A Dominant-Negative FGF1 Mutant (the R50E Mutant) Suppresses Tumorigenesis and Angiogenesis

Mori, Seiji; Tran, Vu; Nishikawa, Kyoko; Kaneda, Teruya; Hamada, Yoshinosuke; Kawaguchi, Naomasa; Fujita, Masaaki; Takada, Yoko K.; Matsuura, Nariaki; Zhao, Min; Takada, Yoshikazu
February 2013
PLoS ONE;Feb2013, Vol. 8 Issue 2, p1
Academic Journal
Fibroblast growth factor-1 (FGF1) and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels. Integrins are critically involved in FGF signaling through crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and induces FGF receptor-1 (FGFR1)-FGF1-integrin αvβ3 ternary complex. We previously generated an integrin binding defective FGF1 mutant (Arg-50 to Glu, R50E). R50E is defective in inducing ternary complex formation, cell proliferation, and cell migration, and suppresses FGF signaling induced by WT FGF1 (a dominant-negative effect) in vitro. These findings suggest that FGFR and αvβ3 crosstalk through direct integrin binding to FGF, and that R50E acts as an antagonist to FGFR. We studied if R50E suppresses tumorigenesis and angiogenesis. Here we describe that R50E suppressed tumor growth in vivo while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E. Since R50E did not affect proliferation of cancer cells in vitro, we hypothesized that R50E suppressed tumorigenesis indirectly through suppressing angiogenesis. We thus studied the effect of R50E on angiogenesis in several angiogenesis models. We found that excess R50E suppressed FGF1-induced migration and tube formation of endothelial cells, FGF1-induced angiogenesis in matrigel plug assays, and the outgrowth of cells in aorta ring assays. Excess R50E suppressed FGF1-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) assays. Interestingly, excess R50E suppressed FGF2-induced angiogenesis in CAM assays as well, suggesting that R50E may uniquely suppress signaling from other members of the FGF family. Taken together, our results suggest that R50E suppresses angiogenesis induced by FGF1 or FGF2, and thereby indirectly suppresses tumorigenesis, in addition to its possible direct effect on tumor cell proliferation in vivo. We propose that R50E has potential as an anti-cancer and anti-angiogenesis therapeutic agent (“FGF1 decoy”).


Related Articles

  • Fibulin-5 is a tumour suppressor inhibiting cell migration and invasion in ovarian cancer. Jin Hyung Heo; Ji-ye Song; Ju-yeong Jeong; Gwangil Kim; Tae Heon Kim; Haeyoun Kang; Ah-young Kwon; Hee Jung An // Journal of Clinical Pathology;Feb2016, Vol. 69 Issue 2, p109 

    Aims Fibulin-5 is an extracellular matrix (ECM) glycoprotein which has a role in the organisation and stabilisation of ECM structures and regulating cell proliferation and tumourigenesis. Here, the expression of fibulin-5 and its functional effects on the migration and invasion of ovarian cancer...

  • Targeting the heparin-binding domain of fibroblast growth factor receptor 1 as a potential cancer therapy. Ling Ling; Si Kee Tan; Ting Hwee Goh; Cheung, Edwin; Nurcombe, Victor; van Wijnen, Andre J.; Cool, Simon M. // Molecular Cancer;Jul2015, Vol. 14 Issue 1, p1 

    Background: Aberrant activation of fibroblast growth factor receptors (FGFRs) deregulates cell proliferation and promotes cell survival, and may predispose to tumorigenesis. Therefore, selective inactivation of FGFRs is an important strategy for cancer therapy. Here as a proof-of-concept study,...

  • Correction: A Dominant-Negative FGF1 Mutant (the R50E Mutant) Suppresses Tumorigenesis and Angiogenesis.  // PLoS ONE;Feb2014, Vol. 9 Issue 2, p1 

    No abstract available.

  • Simulation of tumor-induced angiogenesis and its response to anti-angiogenic drug treatment: mode of drug delivery and clearance rate dependencies. Daniel Tee; Joseph DiStefano III // Journal of Cancer Research & Clinical Oncology;Jan2004, Vol. 130 Issue 1, p15 

    Tumor cells secrete diffusible substances collectively called tumor angiogenic factors (TAFs), most notably vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which in turn stimulate endothelial cell migration and thus angiogenesis, or new blood vessel...

  • Connective Tissue Growth Factor Participates in Scar Formation of Crescentic Glomerulonephritis. Kanemoto, Katsuyoshi; Usui, Joichi; Tomari, Shinsuke; Yokoi, Hideki; Mukoyama, Masashi; Aten, Jan; Weening, Jan J.; Nagata, Michio // Laboratory Investigation (00236837);Nov2003, Vol. 83 Issue 11, p1615 

    Glomerular crescents are a major determinant of progression in various renal diseases. Some types of growth factors are known to be involved in the evolution of crescents and the subsequent scar formation. Although glomerular parietal epithelial cells (FECs) are the major component of cellular...

  • A new tumor suppressor role for the Notch pathway in bladder cancer. Rampias, Theodoros; Vgenopoulou, Paraskevi; Avgeris, Margaritis; Polyzos, Alexander; Stravodimos, Konstantinos; Valavanis, Christos; Scorilas, Andreas; Klinakis, Apostolos // Nature Medicine;Oct2014, Vol. 20 Issue 10, p1199 

    The Notch signaling pathway controls cell fates through interactions between neighboring cells by positively or negatively affecting the processes of proliferation, differentiation and apoptosis in a context-dependent manner. This pathway has been implicated in human cancer as both an oncogene...

  • EGF-Like-Domain-7 Is Required for VEGF-Induced Akt/ERK Activation and Vascular Tube Formation in an Ex Vivo Angiogenesis Assay. Takeuchi, Kimio; Yanai, Ryoji; Kumase, Fumiaki; Morizane, Yuki; Suzuki, Jun; Kayama, Maki; Brodowska, Katarzyna; Nakazawa, Mitsuru; Miller, Joan W.; Connor, Kip M.; Vavvas, Demetrios G. // PLoS ONE;Mar2014, Vol. 9 Issue 3, p1 

    EGFL7 is a secreted angiogenic factor, which in contrast to the well-known secreted angiogenic molecules VEGF and FGF-2, is almost exclusively expressed by endothelial cells and may act in an autocrine fashion. Prior studies have shown EGFL7 to mediate its angiogenic effects by interfering with...

  • A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate. Bhattacharyya, S.; Ishida, W.; Wu, M.; Wilkes, M.; Mori, Y.; Hinchcliff, M.; Leof, E.; Varga, J. // Oncogene;3/12/2009, Vol. 28 Issue 10, p1285 

    The nonreceptor protein tyrosine kinase c-Abl regulates cell proliferation and survival. Recent studies provide evidence that implicate c-Abl as a mediator for fibrotic responses induced by transforming growth factor-β (TGF-β), but the precise mechanisms underlying this novel oncogene...

  • Comparative Histomorphological Review of Rat and Human Hepatocellular Proliferative Lesions. Thoolen, Bob; ten Kate, Fiebo J. W.; van Diest, Paul J.; Malarkey, David E.; Elmore, Susan A.; Maronpot, Robert R. // Journal of Toxicologic Pathology;2012, Vol. 25 Issue 3, p189 

    In this comparative review, histomorphological features of common nonneoplastic and neoplastic hepatocyte lesions of rats and humans are examined using H&E-stained slides. The morphological similarities and differences of both neoplastic (hepatocellular carcinoma and hepatocellular adenoma) and...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics