Essential Role of PDGFRα-p70S6K Signaling in Mesenchymal Cells During Therapeutic and Tumor Angiogenesis In Vivo

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

doi:10.1161/01.res.0000126925.66005.39

Cited by 59 publications

(87 citation statements)

References 27 publications

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“…We thus next focused on the role of VEGF-A/VPF and its potent autocrine upstream regulator, platelet-derived growth factor AA (PDGF-AA; refs. [29][30][31]. Of interest, accumulation of VEGF-A/VPF, but not of PDGF-AA, in MA was found (data not shown); therefore, elevated levels of VEGF-A/VPF might be due to the unregulated expression of VEGF-A/VPF from cancer cells.…”

Section: Discussionmentioning

confidence: 92%

Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites

Shimada

Kakeji

Tsujitani

et al. 2011

Molecular Cancer Therapeutics

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Malignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryrosine kinase receptor-1 (sFLT-1), was a major cause of MA resistance to dendritic cell (DC)-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene-deleted recombinant Sendai virus (rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors. These findings were not seen in immunodeficient mice, indicating that a VEGF-A/sFLT-1 imbalance is critical for determining the antitumor immune response by DC-vaccination therapy against MA.

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Section: Discussionmentioning

confidence: 92%

Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites

Shimada

Kakeji

Tsujitani

et al. 2011

Molecular Cancer Therapeutics

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“…Rapamycin also targets vascular mesenchymal cells (pericytes, smooth muscle cells, and adventitial fibroblasts) inhibiting sustained VEGF and hepatocyte growth factor expression via silencing of the platelet-derived growth factor receptor-a/S6 kinase 1 (S6K1) pathway. As rapamycin showed only a minimal effect on hypoxia-related expression of VEGF in culture, these results suggest targeting of the host vasculature rather than tumor itself in vivo (12,13).…”

Section: Introductionmentioning

confidence: 79%

Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors

Kurmasheva

Harwood

Houghton

2007

Molecular Cancer Therapeutics

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Levels of vascular endothelial growth factor (VEGF) are regulated, in part, through activation of the phosphatidylinositol 3′-kinase/Akt pathway. Using pharmacologic inhibitors, we have examined the relative contributions of Akt and mammalian target of rapamycin (mTOR) signaling to VEGF production in neuroblastoma and rhabdomyosarcoma cells growing under normoxic (21% O2) or hypoxic (1% O2) conditions. Exogenous VEGF stimulated both Akt and extracellular signal–regulated kinase 1/2 phosphorylation in six of seven rhabdomyosarcoma cell lines but in only one of seven neuroblastoma cells, suggesting autocrine stimulation predominantly in rhabdomyosarcoma cell lines. In general, under normoxic conditions, neuroblastoma cells produced more VEGF (120–1,180 pg/106 cells/24 h) compared with rhabdomyosarcoma lines (0–200 pg/106 cells/24 h). Rapamycin, a selective inhibitor of mTOR, reduced VEGF production in rhabdomyosarcoma cells under normoxic conditions and partially suppressed hypoxia-driven increases in VEGF. However, it poorly inhibited VEGF production under either condition in the majority of neuroblastoma cell lines despite inhibition of mTOR signaling. Rapamycin failed to modulate levels of hypoxia-inducible factor 1α (HIF-1α) under normoxic conditions and modestly reduced hypoxia-driven increases in HIF-1α only in rhabdomyosarcoma cells. In contrast to rapamycin, inhibition of Akt by A-443654 completely blocked signaling to glycogen synthase kinase 3β and had more dramatic effects on VEGF production. Notably, A-443654 significantly inhibited VEGF production in rapamycin-refractory neuroblastoma cell lines. Importantly, whereas combining A-443654 with rapamycin had variable effect on cell proliferation, the combination essentially blocked hypoxia-driven increases in VEGF in all cell lines examined, suggesting that dual blockade at different levels in the phosphatidylinositol 3′-kinase–initiated signaling pathway may be a reasonable strategy for preventing VEGF production in cancer cells derived from pediatric solid tumors. However, this will require formal testing in vivo using animal models of childhood cancer. [Mol Cancer Ther 2007;6(5):1620–8]

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“…A possible target cell for PDGF-A is the smooth muscle cell [Edelberg et al, 2002;Machens et al, 2002;Tsutsumi et al, 2004]. PDGF has a potent mitogenic effect in cells of mesenchymal origin.…”

Section: Discussionmentioning

confidence: 99%

Elucidating progesterone effects in breast cancer: Cross talk with PDGF signaling pathway in smooth muscle cell

Soares

Guerreiro

Botelho

2006

J of Cellular Biochemistry

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Several studies indicate that progesterone exerts relevant effects in breast tissue. However, the exact role of this steroid in breast cancer development and progression has not been elucidated. Here, we show that platelet-derived growth factor (PDGF)-A is one of the progesterone target genes on breast cancer MCF7 and T47D cells. A paracrine role for PDGF-A was investigated, since its receptor expression was down-regulated from breast cancer cells. Progesterone increased PDGF-A protein release as evaluated by Western blotting and ELISA. Medium from Progesterone-treated MCF7 cells resulted in phosphorylation of smooth muscle cells PDGF receptor a. This effect was not observed after treatment with PDGF inhibitor. MCF7 cells-secreted PDGF-A was able to increase smooth muscle cell viability and proliferation and decrease apoptosis, effects that were prevented by the use of a PDGF-A neutralizing antibody. Notably, cell invasion was not influenced by PDGF-A secreted by MCF7 cells. Our results elucidated for the first time the cross talk between progesterone and PDGF signaling pathway. The fact that MCF7-secreted PDGF elicited crucial roles in vascular wall smooth muscle cells, suggested a paracrine pathway for progesterone. Targeting these progesterone-induced processes may provide novel therapeutic strategies for hormone-dependent human breast cancer.

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Essential Role of PDGFRα-p70S6K Signaling in Mesenchymal Cells During Therapeutic and Tumor Angiogenesis In Vivo

Cited by 59 publications

References 27 publications

Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites

Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites

Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors

Elucidating progesterone effects in breast cancer: Cross talk with PDGF signaling pathway in smooth muscle cell

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