A BMP7 Variant Inhibits Tumor Angiogenesis In Vitro and In Vivo through Direct Modulation of Endothelial Cell Biology

Roberto Pallini, Stefano Giannetti, Luigi Maria Larocca, Ruggero De Maria Marchiano, Quintino Giorgio D'Alessandris, Liliana Morgante, Courtney M. Tate, Jacquelyn Mc Entire, Eliza Vakana, Lisa Wyss, Wayne Blosser, Lucia Ricci-Vitiani, Matilde Todaro, Antonina Benfante, Maria Luisa Colorito, Giorgio Stassi, Scott Rowlinson, Louis Stancato

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7 Citazioni (Scopus)

Abstract

Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have numerous biological activities including control of growth, differentiation, and vascular development. Using an in vitro co-culture endothelial cord formation assay, we investigated the role of a BMP7 variant (BMP7v) in VEGF, bFGF, and tumor-driven angiogenesis. BMP7v treatment led to disruption of neo-endothelial cord formation and regression of existing VEGF and bFGF cords in vitro. Using a series of tumor cell models capable of driving angiogenesis in vitro, BMP7v treatment completely blocked cord formation. Pre-treatment of endothelial cells with BMP7v significantly reduced their cord forming ability, indicating a direct effect on endothelial cell function. BMP7v activated the canonical SMAD signaling pathway in endo- thelial cells but targeted gene knockdown using shRNA directed against SMAD4 suggests this pathway is not required to mediate the anti-angiogenic effect. In contrast to SMAD acti- vation, BMP7v selectively decreased ERK and AKT activation, significantly decreased en- dothelial cell migration and down-regulated expression of critical RTKs involved in VEGF and FGF angiogenic signaling, VEGFR2 and FGFR1 respectively. Importantly, in an in vivo angiogenic plug assay that serves as a measurement of angiogenesis, BMP7v significantly decreased hemoglobin content indicating inhibition of neoangiogenesis. In addition, BMP7v significantly decreased angiogenesis in glioblastoma stem-like cell (GSLC) Matrigel plugs and significantly impaired in vivo growth of a GSLC xenograft with a concomitant reduction in microvessel density. These data support BMP7v as a potent anti-angiogenic molecule that is effective in the context of tumor angiogenesis.
Lingua originaleEnglish
pagine (da-a)N/A-N/A
Numero di pagine20
RivistaPLoS One
DOI
Stato di pubblicazionePubblicato - 2015

Keywords

  • glioblastoma

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