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- Title
Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis.
- Authors
Nissen, Lars Johan; Renhai Cao; Hedlund, Eva-Maria; Zongwei Wang; Xing Zhao; Wetterskog, Daniel; Funa, Keiko; Bråkenhielm, Ebba; Yihai Cao; Cao, Renhai; Wang, Zongwei; Zhao, Xing; Bråkenhielm, Ebba; Cao, Yihai
- Abstract
Tumors produce multiple growth factors, but little is known about the interplay between various angiogenic factors in promoting tumor angiogenesis, growth, and metastasis. Here we show that 2 angiogenic factors frequently upregulated in tumors, PDGF-BB and FGF2, synergistically promote tumor angiogenesis and pulmonary metastasis. Simultaneous overexpression of PDGF-BB and FGF2 in murine fibrosarcomas led to the formation of high-density primitive vascular plexuses, which were poorly coated with pericytes and VSMCs. Surprisingly, overexpression of PDGF-BB alone in tumor cells resulted in dissociation of VSMCs from tumor vessels and decreased recruitment of pericytes. In the absence of FGF2, capillary ECs lacked response to PDGF-BB. However, FGF2 triggers PDGFR-alpha and -beta expression at the transcriptional level in ECs, which acquire hyperresponsiveness to PDGF-BB. Similarly, PDGF-BB-treated VSMCs become responsive to FGF2 stimulation via upregulation of FGF receptor 1 (FGFR1) promoter activity. These findings demonstrate that PDGF-BB and FGF2 reciprocally increase their EC and mural cell responses, leading to disorganized neovascularization and metastasis. Our data suggest that intervention of this non-VEGF reciprocal interaction loop for the tumor vasculature could be an important therapeutic target for the treatment of cancer and metastasis.
- Subjects
NEOVASCULARIZATION; TUMORS; METASTASIS; GROWTH factors; BLOOD vessels; TISSUES
- Publication
Journal of Clinical Investigation, 2007, Vol 117, Issue 10, p2766
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI32479