Hyperactivated FRS2α-mediated signaling in prostate cancer cells promotes tumor angiogenesis and predicts poor clinical outcome of patients

• Published in: Oncogene Vol. 35; no. 14; pp. 1750 - 1759
• Main Authors: Liu, J, You, P, Chen, G, Fu, X, Zeng, X, Wang, C, Huang, Y, An, L, Wan, X, Navone, N, Wu, C-L, McKeehan, W L, Zhang, Z, Zhong, W, Wang, F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-04-2016; Nature Publishing Group
• Subjects: 13/105; 13/109; 13/51; 13/89; 13/95; 14/1; 14/63; 38/77; 631/67/2328; 64/60; Adaptor Proteins, Signal Transducing - biosynthesis; Adaptor Proteins, Signal Transducing - genetics; AKT protein; Angiogenesis; Animals; Apoptosis; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Blood Vessels - growth & development; Blood Vessels - pathology; Bone growth; Bone tumors; Cell Biology; Cell Line, Tumor; Cellular proteins; Cellular signal transduction; Development and progression; Endothelial cells; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Fibroblast growth factors; Gene Expression Regulation, Neoplastic; Genetic aspects; Growth factors; Health aspects; Human Genetics; Humans; Hyperactivity; Internal Medicine; Kinases; Male; Malignancy; Medicine; Medicine & Public Health; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Metastases; Mice; Neoplasm Metastasis; Neovascularization; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Oncology; original-article; Phosphorylation; Properties; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Signal Transduction; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.239

Metastasis of tumors requires angiogenesis, which is comprised of multiple biological processes that are regulated by angiogenic factors. The fibroblast growth factor (FGF) is a potent angiogenic factor and aberrant FGF signaling is a common property of tumors. Yet, how the aberration in cancer cells contributes to angiogenesis in the tumor is not well understood. Most studies of its angiogenic signaling mechanisms have been in endothelial cells. FGF receptor substrate 2α (FRS2α) is an FGF receptor-associated protein required for activation of downstream signaling molecules that include those in the mitogen-activated protein and AKT kinase pathways. Herein, we demonstrated that overactivation and hyperactivity of FRS2α, as well as overexpression of cJUN and HIF1α, were positively correlated with vessel density and progression of human prostate cancer (PCa) toward malignancy. We also demonstrate that FGF upregulated the production of vascular endothelial growth factor A mainly by increasing expression of cJUN and HIF1α. This then promoted recruitment of endothelial cells and vessel formation for the tumor. Tumor angiogenesis in mouse PCa tissues was compromised by tissue-specific ablation of
Frs2
α in prostate epithelial cells. Depletion of Frs2α expression in human PCa cells and in a preclinical xenograft model, MDA PCa 118b, also significantly suppressed tumor angiogenesis accompanied with decreased tumor growth in the bone. The results underscore the angiogenic role of FRS2α-mediated signaling in tumor epithelial cells in angiogenesis. They provide a rationale for treating PCa with inhibitors of FGF signaling. They also demonstrate the potential of overexpressed FRS2α as a biomarker for PCa diagnosis, prognosis and response to therapies.