Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis
Lars Johan Nissen, … , Ebba Bråkenhielm, Yihai Cao
Lars Johan Nissen, … , Ebba Bråkenhielm, Yihai Cao
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2766-2777. https://doi.org/10.1172/JCI32479.
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Research Article

Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis

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-α and -β 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.

Authors

Lars Johan Nissen, Renhai Cao, Eva-Maria Hedlund, Zongwei Wang, Xing Zhao, Daniel Wetterskog, Keiko Funa, Ebba Bråkenhielm, Yihai Cao

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Figure 9

Schematic representation of reciprocal interplay between FGF2 and PDGF-BB in promoting tumor angiogenesis and metastasis.

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Schematic representation of reciprocal interplay between FGF2 and PDGF-B...
FGF2 induces expression of PDGFR-α and -β in ECs, which are activated by PDGF-BB. Activation of PDGFRs leads to enhanced EC migration, which would synergistically coordinate with FGF2-induced EC proliferation. Both proliferation and migration of ECs are essential steps of tumor angiogenesis and are manifested in vivo as angiogenic synergism, which promotes metastasis. Conversely, PDGF-BB upregulates FGFR1 expression in VSMCs, which mediates proliferation signals triggered by FGF2. The FGF2-induced VSMC proliferation synergistically cooperates with PDGF-BB–induced VSMC proliferation and migration to crosstalk to nascent vasculature for remodeling. The coordination between synergistic angiogenesis and synergistic vascular remodeling in facilitating a functional vasculature remains unknown. In the tumor environment, it appears that FGF2/PDGF-BB–induced synergistic angiogenesis is not well coordinated with the angiogenic effects of FGF2 and PDGF-BB vascular remodeling. As a consequence, these 2 factors induce disorganized vasculatures and promote cancer metastasis.