TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression
The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivatio...
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| Format: | Article |
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MDPI AG
2022-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/24/6020 |
| _version_ | 1797461059708125184 |
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| author | John J. Krolewski Shalini Singh Kai Sha Neha Jaiswal Steven G. Turowski Chunliu Pan Laurie J. Rich Mukund Seshadri Kent L. Nastiuk |
| author_facet | John J. Krolewski Shalini Singh Kai Sha Neha Jaiswal Steven G. Turowski Chunliu Pan Laurie J. Rich Mukund Seshadri Kent L. Nastiuk |
| author_sort | John J. Krolewski |
| collection | DOAJ |
| description | The mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. In addition to this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death, which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostates. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area, and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely by inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer microenvironment that mediates prostate cancer regression following androgen deprivation. |
| first_indexed | 2024-03-09T17:14:02Z |
| format | Article |
| id | doaj.art-18093fd5f4df478fac06fcb6d25a4d5d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T17:14:02Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-18093fd5f4df478fac06fcb6d25a4d5d2023-11-24T13:44:47ZengMDPI AGCancers2072-66942022-12-011424602010.3390/cancers14246020TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer RegressionJohn J. Krolewski0Shalini Singh1Kai Sha2Neha Jaiswal3Steven G. Turowski4Chunliu Pan5Laurie J. Rich6Mukund Seshadri7Kent L. Nastiuk8Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USALaboratory of Translational Imaging, Center for Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USALaboratory of Translational Imaging, Center for Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USAThe mainstay treatment for locally advanced, recurrent, or metastatic prostate cancer (PrCa) is androgen deprivation therapy (ADT). ADT causes prostate cancers to shrink in volume, or regress, by inducing epithelial tumor cell apoptosis. In normal, non-neoplastic murine prostate, androgen deprivation via castration induces prostate gland regression that is dependent on TNF signaling. In addition to this direct mechanism of action, castration has also been implicated in an indirect mechanism of prostate epithelial cell death, which has been described as vascular regression. The initiating event is endothelial cell apoptosis and/or increased vascular permeability. This subsequently leads to reduced blood flow and perfusion, and then hypoxia, which may enhance epithelial cell apoptosis. Castration-induced vascular regression has been observed in both normal and neoplastic prostates. We used photoacoustic, power Doppler, and contrast-enhanced ultrasound imaging, and CD31 immunohistochemical staining of the microvasculature to assess vascular integrity in the period immediately following castration, enabling us to test the role of TNF signaling in vascular regression. In two mouse models of androgen-responsive prostate cancer, TNF signaling blockade using a soluble TNFR2 ligand trap reversed the functional aspects of vascular regression as well as structural changes in the microvasculature, including reduced vessel wall thickness, cross-sectional area, and vessel perimeter length. These results demonstrate that TNF signaling is required for vascular regression, most likely by inducing endothelial cell apoptosis and increasing vessel permeability. Since TNF is also the critical death receptor ligand for prostate epithelial cells, we propose that TNF is a multi-purpose, comprehensive signal within the prostate cancer microenvironment that mediates prostate cancer regression following androgen deprivation.https://www.mdpi.com/2072-6694/14/24/6020photoacoustic imagingtumor hypoxiacontrast-enhanced ultrasoundtumor perfusionpower Dopplertumor blood flow |
| spellingShingle | John J. Krolewski Shalini Singh Kai Sha Neha Jaiswal Steven G. Turowski Chunliu Pan Laurie J. Rich Mukund Seshadri Kent L. Nastiuk TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression Cancers photoacoustic imaging tumor hypoxia contrast-enhanced ultrasound tumor perfusion power Doppler tumor blood flow |
| title | TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression |
| title_full | TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression |
| title_fullStr | TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression |
| title_full_unstemmed | TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression |
| title_short | TNF Signaling Is Required for Castration-Induced Vascular Damage Preceding Prostate Cancer Regression |
| title_sort | tnf signaling is required for castration induced vascular damage preceding prostate cancer regression |
| topic | photoacoustic imaging tumor hypoxia contrast-enhanced ultrasound tumor perfusion power Doppler tumor blood flow |
| url | https://www.mdpi.com/2072-6694/14/24/6020 |
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