Tumour-derived fibroblast growth factor-2 exerts lymphangiogenic effects through Akt/mTOR/p70S6kinase pathway in rat lymphatic endothelial cells

Matsuo, Mitsuhiro; Yamada, Shûzô; Koizumi, Keiichi; Sakurai, Hiroaki; Saiki, Ikuo

doi:10.1016/j.ejca.2007.04.024

Cited by 53 publications

(45 citation statements)

References 26 publications

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“…However, the results suggest that FGF2 is the primary factor involved in maintaining endothelial cell marker expression and plays a unique role in the suppression of mesenchymal markers expression in mLECs. Next, we confirmed that fibroblast growth factor receptors (FGFRs) are expressed in LECs at the mRNA level, as described previously (Cao et al, 2012;Choi et al, 2012;Kazenwadel et al, 2012;Matsuo et al, 2007;Shin et al, 2006). We checked FGFR expression by real-time RT-PCR, using mLECs cultured in EGM2, and pre-optimised TaqMan expression assays.…”

Section: Resultsmentioning

confidence: 81%

“…2B). The lymphangiogenic activity of FGF2 has been demonstrated in vivo and in vitro (Cao et al, 2012;Chang et al, 2004;Choi et al, 2012;Kazenwadel et al, 2012;Kubo et al, 2002;Matsuo et al, 2007;Pepper et al, 1994;Shin et al, 2006), but the role of FGF2 in EndMT of LECs has not been studied previously. Therefore, we focused on the anti-EndMT activity of FGF2 in LECs.…”

Section: Resultsmentioning

confidence: 99%

“…Two distinct mechanisms underlying FGF2-induced lymphangiogenesis have been suggested. One mechanism is that FGF2 directly activates FGFRs on LECs, leading to lymphangiogenic responses such as proliferation, migration and tube-like morphogenesis of LECs (Cao et al, 2012;Choi et al, 2012;Kazenwadel et al, 2012;Matsuo et al, 2007;Pepper et al, 1994;Shin et al, 2006). In addition, the use of high concentration of FGF2 in culture medium and FGF2 stimulation after starvation were associated with upregulation of pro-lymphangiogenic gene expression in LECs (Cao et suggested mechanism is that FGF2 might induce expression and secretion of lymphangiogenic factors other than FGF2 from smooth muscle cells, BECs and perivascular cells, and then stimulate lymphangiogenesis in an indirect fashion (Bruyère et al, 2008;Chang et al, 2004;Kubo et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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FGF2-induced Ras/Erk MAPK signalling maintains lymphatic endothelial cell identity by up-regulating endothelial cell-specific gene expression and suppressing TGFβ signalling via Smad2

Ichise

Yoshida

Ichise

2013

Journal of Cell Science

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The lymphatic endothelial cell (LEC) fate decision program during development has been described. However, the mechanism underlying the maintenance of differentiated LEC identity remains largely unknown. Here, we show that fibroblast growth factor 2 (FGF2) plays a fundamental role in maintaining a differentiated LEC trait. In addition to demonstrating the appearance of LECs expressing a-smooth muscle actin in mouse lymphedematous skin in vivo, we found that mouse immortalised LECs lose their characteristics and undergo endothelial-to-mesenchymal transition (EndMT) when cultured in FGF2-depleted medium. FGF2 depletion acted synergistically with transforming growth factor (TGF) b to induce EndMT. We also found that H-Ras-overexpressing LECs were resistant to EndMT. Activation of H-Ras not only upregulated FGF2-induced activation of the Erk mitogen activated protein kinases (MAPK3 and MAPK1), but also suppressed TGFb-induced activation of Smad2 by modulating Smad2 phosphorylation by MAPKs. These results suggest that FGF2 regulates LEC-specific gene expression and suppresses TGFb signalling in LECs through Smad2 in a Ras-MAPK-dependent manner. Taken together, our findings provide a new insight into the FGF2-Ras-MAPK-dependent mechanism that maintains and modulates the LEC trait.

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Section: Resultsmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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FGF2-induced Ras/Erk MAPK signalling maintains lymphatic endothelial cell identity by up-regulating endothelial cell-specific gene expression and suppressing TGFβ signalling via Smad2

Ichise

Yoshida

Ichise

2013

Journal of Cell Science

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“…One of the earliest identified examples of this is HOXB7, which drives fibroblast growth factor 2 (FGF2, also known as bFGF) expression in multiple cancer types [58,85] . FGF2 is a well characterized proangiogenic factor, and has been shown to induce tubule formation by endothelial cells when secreted from a prostate tumor in a rat model of this disease [86] . In addition to FGF2, HOXB7 drives the expression of vascular endothelial growth factor A (VEGFA), C-X-C motif ligand 1 (CXCL1), and interleukin 8 (IL8) [58] .…”

Section: Hox Transcription Factors and Angiogenesismentioning

confidence: 99%

HOX transcription factors and the prostate tumor microenvironment

Morgan¹,

Pandha²

2017

JCMT

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It is now well established that the tumor microenvironment plays an essential role in the survival, growth, invasion, and spread of cancer through the regulation of angiogenesis and localized immune responses. This review examines the role of the HOX genes, which encode a family of homeodomain-containing transcription factors, in the interaction between prostate tumors and their microenvironment. Previous studies have established that HOX genes have an important function in prostate cancer cell survival in vitro and in vivo, but there is also evidence that HOX proteins regulate the expression of genes in the cancer cell that influence the tumor microenvironment, and that cells in the microenvironment likewise express HOX genes that confer a tumor-supportive function. Here we provide an overview of these studies that, taken together, indicate that the HOX genes help mediate cross talk between prostate tumors and their microenvironment. Key words:Prostate cancer, tumor microenvironment, HOX, PBX, metastasis, angiogenesis ABSTRACTArticle history:

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“…FGF-2 is able to induce angiogenesis and lymphangiogenesis. Recent studies suggest that in LECs lymphangiogenic signalling is mediated through the Akt-mammalian target of rapamycin (mTOR)-p70S6 kinase pathway (Matsuo, Yamada et al 2007). …”

Section: Fibroblast Growth Factorsmentioning

confidence: 99%