Cathepsin G-mediated enhanced TGF-beta signaling promotes angiogenesis via upregulation of VEGF and MCP-1.
Transforming growth factor (TGF)-beta signaling makes a significant contribution to the pathogenesis of breast cancer bone metastasis. In other tumor types, TGF-beta has been shown to promote tumor vascularity. Here, we report that inhibition of TGF-beta significantly reduces microvessel density in mammary tumor-induced bone lesions, mediated by decreased expression of both vascular endothelial growth factor (VEGF) and monocyte chemotactic protein (MCP)-1, both known angiogenic factors. Cathepsin G upregulation at the tumor-bone interface has been linked to increased TGF-beta signaling, and we also report that inhibition of Cathepsin G reduced tumor vascularity, as well as VEGF and MCP-1 expression.
Wilson
Thomas J
TJ
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, 68198-5845, United States.
Nannuru
Kalyan C
KC
Futakuchi
Mitsuru
M
Singh
Rakesh K
RK
D000818:Animals; D000906:Antibodies; D001859:Bone Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology* / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology*; D056649:Cathepsin G / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D000906:Antibodies; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D014108:Tosylphenylalanyl Chloromethyl Ketone; D056649:Cathepsin G; C534096:Ctsg protein, mouse