 2) VEGF/VEGF receptor in haematological tumors (leukemias); 3) the mechanisms of VEGF receptor signalling on endothelial and malignant cells; 4) the interaction between bone marrow vasculogenesis and hematopoietic differentiation.
General Introduction: The process of neo-vascularization (angiogenesis) is essential for the growth of solid tumors and formation of metastasis, while it may also determine the progression of haematological cancers such as leukaemia and lymphomas. The cellular mechanisms responsible for capillary extension, endothelial cell (EC) migration and formation of tumor blood vessels, have been characterized to some extent, with the resulting identification of numerous growth factor/receptor families. However, the molecular mechanisms whereby EC -originated in pre-existing blood vessels or from bone marrow derived endothelial precursors- incorporate and differentiate into functional vascular units are still largely unknown. Moreover, the signalling pathways activated by pro-angiogenic growth factors, and the importance of the cell structure in transmitting such signals, are still undefined. Finally, it is now well established that malignant cells share numerous markers with their endothelial counterparts, such as the expression of functional tyrosine kinase receptors, for instance. Whether tumor cells with endothelial features retain the ability to differentiate into vascular structures, and what are the molecular pathways involved in this process, is also unknown.

Publicações

Dias, S.*, Choy, M.*, Alitalo, K. and Rafii, S. (2002). VEGF-C signaling through Flt-4 (VEGFR-3) Mediates Leukemic cell proliferation and survival. Blood 99 :2179-2184

Dias, S.*, Shmelkov ,V. S.*, Lam, G., and Rafii, S. (2002). VEGF promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression. Blood 99(7) :2532-40

Heissig, B., Hattori, K., Dias, S. et al. (2002). Recruitment of Stem and Progenitor Cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109(5) :625-37

Hattori, K., Heissig, B., Wu, Y., Dias, S., et al. (2002). Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nature Medicine 8(8) :841-49

Dias, S., Choy, M. and Rafii, S. (2001). The role of C-X-C chemokines in the regulation of tumor angiogenesis. Cancer Investigation 19(7) :732-738

Hattori, K., Dias, S., Heissig, B., Tateno, M., Witte, L., Yancopoulos, G. and Rafii, S. (2001). VEGF and Angiopoietin-1 stimulate post-natal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. Journal of Experimental Medicine 193 :1005-1014

Dias, S., Hattori, K., Heissig, B., Zhu, Z., Wu, Y., Witte, L., Hicklin, D.J., Tateno, M., Bohlen, P., Moore, M.A., Rafii, S. (2001). Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci (PNAS) 98(19) :10857-62

Lyden, D., Hattori, K., Dias, S., Costa, C., et al. (2001). Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Medicine 7(11): :1194-201

Roboz, G., Dias, S., Lam, G., Lane, W., Soignet, S.L., Warrel Jr, R.P. and Rafii, S. (2000). ArsenicTrioxide induces a dose and time-dependent apoptosis of endothelium and may exert an anti-leukemic effect via inhibition of angiogenesis. Blood 96(4) :1525-30

Dias, S., Hattori, K., Zhu, Z., Heissig, B., Choy, M., Lane, W., Wu, Y., Chadburn, A., Hyjeck, E., Gill, M., Hicklin, D.J., Witte, L., Moore, M.A.S. and Rafii, S. (2000). Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. Journal of Clinical Investigation 106 :511-521

Lane, W.*, Dias, S.*, Hattori, K., Choy, M., Rabbany, S., Wood, J., Moore, M. and Rafii, S. (2000). SDF-1 induced megakaryocyte migration and platelet production is dependent on matrix metalloproteinases Blood 96 :4152-4159