A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor

Suyama, Kimita; Shapiro, Irina M.; Guttman, Mitchell; Hazan, Rachel B.

doi:10.1016/s1535-6108(02)00150-2

Cited by 461 publications

(468 citation statements)

References 37 publications

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“…Our finding that P-cadherin as a critical mediator of the invasive phenotype further supports the view that the incorrect expression of another adhesion molecule, rather than a decrease in E-cadherin, is associated with an increased invasive potential (Nieman et al, 1999;Feltes et al, 2002;Suyama et al, 2002;Maeda et al, 2006). Unlike E-cadherin, P-cadherin can promote motility and invasion in carcinoma cells.…”

Section: Discussionsupporting

confidence: 84%

“…For example, E-cadherin is associated with epidermal growth factor receptor, thus activating the mitogenactivated protein kinase pathway, and N-cadherin has also been found to interact with fibroblast growth factor receptor (Pece and Gutkind, 2000;Suyama et al, 2002;Qian et al, 2004). In this context, we have found that P-cadherin was able to transactivate the insulin-like growth factor-1 receptor in regulation of p120 ctn signaling (our unpublished observations).…”

Section: Discussionmentioning

confidence: 72%

“…Instead, GnRHa stimulated activation of the P-cadherin promoter (Figure 2b; Po0.05), suggesting a transcriptional mechanism of regulation. P-cadherin contributes to the invasive phenotype It has been suggested that expression of an inappropriate cadherin may directly contribute to the invasive phenotype (Nieman et al, 1999;Feltes et al, 2002;Suyama et al, 2002;Maeda et al, 2006). To test whether P-cadherin may promote migration/invasion, we stably transfected Caov-3 and OVCAR-3 cells with P-cadherin and analyzed their effects on cell migration/invasion.…”

Section: Resultsmentioning

confidence: 99%

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Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

2010

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Gonadotropin-releasing hormone (GnRH) receptor expression is often elevated in ovarian cancer, but its potential role in ovarian cancer metastasis has just begun to be revealed. Cadherin switching is a crucial step during tumorigenesis, particularly in metastasis. Here, we showed that GnRH is an inducer of E-to P-cadherin switching, which is reminiscent of that seen during ovarian tumor progression. Overexpression of P-cadherin significantly enhanced, whereas knockdown of P-cadherin reduced migration and invasion regardless of E-cadherin expression, suggesting that inappropriate expression of P-cadherin contributes to the invasive phenotype. These effects of P-cadherin were mediated by activation of the Rho GTPases, Rac1, and Cdc42, through accumulation of p120 catenin (p120 ctn ) in the cytoplasm. The use of p120 ctn small interfering RNA or chimeric cadherin construct to inhibit p120 ctn expression and cytoplasmic localization, respectively, resulted in significant inhibition of cell migration and invasion, with a concomitant reduction in Rac1 and Cdc42 activation, confirming that the effect was p120 ctn specific. Similarly, the migratory/invasive phenotype could be reversed by expression of dominant-negative Rac1 and Cdc42. These results identify for the first time cadherin switching and p120 ctn signaling as important targets of GnRH function and as novel mediators of invasiveness and tumor progression in ovarian cancer.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

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Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

2010

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“…FGFRs were also shown to mediate cell survival and motility in numerous cancer types. [9][10][11][12] Promotion of oncogenesis by the FGF-FGFR signaling pathway is known to be mediated through mechanisms such as gene amplification, somatic mutations, translocations and increased expression of FGFs and/or FGFRs. 8,9,12 Amplification of the FGFR1 locus at chromosome 8p in particular was described in several cancer types, [12][13][14] such as breast, esophageal and head and neck carcinomas.…”

mentioning

confidence: 99%

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer

et al. 2014

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Small-cell lung cancer (SCLC) comprises about 13-15% of all lung cancers, and more than 29 400 new cases have been diagnosed in the United States in the year 2012. SCLC is a biologically complex tumor typically occurring in heavy smokers. Its medical treatment has almost remained unchanged over the last decades and selected treatment options have not been established so far, mainly due to the lack of targetable genetic alterations. In this study we analyzed a cohort of 307 SCLC samples for fibroblast growth factor receptor 1 (FGFR1) amplification using a dual color FISH probe. FGFR1 status was correlated with clinical data. FGFR1 amplifications were observed in 5.6% of evaluable pulmonary SCLCs. Most of them (93%) fulfilled the criteria for high-level amplification and only one case showed low-level amplification. Amplification patterns were homogenous in the entire tumor area without occurrence of any 'hot spot' areas. FGFR1 amplification status was not associated with age, sex, stage, smoking status or overall survival. FGFR1 amplification analysis by FISH analysis in SCLC is, under respect of certain technical issues, applicable in the routine clinical setting. However, the FGFR1 amplification patterns in SCLC differs strongly from the previously described FGFR1 amplification pattern in squamous cell carcinoma of the lung, as positive SCLC harbor mostly homogeneous high-level amplifications. We provide evidence that an estimated number of 1640 newly diagnosed FGFR1-positive SCLC cases in the United States annually could benefit from targeted therapy. Therefore, we recommend including SCLC in the screening for ongoing clinical trials with FGFR1 inhibitors.

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“…However, the net result is a reduction in cadherin/catenin complexes at the cells' periphery (Morita et al, 1999;Davies et al, 2000). Thus, to better understand the mechanisms of tumour cell dissociation, the role of cadherins must be taken into account, as they are crucial in cell -cell adhesion (Takeichi, 1993;Kim et al, 1999;Suyama et al, 2002).…”

mentioning

confidence: 99%

Luteinising hormone-releasing hormone analogue reverses the cell adhesion profile of EGFR overexpressing DU-145 human prostate carcinoma subline

2005

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Cetrorelix, a luteinising hormone-releasing hormone (LHRH) analogue, has been shown to limit growth of the human androgenindependent prostate cell line DU-145, although other inhibitory actions may also be affected. Both growth and invasion of DU-145 cells are linked to autocrine epidermal growth factor receptor (EGFR) signalling. Invasiveness requires not only cells to migrate to conduits, but also reduced adhesiveness between tumour cells to enable separation from the tumour mass. Thus, we investigated whether Cetrorelix alters the DU-145 cell -cell adhesion and if this occurs via altered EGFR signalling. Pharmacologic levels of Cetrorelix limited the invasiveness of a highly invasive DU-145 subline overexpressing full-length EGFR (DU-145 WT). Extended exposure of the cells to Cetrorelix resulted in increased levels of the cell -cell adhesion complex molecules E-cadherin, a-and bcatenin, and p120. Puromycin blocked the increases in E-cadherin and b-catenin levels, suggesting that de novo protein synthesis is required. The Cetrorelix effect appears to occur via transmodulation of EGFR by a protein kinase C (PKC)-dependent mechanism, as there were no changes in DU-145 cells expressing EGFR engineered to negate the PKC transattenuation site (DU-145 A654); downregulation of EGFR signalling produced a similar upregulation in adhesion complex proteins, further suggesting a role for autocrine signalling. Cetrorelix increased the cell -cell adhesiveness of DU-145 WT cells to an extent similar to that seen when autocrine EGFR signalling is blocked; as expected, DU-145 A654 cell -cell adhesion also was unaffected by Cetrorelix. The increased adhesiveness is expected as the adhesion complex molecules moved to the cells' periphery. These data offer direct insight into the possible crosstalk pathways between the LHRH and EGFR receptor signalling. The ability of Cetrorelix to downregulate EGFR signalling and subsequently reverse the antiadhesiveness found in metastatic prostate cancer highlights a novel potential target for therapeutic strategies.

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A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor

Cited by 461 publications

References 37 publications

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer

Luteinising hormone-releasing hormone analogue reverses the cell adhesion profile of EGFR overexpressing DU-145 human prostate carcinoma subline

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