title: Responses of vascular endothelial cells to angiogenic signaling are important for tumor cell survival.
abstract: Neoplastic cells overexpress several angiogenic cytokines, which stimulate neovascularization. Whether the responses of the host endothelial cells to these signaling molecules affect tumor cells during early tumorigenesis has not been investigated. We investigated pre-angiogenic tumor cell survival and angiogenesis initiation by two murine tumor lines (4T1 mammary carcinoma and B16 melanoma), which constitutively expressed GFP, in dorsal skin-fold window chambers of mice treated with extracellular domain of Tie-2 (ExTek) or bFGF. ExTek reduced tumor cell survival, retarded tumor growth, and inhibited angiogenesis onset compared with controls. bFGF increased tumor cell survival and promoted earlier angiogenesis and tumor growth. Neither bFGF nor ExTek affected cell proliferation in vitro. RT-PCR showed mRNA expression of bFGF receptor 2 (FGFR2) IIIb, which does not bind bFGF efficiently, by 4T1 cells and B16 cells express FGFR1 but not FGFR2. B16 cells expressed angiopoietin (Ang) 2, but neither cell line expresses Ang1. Both tumor lines express VEGF. These findings suggested that effects of bFGF and ExTek on tumor cell survival and angiogenesis were not due to direct action but were instead a result of paracrine factors secreted by endothelial cells. These subsequent signals from endothelial cells promote early survival and proliferation of disseminated tumor cells before onset of angiogenesis.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710-3455, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Shan
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Robson
authors.forename: Yiting
authors.initials: Y
authors.lastname: Cao
authors.forename: Tong
authors.initials: T
authors.lastname: Qiao
authors.forename: Chuan Y
authors.initials: CY
authors.lastname: Li
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Kontos
authors.forename: Mariano
authors.initials: M
authors.lastname: Garcia-Blanco
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000737:chemistry; D042787:Receptor, TIE-2 / Q000737:chemistry*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D010446:Peptide Fragments; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D016186:Receptor, Macrophage Colony-Stimulating Factor; D042787:Receptor, TIE-2