title: Increased angiogenesis induced by chronic lymphocytic leukemia B cells is mediated by leukemia-derived Ang2 and VEGF.
abstract: Emerging evidence suggests that angiogenic signalling pathways play important role in the patho-biology of chronic lymphocytic leukemia (CLL). Our goal was to investigate: (i) the spontaneous and hypoxia-induced production of pro-angiogenic factors, VEGF and Ang2, by Real-time PCR and ELISA, (ii) the degree of vascularization in CLL-infiltrated bone marrow (BM) compartment by CD34 immunohistochemical staining of microvessels and (iii) the direct angiogenic effect of CLL-derived VEGF and Ang2 by function-blocking experiments in Matrigel assays. The results demonstrated that CLL cells spontaneously express both VEGF and Ang2 and are able to secrete these factors in surrounding microenvironment. Full-length Ang2 mRNA and truncated form Ang2(443) were detectable. Moreover, CLL cells were shown to enhance secretion of both VEGF and Ang2 proteins when subjected to hypoxic condition. Furthermore, increased in vivo and in vitro angiogenesis was induced by CLL cells. Enhanced BM vascularity correlated with Ig-unmutated CLL subset and increased expression of Ang2. Then, we demonstrated that supernatants obtained from CLL cells significantly increase the HUVEC tube formation in Matrigel assays and that this enhanced angiogenic capacity is mediated by both CLL-derived VEGF and Ang2. Taken together, these results suggest that several simultaneous mechanisms may be involved in the CLL capacity to induce the disruption of pre-existing vessel structures to give rise to tumor neoangiogenesis. The preliminary studies in solid tumors, showing that the disruption of Ang2 function can inhibit tumor vessel density and growth, are encouraging and suggest the possibility of new future therapeutic options targeting CLL microenvironment.
authors.affiliation: Hematology Unit, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Maffei
authors.forename: Silvia
authors.initials: S
authors.lastname: Martinelli
authors.forename: Ilaria
authors.initials: I
authors.lastname: Castelli
authors.forename: Rita
authors.initials: R
authors.lastname: Santachiara
authors.forename: Patrizia
authors.initials: P
authors.lastname: Zucchini
authors.forename: Marcella
authors.initials: M
authors.lastname: Fontana
authors.forename: Stefania
authors.initials: S
authors.lastname: Fiorcari
authors.forename: Goretta
authors.initials: G
authors.lastname: Bonacorsi
authors.forename: Fiorella
authors.initials: F
authors.lastname: Ilariucci
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Torelli
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042702:Angiopoietin-2 / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism; D001853:Bone Marrow / Q000098:blood supply / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042702:Angiopoietin-2; D018952:Antigens, CD34; D042461:Vascular Endothelial Growth Factor A