Essential role of PDGFRalpha-p70S6K signaling in mesenchymal cells during therapeutic and tumor angiogenesis in vivo: role of PDGFRalpha during angiogenesis.
Discovery of the common and ubiquitous molecular targets for the disruption of angiogenesis, that are independent of the characteristics of malignant tumors, is desired to develop the more effective antitumor drugs. In this study, we propose that the platelet-derived growth factor receptor-alpha (PDGFRalpha)-p70S6K signal transduction pathway in mesenchymal cells, which is required for functional angiogenesis induced by fibroblast growth factor-2, is the potent candidate. Using murine limb ischemia as a tumor-free assay system, we demonstrated that p70S6K inhibitor rapamycin (RAPA) targets mesenchymal cells to shut down the sustained expression of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), via silencing of the PDGFRalpha-p70S6K pathway. Irrespective of the varied expression profiles of angiogenic factors in each tumor tested, RAPA constantly led the tumors to dormancy and severe ischemia in the time course, even associated with upregulated expression of VEGF from tumors. Because RAPA showed only a minimal effect to hypoxia-related expression of VEGF in culture, these results suggest that RAPA targets the host-vasculature rather than tumor itself in vivo. Thus, our current study indicates that the PDGFRalpha-p70S6K pathway is an essential regulator for FGF-2-mediated therapeutic neovascularization, as well as for the host-derived vasculature but not tumors during tumor angiogenesis, via controlling continuity of expression of multiple angiogenic growth factors.
Tsutsumi
Norifumi
N
Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yonemitsu
Yoshikazu
Y
Shikada
Yasunori
Y
Onimaru
Mitsuho
M
Tanii
Mitsugu
M
Okano
Shinji
S
Kaneko
Kazuhiro
K
Hasegawa
Mamoru
M
Hashizume
Makoto
M
Maehara
Yoshihiko
Y
Sueishi
Katsuo
K
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000473:pathology; D015687:Cell Hypoxia; D004815:Epidermal Growth Factor / Q000096:biosynthesis / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000503:physiopathology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics; D008297:Male; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
D009363:Neoplasm Proteins; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D020796:Receptor, Platelet-Derived Growth Factor alpha; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus