Le Cellule Endoteliali Circolanti nelle Neoplasie Ematologiche

Accumulating evidences showed that bone marrow endothelial cells play a key role in neoplastic angiogenesis. In neoplastic progression they are more circulating endothelial cells than in remission or in health volunteers. Some circulating endothelial cells are characterized by a mature well differentiated phenotype while other entothelial cell show antigens of progenitor cells indicating that these circulating endothelial progenitor cells (EPC) might be inside in angiogenic tissues and take active part in angiogenesis of new vessels, in particular in neoplasia. It is demonstrated that circulating endothelial cells (CEC) are characterized by a limited proliferating capacity, while EPC, coming from bone marrow, have got a elevated proliferating capacity. Bone marrow endothelial cells can contribute to neoplastic angiogenesis. Increasing evidences suggest that angiogenesis is involved in pathology of hematological malignant diseases included Multiple Myeloma (MM), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL). Taken together these findings suggest that angiogenesis plays a role in progression of oncohematological disease by synthesis of pro angiogenetic factors and neoplastic cells, mimicking a endothelial activity, taking part in synthesis of new vascular net-works by a autocrine loop, promoting leukemic progression. To clarify whether CEC in MM, in AML and in CLL originate from cancer, we evaluated 8 patients with deletion of 13q (5 with MM and 3 with Monoclonal Uncertain Gammopathy), 7 patients with AML and 74 patients with CLL with known cytogenetic abnormalities; we extracted CEC by immunomagnetic sorting from circulating cells and we characterized CEC by immunophenotype analysis and by Fluorescence In Situ Hybridization (FISH). In CLL we performed also a gene expression profile of 12 samples of CEC from patients with CLL using microarrays of 33.000 genes and comparing the results with gene expression profile of 2 health volunteers. The findings of these studies have shown that CEC levels both in MM and in AML and in CLL are increased compared to CEC levels in health volunteers or to CEC levels of patients in remission. Entothelial cell are in part endothelial progenitor cell (EPC) characterized by CD133 surface expression, a early endothelial marker lost during maturation of endothelial cell. FISH analysis highlighted that endothelial cells are positive for know cytogenetic abnormalities of MM, AML and CLL. Gene expression profiling in CEC of CLL has showed a well defined genetic pattern whose genes are involved in neoplastic progression and in neo-vasulogenesis identifying a cellular population co-expressing endothelial and lymphatic genes (CD19, von Willebrand Factor, VEGFR2). In conclusion our findings suggest that in MM, AML and in CLL, CEC are increased, are tumor related, show a EPC immuno phenotype and have a gene expression profile not only of endothelial cells but also of hematological malignance; in particular we find a increased expression of genes involved in proliferation, progression and angiogenesis. CEC can contribute to neoplastic angiogenesis and to progression acting as a sort bridgehead on which more numerous and possibly more specialized and functional active non clonal bone marrow derived EPCs could actively differentiate in mature vessels and contribute to tumor neovascularization and spreading. The results presented in this study, by showing a subset of CEC harbors cytogenetic abnormalities, suggest several theories. First, ECs and hematologic malignancies may derive from the same multipotent hemangioblast precursor cell; alternatively we may advocate theory about dedifferentiation, trans differentiation or theory of cellular fusion even if the last seems unlikely. Findings about CEC might play a key role non only in understanding of hematological malignancies biological specific features of but also in translation of new anti-angiogenic therapies to the clinic.