Estefania Labanca1, Jun Yang2, Peter D A Shepherd2, Xinhai Wan2, Michael W Starbuck2, Leah D Guerra2, Nicolas Anselmino2, Juan A Bizzotto3, Jiabin Dong2, Arul M Chinnaiyan4, Murali K Ravoori5, Vikas Kundra6, Bradley M Broom7, Paul G Corn2, Patricia Troncoso8, Geraldine Gueron3, Christopher J Logothethis2, Nora M Navone9. 1. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. 2. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3. Laboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina. 4. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA. 5. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 7. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 8. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 9. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: nnavone@mdanderson.org.
Abstract
BACKGROUND: No curative therapy is currently available for metastatic prostate cancer (PCa). The diverse mechanisms of progression include fibroblast growth factor (FGF) axis activation. OBJECTIVE: To investigate the molecular and clinical implications of fibroblast growth factor receptor 1 (FGFR1) and its isoforms (α/β) in the pathogenesis of PCa bone metastases. DESIGN, SETTING, AND PARTICIPANTS: In silico, in vitro, and in vivo preclinical approaches were used. RNA-sequencing and immunohistochemical (IHC) studies in human samples were conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In mice, bone metastases (chi-square/Fisher's test) and survival (Mantel-Cox) were assessed. In human samples, FGFR1 and ladinin 1 (LAD1) analysis associated with PCa progression were evaluated (IHC studies, Fisher's test). RESULTS AND LIMITATIONS: FGFR1 isoform expression varied among PCa subtypes. Intracardiac injection of mice with FGFR1-expressing PC3 cells reduced mouse survival (α, p < 0.0001; β, p = 0.032) and increased the incidence of bone metastases (α, p < 0.0001; β, p = 0.02). Accordingly, IHC studies of human castration-resistant PCa (CRPC) bone metastases revealed significant enrichment of FGFR1 expression compared with treatment-naïve, nonmetastatic primary tumors (p = 0.0007). Expression of anchoring filament protein LAD1 increased in FGFR1-expressing PC3 cells and was enriched in human CRPC bone metastases (p = 0.005). CONCLUSIONS: FGFR1 expression induces bone metastases experimentally and is significantly enriched in human CRPC bone metastases, supporting its prometastatic effect in PCa. LAD1 expression, found in the prometastatic PCa cells expressing FGFR1, was also enriched in CRPC bone metastases. Our studies support and provide a roadmap for the development of FGFR blockade for advanced PCa. PATIENT SUMMARY: We studied the role of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. We found that PCa cells with high FGFR1 expression increase metastases and that FGFR1 expression is increased in human PCa bone metastases, and identified genes that could participate in the metastases induced by FGFR1. These studies will help pinpoint PCa patients who use fibroblast growth factor to progress and will benefit by the inhibition of this pathway.
BACKGROUND: No curative therapy is currently available for metastatic prostate cancer (PCa). The diverse mechanisms of progression include fibroblast growth factor (FGF) axis activation. OBJECTIVE: To investigate the molecular and clinical implications of fibroblast growth factor receptor 1 (FGFR1) and its isoforms (α/β) in the pathogenesis of PCa bone metastases. DESIGN, SETTING, AND PARTICIPANTS: In silico, in vitro, and in vivo preclinical approaches were used. RNA-sequencing and immunohistochemical (IHC) studies in human samples were conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In mice, bone metastases (chi-square/Fisher's test) and survival (Mantel-Cox) were assessed. In human samples, FGFR1 and ladinin 1 (LAD1) analysis associated with PCa progression were evaluated (IHC studies, Fisher's test). RESULTS AND LIMITATIONS: FGFR1 isoform expression varied among PCa subtypes. Intracardiac injection of mice with FGFR1-expressing PC3 cells reduced mouse survival (α, p < 0.0001; β, p = 0.032) and increased the incidence of bone metastases (α, p < 0.0001; β, p = 0.02). Accordingly, IHC studies of human castration-resistant PCa (CRPC) bone metastases revealed significant enrichment of FGFR1 expression compared with treatment-naïve, nonmetastatic primary tumors (p = 0.0007). Expression of anchoring filament protein LAD1 increased in FGFR1-expressing PC3 cells and was enriched in human CRPC bone metastases (p = 0.005). CONCLUSIONS: FGFR1 expression induces bone metastases experimentally and is significantly enriched in human CRPC bone metastases, supporting its prometastatic effect in PCa. LAD1 expression, found in the prometastatic PCa cells expressing FGFR1, was also enriched in CRPC bone metastases. Our studies support and provide a roadmap for the development of FGFR blockade for advanced PCa. PATIENT SUMMARY: We studied the role of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. We found that PCa cells with high FGFR1 expression increase metastases and that FGFR1 expression is increased in human PCa bone metastases, and identified genes that could participate in the metastases induced by FGFR1. These studies will help pinpoint PCa patients who use fibroblast growth factor to progress and will benefit by the inhibition of this pathway.
Authors: Pablo Sanchis; Nicolas Anselmino; Sofia Lage-Vickers; Agustina Sabater; Rosario Lavignolle; Estefania Labanca; Peter D A Shepherd; Juan Bizzotto; Ayelen Toro; Antonina Mitrofanova; Maria Pia Valacco; Nora Navone; Elba Vazquez; Javier Cotignola; Geraldine Gueron Journal: Cancers (Basel) Date: 2022-04-21 Impact factor: 6.575