title: Hyperactivated FRS2α-mediated signaling in prostate cancer cells promotes tumor angiogenesis and predicts poor clinical outcome of patients.
abstract: 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 Frs2α 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.
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.|Xiamen University Affiliated Zhongshan Hospital, Xiamen, China.
authors.forename: P
authors.initials: P
authors.lastname: You
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.|Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.|Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Fu
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.|Institute for Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.|College of Pharmacy, Wenzhou Medical University, Wenzhou, China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: An
authors.affiliation: The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wan
authors.affiliation: The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Navone
authors.affiliation: Departments of Pathology and Urology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: C-L
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: McKeehan
authors.affiliation: Xiamen University Affiliated Zhongshan Hospital, Xiamen, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology and College of Medicine, Texas A&M Health Science Center, Houston, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001808:Blood Vessels / Q000254:growth & development / Q000473:pathology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C106534:FRS2 protein, human; D008565:Membrane Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A