FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer

Abstract

Pancreatic cancer has one of the highest mortalities among all malignancies and there is an urgent need for new therapy. This might be achieved by resolving the detailed biological mechanism, and in this study we examined how pancreatic cancer cells develop aggressive properties by focusing on signalling through the fibroblast growth factor (FGF)10 and FGF receptor (FGFR)2, which play important roles in pancreatic organogenesis. Immunostaining of pancreatic cancer tissues showed that FGFR2 was expressed in cancer cells, whereas FGF10 was expressed in stromal cells surrounding the cancer cells. Patients with high FGFR2 expression in cancer cells had a shorter survival time compared to those with low FGFR2 expression. Fibroblast growth factor 10 induced cell migration and invasion of CFPAC-1 and AsPC-1 pancreatic cancer cells through interaction with FGFR2-IIIb, a specific isoform of FGFR2. Fibroblast growth factor 10 also induced expression of mRNA for membrane type 1-matrix metalloproteinase (MT1-MMP) and transforming growth factor (TGF)-b1, and increased secretion of TGF-b1 protein from these cell lines. These data indicate that stromal FGF10 induces migration and invasion in pancreatic cancer cells through interaction with FGFR2, resulting in a poor prognosis. This suggests that FGF10/FGFR2 signalling is a promising target for new molecular therapy against pancreatic cancer.

A Novel, Selective Inhibitor of Fibroblast Growth Factor Receptors That Shows a Potent Broad Spectrum of Antitumor Activity in Several Tumor Xenograft Models

“…Overexpression of FGFR or FGF has also been found in many different types of tumors including bladder, prostate, and lung cancers and multiple myeloma (5,(12)(13)(14)(15) and leads to tumor formation in animals (16)(17)(18). Cell lines that ectopically overexpress FGF or FGFR display transformed phenotype and grow as tumors in nude mice (12,(16)(17)(18)(19)(20)(21). In addition to their roles in tumor formation and progression, FGF and FGFR also act as key regulators of angiogenesis (2,(22)(23)(24), especially during tumor growth.…”

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

“…Certain integrins, cell adhesion molecules, and cadherins mediate endothelial cells interaction with surrounding extracellular components. FGF-2 governs the expression of these molecules on the cell surface of endothelial cells, assisting in the cell distribution, cell-cell communication, and maturation [161,162]. Finally, endothelial cell organization and maturation to form the vessel lumen is simplified by the effect of FGF-2 and FGF-8b [163].…”

Role of Fibroblast Growth Factor Receptor 2 in Pancreatic Cancer: Potential Target for New Therapeutic Approach?

“…For example, cell-derived factor-1 (SDF-1/ CXCL12) released by fibroblasts can promote cancer cells proliferation, while CXCR4 is released in several types of malignancies, such as breast cancer [35] and pancreatic cancer [36,37]. Also FGF10, produced by fibroblasts, has been demonstrated to induce cell migration and invasion in pancreatic cancer cells [19], while FGF7 is able to promote pancreatic cell proliferation. Nomura et al, have investigated the role of FGF10/FGFR2 pathway in pancreatic cancer.…”

“…Several growth factors and their receptors are overexpressed in PDAC, such as transforming growth factor-a, epidermal growth factor receptor, FGFs, and FGFRs [17]. Several FGFs are overexpressed in pancreatic cancer [18] and their altered expression has been linked to increased pancreatic cancer cell motility, proliferation, invasion and metastatic potential [19,20]. Expression levels of FGFR1 and FGFR2 have been reported to be involved in pancreatic cancer development.…”