Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer
Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/9/2336 |
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| author | Mamatha Kakarla Sathyavathi ChallaSivaKanaka Mary F. Dufficy Victoria Gil Yana Filipovich Renee Vickman Susan E. Crawford Simon W. Hayward Omar E. Franco |
| author_facet | Mamatha Kakarla Sathyavathi ChallaSivaKanaka Mary F. Dufficy Victoria Gil Yana Filipovich Renee Vickman Susan E. Crawford Simon W. Hayward Omar E. Franco |
| author_sort | Mamatha Kakarla |
| collection | DOAJ |
| description | Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector cells. The consequences of continuous reverse Ephrin signaling activation in fibroblasts on prostate cancer (PCa) is unknown. When compared to benign prostate fibroblast, CAF displayed higher expression of Ephrin B1, B2, and B3 ligands (EFNB1, EFNB2, and EFNB3). In this study, we found that continuous activation of EFNB1 and EFNB3 in a benign human prostate stromal cell line (BHPrS1) increased the expression of CAF markers and induced a CAF phenotype. BHPrS1<sup>EFNB1</sup> and BHPrS1<sup>EFNB3</sup> displayed a pro-tumorigenic secretome with multiple effects on neovascularization, collagen deposition, and cancer cell proliferation, overall increasing tumorigenicity of a premalignant prostate epithelial cell line BPH1 and PCa cell line LNCaP, both in vitro and in vivo. Inhibition of Src family kinases (SFK) in BHPrS1<sup>EFNB1</sup> and BHPrS1<sup>EFNB3</sup> suppressed EFNB-induced ɑ-SMA (Alpha-smooth muscle actin) and TN-C (Tenascin-C) in vitro. Our study suggests that acquisition of CAF characteristics via SFK activation in response to increased EFNB ligands could promote carcinogenesis via modulation of TME in PCa. |
| first_indexed | 2024-03-10T04:16:45Z |
| format | Article |
| id | doaj.art-2dd0f122a31b44998a28b9e8b0223adc |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:16:45Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2dd0f122a31b44998a28b9e8b0223adc2023-11-23T07:58:14ZengMDPI AGCancers2072-66942022-05-01149233610.3390/cancers14092336Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate CancerMamatha Kakarla0Sathyavathi ChallaSivaKanaka1Mary F. Dufficy2Victoria Gil3Yana Filipovich4Renee Vickman5Susan E. Crawford6Simon W. Hayward7Omar E. Franco8Department of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USADepartment of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USADepartment of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USADepartment of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USADepartment of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USADepartment of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USADepartment of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USADepartment of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USADepartment of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USAThrough stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector cells. The consequences of continuous reverse Ephrin signaling activation in fibroblasts on prostate cancer (PCa) is unknown. When compared to benign prostate fibroblast, CAF displayed higher expression of Ephrin B1, B2, and B3 ligands (EFNB1, EFNB2, and EFNB3). In this study, we found that continuous activation of EFNB1 and EFNB3 in a benign human prostate stromal cell line (BHPrS1) increased the expression of CAF markers and induced a CAF phenotype. BHPrS1<sup>EFNB1</sup> and BHPrS1<sup>EFNB3</sup> displayed a pro-tumorigenic secretome with multiple effects on neovascularization, collagen deposition, and cancer cell proliferation, overall increasing tumorigenicity of a premalignant prostate epithelial cell line BPH1 and PCa cell line LNCaP, both in vitro and in vivo. Inhibition of Src family kinases (SFK) in BHPrS1<sup>EFNB1</sup> and BHPrS1<sup>EFNB3</sup> suppressed EFNB-induced ɑ-SMA (Alpha-smooth muscle actin) and TN-C (Tenascin-C) in vitro. Our study suggests that acquisition of CAF characteristics via SFK activation in response to increased EFNB ligands could promote carcinogenesis via modulation of TME in PCa.https://www.mdpi.com/2072-6694/14/9/2336tumor microenvironment (TME)carcinoma-associated fibroblasts (CAF)stromaprostate cancerEphrinsreverse signaling |
| spellingShingle | Mamatha Kakarla Sathyavathi ChallaSivaKanaka Mary F. Dufficy Victoria Gil Yana Filipovich Renee Vickman Susan E. Crawford Simon W. Hayward Omar E. Franco Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer Cancers tumor microenvironment (TME) carcinoma-associated fibroblasts (CAF) stroma prostate cancer Ephrins reverse signaling |
| title | Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer |
| title_full | Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer |
| title_fullStr | Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer |
| title_full_unstemmed | Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer |
| title_short | Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer |
| title_sort | ephrin b activate src family kinases in fibroblasts inducing stromal remodeling in prostate cancer |
| topic | tumor microenvironment (TME) carcinoma-associated fibroblasts (CAF) stroma prostate cancer Ephrins reverse signaling |
| url | https://www.mdpi.com/2072-6694/14/9/2336 |
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