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Fibrinogen Regulates MMP‐9 Processing of VEGF‐induced Angiogenesis and Tumor Growth in Osteosarcoma
Author(s) -
Moore Stephanie,
Ohba Tetsuro,
Cates Justin,
Cole Heather,
Mignemi Nicholas,
ichikawa Jiro,
Hirotaka Haro,
Schwartz Herbert,
Schoenecker Jonathan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.347.6
Subject(s) - angiogenesis , fibrin , matrix metalloproteinase , vascular endothelial growth factor , cancer research , osteosarcoma , tumor progression , neovascularization , medicine , pathology , vascularity , chemistry , immunology , cancer , vegf receptors
Purpose Osteosarcoma (OGS) is the most common primary malignant bone tumor in children and adolescents. Traditionally, fibrin, the essential structural matrix protein of a blood clot, is thought to enhance tumor adhesion and provide a matrix to support tumor growth. Evidence strongly supports that major angiogenic factors, such as vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP‐9), can bind fibrin in a concentration‐dependent manner. Therefore, we designed experiments to determine the effects of fibrin on OGS tumor angiogenesis by interacting with VEGF and MMP‐9. Methods Aggressive murine OGS cells are intratibially injected into Balb/C mice. OGS establishment is determined by radiographic analysis, micro‐CT, histology, and angiography. Results Opposed to traditional beliefs surrounding fibrin's role in tumor establishment, this work has shown that the loss of fibrin promotes the proliferation and vascularity of OGS, therefore promoting tumor establishment and disease progression.Therefore, we have confirmed that fibrin does play a role in tumor angiogenesis through its interaction with VEGF, however we have also shown for the first time that MMP‐9 is a novel intermediary factor for this interaction. Conclusions In this study, we have demonstrated that fibrin can inhibit tumor angiogenesis by inhibiting MMP‐9 activity and by sequestering VEGF that is cleaved by MMP‐9. This finding demonstrates a novel synergistic relationship between fibrin and MMP‐9 in the progression of OGS, while also identifying new therapeutic targets.