title: 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-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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Lars Johan
authors.initials: LJ
authors.lastname: Nissen
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Hedlund
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Xing
authors.initials: X
authors.lastname: Zhao
authors.forename: Daniel
authors.initials: D
authors.lastname: Wetterskog
authors.forename: Keiko
authors.initials: K
authors.lastname: Funa
authors.forename: Ebba
authors.initials: E
authors.lastname: Bråkenhielm
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002196:Capillaries; D002465:Cell Movement; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005354:Fibrosarcoma / Q000097:blood* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D015398:Signal Transduction
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D051496:Receptor, Fibroblast Growth Factor, Type 1