Joshua M Corbin1, Ryan F Overcash2, Jonathan D Wren3, Anita Coburn4, Greg J Tipton5, Jennifer A Ezzell6, Kirk K McNaughton6, Kar-Ming Fung1,7, Stanley D Kosanke1, Maria J Ruiz-Echevarria1,8. 1. Department of Pathology, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma. 2. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina. 3. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma. 4. Department of Comparative Medicine, East Carolina University, Greenville, North Carolina. 5. Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 6. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 7. Department of Pathology, Oklahoma City Veterans Affairs Medical Center, Oklahoma City, Oklahoma. 8. Stephenson Cancer Center, Oklahoma City, Oklahoma.
Abstract
BACKGROUND: Previous results from our lab indicate a tumor suppressor role for the transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) in prostate cancer (PCa). Here, we further characterize this role and uncover new functions for TMEFF2 in cancer and adult prostate regeneration. METHODS: The role of TMEFF2 was examined in PCa cells using Matrigel(TM) cultures and allograft models of PCa cells. In addition, we developed a transgenic mouse model that expresses TMEFF2 from a prostate specific promoter. Anatomical, histological, and metabolic characterizations of the transgenic mouse prostate were conducted. The effect of TMEFF2 in prostate regeneration was studied by analyzing branching morphogenesis in the TMEFF2-expressing mouse lobes and alterations in branching morphogenesis were correlated with the metabolomic profiles of the mouse lobes. The role of TMEFF2 in prostate tumorigenesis in whole animals was investigated by crossing the TMEFF2 transgenic mice with the TRAMP mouse model of PCa and analyzing the histopathological changes in the progeny. RESULTS: Ectopic expression of TMEFF2 impairs growth of PCa cells in Matrigel or allograft models. Surprisingly, while TMEFF2 expression in the TRAMP mouse did not have a significant effect on the glandular prostate epithelial lesions, the double TRAMP/TMEFF2 transgenic mice displayed an increased incidence of neuroendocrine type tumors. In addition, TMEFF2 promoted increased branching specifically in the dorsal lobe of the prostate suggesting a potential role in developmental processes. These results correlated with data indicating an alteration in the metabolic profile of the dorsal lobe of the transgenic TMEFF2 mice. CONCLUSIONS: Collectively, our results confirm the tumor suppressor role of TMEFF2 and suggest that ectopic expression of TMEFF2 in mouse prostate leads to additional lobe-specific effects in prostate regeneration and tumorigenesis. This points to a complex and multifunctional role for TMEFF2 during PCa progression.
BACKGROUND: Previous results from our lab indicate a tumor suppressor role for the transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) in prostate cancer (PCa). Here, we further characterize this role and uncover new functions for TMEFF2 in cancer and adult prostate regeneration. METHODS: The role of TMEFF2 was examined in PCa cells using Matrigel(TM) cultures and allograft models of PCa cells. In addition, we developed a transgenicmouse model that expresses TMEFF2 from a prostate specific promoter. Anatomical, histological, and metabolic characterizations of the transgenicmouse prostate were conducted. The effect of TMEFF2in prostate regeneration was studied by analyzing branching morphogenesis in the TMEFF2-expressing mouse lobes and alterations in branching morphogenesis were correlated with the metabolomic profiles of the mouse lobes. The role of TMEFF2in prostate tumorigenesis in whole animals was investigated by crossing the TMEFF2transgenic mice with the TRAMPmouse model of PCa and analyzing the histopathological changes in the progeny. RESULTS: Ectopic expression of TMEFF2 impairs growth of PCa cells in Matrigel or allograft models. Surprisingly, while TMEFF2 expression in the TRAMPmouse did not have a significant effect on the glandular prostate epithelial lesions, the double TRAMP/TMEFF2transgenic mice displayed an increased incidence of neuroendocrine type tumors. In addition, TMEFF2 promoted increased branching specifically in the dorsal lobe of the prostate suggesting a potential role in developmental processes. These results correlated with data indicating an alteration in the metabolic profile of the dorsal lobe of the transgenicTMEFF2mice. CONCLUSIONS: Collectively, our results confirm the tumor suppressor role of TMEFF2 and suggest that ectopic expression of TMEFF2 in mouse prostate leads to additional lobe-specific effects in prostate regeneration and tumorigenesis. This points to a complex and multifunctional role for TMEFF2 during PCa progression.
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Authors: Constantin Georgescu; Joshua M Corbin; Sandra Thibivilliers; Zachary D Webb; Yan D Zhao; Jan Koster; Kar-Ming Fung; Adam S Asch; Jonathan D Wren; Maria J Ruiz-Echevarría Journal: BMC Cancer Date: 2019-05-06 Impact factor: 4.430