Essential role of PDGFRα-p70S6K signaling in mesenchymal cells during therapeutic and tumor angiogenesis in vivo role of PDGFRα during angiogenesis

Norifumi Tsutsumi, Yoshikazu Yonemitsu, Yasunori Shikada, Mitsuho Onimaru, Mitsugu Tanii, Shinji Okano, Kazuhiro Kaneko, Mamoru Hasegawa, Makoto Hashizume, Yoshihiko Maehara, Katsuo Sueishi

Research output: Contribution to journalArticle

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Abstract

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-α (PDGFRα)-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 PDGFRα-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 PDGFRα-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.

Original languageEnglish
Pages (from-to)1186-1194
Number of pages9
JournalCirculation research
Volume94
Issue number9
DOIs
Publication statusPublished - May 14 2004

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70-kDa Ribosomal Protein S6 Kinases
Platelet-Derived Growth Factor Receptors
Sirolimus
Neoplasms
Vascular Endothelial Growth Factor A
Angiogenesis Inducing Agents
Fibroblast Growth Factor 2
Therapeutics
Ischemia
Hepatocyte Growth Factor
Antineoplastic Agents
Signal Transduction
Intercellular Signaling Peptides and Proteins
Extremities

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Essential role of PDGFRα-p70S6K signaling in mesenchymal cells during therapeutic and tumor angiogenesis in vivo role of PDGFRα during angiogenesis. / Tsutsumi, Norifumi; Yonemitsu, Yoshikazu; Shikada, Yasunori; Onimaru, Mitsuho; Tanii, Mitsugu; Okano, Shinji; Kaneko, Kazuhiro; Hasegawa, Mamoru; Hashizume, Makoto; Maehara, Yoshihiko; Sueishi, Katsuo.

In: Circulation research, Vol. 94, No. 9, 14.05.2004, p. 1186-1194.

Research output: Contribution to journalArticle

Tsutsumi, Norifumi ; Yonemitsu, Yoshikazu ; Shikada, Yasunori ; Onimaru, Mitsuho ; Tanii, Mitsugu ; Okano, Shinji ; Kaneko, Kazuhiro ; Hasegawa, Mamoru ; Hashizume, Makoto ; Maehara, Yoshihiko ; Sueishi, Katsuo. / Essential role of PDGFRα-p70S6K signaling in mesenchymal cells during therapeutic and tumor angiogenesis in vivo role of PDGFRα during angiogenesis. In: Circulation research. 2004 ; Vol. 94, No. 9. pp. 1186-1194.
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