Abstract
Alternate splicing yields two distinct isoforms of the fibroblast growth factor (FGF) receptor FGFR2-IIIb and FGFR2-IIIc varying their extracellular structure in human thyroid cancer, in which FGFR expression is commonly dysregulated. In this study, we characterized the function of these variants in modulating thyroid cancer behavior. Enforced expression of either FGFR2-IIIb or FGFR2-IIIc in thyroid epithelial cancer cells reduced expression of fibronectin, MAGE-A3 and MMP9, while increasing p21 and enhancing Rb dephosphorylation. Consistent with these tumor-suppressive properties, FGFR2-IIIb and FGFR2-IIIc each diminished invasive behavior in vitro and reduced tumor growth and metastasis in vivo. Notably, these effects contrasted with those produced by expression of these FGFR isoforms in fibroblasts, in which they both stimulated cell growth. Moreover, in xenograft tumors generated by coimplantation of epithelial and fibroblast cells expressing that same isoform, there was no significant effect on tumor progression. Conversely, FGFR2-IIIb expression in epithelial cells yielded higher FGF4/FGF7 expression that, in the presence of FGFR2-IIIc-expressing fibroblasts, enhanced tumor progression. Together, our findings highlight the importance of cellular context in assigning growth properties to growth factor receptor isoforms. More specifically, they show how alternative splicing of FGFR2 yields heteroisoforms critical to the growth-promoting actions of FGFs that exert distinct epithelial-stromal effects in thyroid cancer.
Highlights
Thyroid cancer is the most common endocrine malignancy and is increasing in incidence [1]
To validate the functionality of the introduced FGFR2 isoforms, we stimulated these cells with the nonselective ligand FGF1, with FGF7 that selectively activates FGFR2-IIIb, or with FGF4 that selectively activates FGFR2-IIIc
Fibroblast growth factors (FGF) stimulation results in FGFR2 isoform-selective responses in TPC-1 and WRO cells transfected with FGFR2 isoforms (Fig. 1B and C)
Summary
Thyroid cancer is the most common endocrine malignancy and is increasing in incidence [1]. The majority of thyroid carcinomas derives from follicular epithelial cells and shows a spectrum of differentiation from indolent well-differentiated papillary and follicular carcinomas to more aggressive poorly differentiated carcinomas and highly lethal anaplastic carcinomas [2, 3]. This spectrum of progression has been linked with a pattern of cumulative genetic defects that correlates with tumor differentiation, aggressiveness, and metastatic potential [4]. Authors' Affiliations: 1The Ontario Cancer Institute, Departments of 2Medicine and 3Pathology, University Health Network; Departments of 4Medicine and 5Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; and 6Department of Neurosurgery, First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning, China
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