Abstract
Fibroblast Growth Factor receptor (FGFR) activity plays crucial roles in tumor growth and patient survival. However, FGF (Fibroblast Growth Factor) signaling as a target for cancer therapy has been under-investigated compared to other receptor tyrosine kinases. Here, we studied the effect of FGFR signaling inhibition on tumor growth, metastasis and lymphangiogenesis by expressing a dominant negative FGFR (FGFR-2DN) in an orthotopic mouse mammary 66c14 carcinoma model. We show that FGFR-2DN-expressing 66c14 cells proliferate in vitro slower than controls. 66c14 tumor outgrowth and lung metastatic foci are reduced in mice implanted with FGFR-2DN-expressing cells, which also exhibited better overall survival. We found 66c14 cells in the lumen of tumor lymphatic vessels and in lymph nodes. FGFR-2DN-expressing tumors exhibited a decrease in VEGFR-3 (Vascular Endothelial Growth Factor Receptor-3) or podoplanin-positive lymphatic vessels, an increase in isolated intratumoral lymphatic endothelial cells and a reduction in VEGF-C (Vascular Endothelial Growth Factor-C) mRNA expression. FGFs may act in an autocrine manner as the inhibition of FGFR signaling in tumor cells suppresses VEGF-C expression in a COX-2 (cyclooxygenase-2) or HIF1-α (hypoxia-inducible factor-1 α) independent manner. FGFs may also act in a paracrine manner on tumor lymphatics by inducing expression of pro-lymphangiogenic molecules such as VEGFR-3, integrin α9, prox1 and netrin-1. Finally, in vitro lymphangiogenesis is impeded in the presence of FGFR-2DN 66c14 cells. These data confirm that both FGF and VEGF signaling are necessary for the maintenance of vascular morphogenesis and provide evidence that targeting FGFR signaling may be an interesting approach to inhibit tumor lymphangiogenesis and metastatic spread.
Highlights
Fibroblast Growth Factors (FGFs), which signal through FGF receptors (FGFR-1-5), are involved in a broad range of biological processes such as migration, tubulogenesis, proliferation, and differentiation of various cell types [1]
Our results demonstrate that Fibroblast Growth Factor receptor (FGFR) signaling, in addition to mediating tumor growth, regulates tumor metastasis and lymphangiogenesis via a VEGF-Cdependent mechanism
To investigate the role of FGFR signaling in tumorigenesis, metastasis and tumor lymphangiogenesis, we first inhibited FGFR signaling in mouse mammary carcinoma cells (66c14) using the dominant-negative FGF receptor strategy [4,13,14]. 66c14 cells are known to metastasize to the lungs mainly via the intratumor lymphatic vessels, in a VEGF-C-dependent manner, when injected directly into the mammary fat pad [18,21]
Summary
Fibroblast Growth Factors (FGFs), which signal through FGF receptors (FGFR-1-5), are involved in a broad range of biological processes such as migration, tubulogenesis, proliferation, and differentiation of various cell types [1]. Evidence shows that FGF signaling promotes tumor development and metastasis by directly regulating cancer cell proliferation, survival and tumor angiogenesis [2,3,4,5]. Several studies have demonstrated the importance of the lymphatic system as a route for tumor dissemination [6] and that metastasis is enhanced by VEGF-C via an increase in tumor lymphangiogenesis [7,8,9]. FGF-2 has been shown to indirectly induce lymphangiogenesis, in vivo, in a mouse cornea assay by upregulating VEGF-C [10]. FGF2 has been shown in vitro to act directly on lymphatic endothelial cell migration, proliferation and tubulogenesis [11,12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
