Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer

Abstract

Epithelial ovarian cancers (EOCs) arise in the Ovarian Surface Epithelium (OSE). This tissue is a simple, poorly committed mesothelium which exhibits characteristics of epithelial and mesenchymal cells when grown in culture. In contrast, EOCs frequently exhibit properties of complex epithelial tissues of the female reproductive tract, such as oviductal, endometrial and cervical epithelia, and show induction of expression of epithelial markers such as E-cadherin. Fibroblast Growth Factor Receptor 2 isoform IIIb (FGF receptor 2-IIIb) is a spliced variant of FGF receptor 2 that binds the ligands FGF-1 and FGF-7 with high a nity, and is expressed exclusively by epithelial cells. We have studied the expression of FGF receptor 2-IIIb and its ligands in primary cultures of normal human OSE, EOC cell lines and snap frozen tissue from EOCs. Expression of FGF receptor 2-IIIb mRNA is undetectable in normal OSE, but is expressed in 16/20 (80%) of EOCs. FGFs 1 and 7 mRNAs are expressed in normal OSE, whilst only 4/20 (20%) and 12/20 (60%) of EOCs demonstrated expression for these ligands respectively. However, FGF-7 protein was detected in 70% (mean level=0.7 ng/ml) of ascitic¯uids obtained from patients with EOC. FGFs 1 and 7 stimulate DNA synthesis in EOC cell lines that express FGF receptor 2-IIIb. Moreover, DNA synthesis in these cell lines can be partially blocked by blocking antisera to FGFs 1 and 7. It is suggested that induction of expression of FGF receptor 2-IIIb may play a role in the development of EOCs by rendering the OSE susceptible to paracrine and/or autocrine stimulation by its requisite FGF ligands. Oncogene (2001) 20, 5878 ± 5887.

Targets of Fibroblast Growth Factor 1 (FGF-1) and FGF-2 Signaling Involved in the Invasive and Tumorigenic Behavior of Carcinoma Cells

“…It has been reported that FGF-1 and -2 are expressed in some human cancers and that autocrine loops for these factors could be linked to aggressive clinical behavior (Yoshimura et al, 1998;Chandler et al, 1999;Powers et al, 2000;Steele et al, 2001). These findings are consistent with constitutive FGF-1 and -2 production directly affecting cell motility, invasiveness, tumorigenicity, and tumor angiogenesis.…”

“…The multifunctional growth factors FGF-1 and -2 and their receptors may play a role in autocrine and paracrine growth control of malignant tumors; their overproduction or a constitutive activation of FGF signaling is often associated with cancer (Yoshimura et al, 1998;Chandler et al, 1999;Steele et al, 2001).…”

P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

“…To test this, we examined a set of inhibitors at effective concentrations that specifically inhibit various RTKs, including general RTKs (genistein), IGF-1R (AG1024), fibroblast growth factor receptor 1 (SU5402), epidermal growth factor receptor (EGFR) (AG1478) and hepatocyte growth factor receptor c-Met (K252a), which have been previously implicated in the progression and metastasis of ovarian cancer (Ellerbroek et al, 2001;Steele et al, 2001;Brokaw et al, 2007;Sawada et al, 2007). Among these inhibitors, we found that only genistein used to block RTK or AG1024 used to inhibit IGF-1R led to a marked decrease in p120 ctn activation ( Figure 3a) and translocation ( Figure 3b) following GnRHa stimulation.…”

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2

“…Furthermore, alternative mRNA splicing leads to isoforms of FGFR that have unique ligand-binding properties (Powers et al, 2000). Taking into account our data and the detailed studies in ovarian cancer (Steele et al, 2001;Valve et al, 2000), we could focus on either FGFR2 or FGFR4 as possible candidates for FGF2 specific signaling. Owing to the reported complexity of FGFs/FGFRs expression and the relevance of the cellular context in their interaction, further studies are needed to define the relative contribution of the two receptors, and to know which isoform of FGFR2 is relevant in FGF2 signaling on normal and tumor cells.…”