title: Angiopoietin-2 in Bone Marrow milieu promotes Multiple Myeloma-associated angiogenesis.
abstract: Angiopoietin-2 (Ang-2) is involved in angiogenesis in both solid and hematological malignancies. In Multiple Myeloma (MM), serum Ang-2 correlates with disease progression and response to therapy. To address the patho-physiologic role of Ang-2 in MM associated angiogenesis, we used sera from patients with active MM, which contained significantly higher levels of the molecule, compared to those from patients with smoldering MM and Monoclonal Gammopathy of Undetermined Significance. MM Bone Marrow (BM) sera with high Ang-2 concentration specifically contributed to endothelial cell (EC) activation, while Ang-1 containing sera maintained EC stabilization. The functional dichotomy of Ang-1 and Ang-2 was confirmed by the triggering of distinctive signaling pathways down-stream the common Tie-2 receptor, i.e., the Akt or the ERK- phosphorylation pathway. Notably, Ang-2 but not VEGF serum levels correlated with BM micro-vessel density, further underscoring the key role of Ang-2 in angiogenesis. Western Blot, RT-PCR and immunocytochemistry identified MMEC as the major source of Ang-2, at variance with MM cells and CD14(+) BM monocytes. These data suggest that Ang-2 produced in the BM milieu may contribute to MM angiogenesis and suggest that the molecule can be further exploited both as angiogenesis biomarker and as a potential therapeutic target.
authors.affiliation: Department of Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Belloni
authors.affiliation: Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Magda
authors.initials: M
authors.lastname: Marcatti
authors.affiliation: Pathology Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.affiliation: Department of Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Veschini
authors.affiliation: Tumor Biology and Vascular Targeting Unit, Division of Molecular Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.affiliation: Department of Oncology, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University School of Medicine, Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris Cappio
authors.affiliation: Department of Oncology, San Raffaele Scientific Institute, Milan, Italy. Electronic address: ferrarini.marina@hsr.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Ferrarini
authors.affiliation: Department of Oncology, San Raffaele Scientific Institute, Milan, Italy. Electronic address: ferrero.elisabetta@hsr.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferrero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042683:Angiopoietin-1 / Q000097:blood / Q000378:metabolism; D042702:Angiopoietin-2 / Q000097:blood / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D042787:Receptor, TIE-2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2
keywords: Angiogenesis; Angiopoietin-2; Bone Marrow microenvironment; Endothelial cells; Multiple Myeloma