Massive T-lymphocyte infiltration into the host stroma is essential for fibroblast growth factor-2-promoted growth and metastasis of mammary tumors via neovascular stability.
Inflammation in the tumor stroma greatly influences tumor development. In the present study, we investigated the roles of fibroblast growth factor (FGF)-2-induced chronic inflammation in the development of 4T1 murine mammary tumors. Administration of FGF-2 into the tumor inoculation site during the initial phase of tumor growth enhanced tumor growth and pulmonary metastasis as well as microvessel density in tumor tissues in normal but not in nude mice. Infiltration of T lymphocytes and macrophages, recruitment of pericytes/vascular mural cells in neovascular walls, and the expression levels of cyclooxygenase (COX)-2 and vascular endothelial growth factor A (VEGFA) were also enhanced in the FGF-2-activated host stroma of normal mice. In addition, FGF-2-induced tumor growth and metastasis was abrogated by administration of either an immunosuppressant, FK506, or a COX-2 inhibitor. FGF-2 enhanced prostaglandin E(2) secretion in cultured T lymphocytes. In addition, VEGFA secretion was increased in a co-culture of T lymphocytes and fibroblasts in vitro. These results indicate that the massive infiltration of T lymphocytes into FGF-2-activated host stroma during the initial phase of tumor growth enhances neovascular stability by regulating endogenous COX-2 and VEGFA levels because both compounds are known to play important roles in marked 4T1 mammary tumor development via FGF-2-induced inflammatory reactions.
Tsunoda
Satoshi
S
Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan. satoshi_t@flute.ocn.ne.jp
Sakurai
Hiroaki
H
Saito
Yurika
Y
Ueno
Yoko
Y
Koizumi
Keiichi
K
Saiki
Ikuo
I
D000818:Animals; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005109:Extracellular Matrix / Q000276:immunology* / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000276:immunology* / Q000473:pathology; D009362:Neoplasm Metastasis / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D052246:Cyclooxygenase 2 Inhibitors; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D051546:Cyclooxygenase 2; D015232:Dinoprostone