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Updated: Jun 4, 2026
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
TNF is necessary for castration-induced prostate regression, whereas TRAIL and FasL are dispensable
Jennifer S Davis1, Kent L Nastiuk, John J Krolewski
1Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Irvine, California 92697-4800, USA.
Abstract:
TNF, a proinflammatory and immune-regulatory cytokine, is a potent apoptotic stimulus in vitro. However, there have been few examples of a physiologic role for TNF-induced apoptosis in vivo. Here, we describe a novel role for TNF in prostate epithelial cell apoptosis after androgen withdrawal. Employing high-resolution serial magnetic resonance imaging to measure mouse prostate volume changes over time, we demonstrate that the extent of castration-induced prostate regression is significantly reduced in mice null for either the Tnf or Tnfr1 genes but not mice deficient for TNF-related apoptosis-inducing ligand or Fas signaling. Wild-type mice receiving soluble TNF (sTNF) receptor 2 (to bind TNF and block signaling) before castration exhibit an identical reduction of prostate regression. Together, these data indicate that uniquely among known extrinsic death signals, TNF is required for castration-induced prostate regression. Additionally, membrane-bound TNF protein and stromal cell specific TNF mRNA levels increase in rat prostate after castration. This is consistent with a paracrine role for TNF in prostate regression. When injected into the peritoneum of Tnf(-/-) mice at the time of castration, sTNF restores normal levels of prostate regression. However, wild-type mice receiving sTNF in the absence of castration do not exhibit prostate regression, indicating that TNF alone is not sufficient but acts in the context of additional castration-induced signals. These findings support a physiologic role for TNF in prostate regression after androgen withdrawal. Understanding this role may lead to novel therapies for prostate cancer.
Insights
Tumor necrosis factor (TNF) plays a crucial role in prostate epithelial cell apoptosis following androgen withdrawal. This cytokine is essential for castration-induced prostate regression, suggesting new therapeutic avenues for prostate cancer.
Area of Science:
- Cell Biology
- Immunology
- Oncology
Background:
- Tumor necrosis factor (TNF) is a pro-inflammatory cytokine with known in vitro apoptotic effects.
- The in vivo physiological role of TNF-induced apoptosis has been less understood.
- Prostate cancer is a significant health concern, and understanding regression mechanisms is key.
Purpose of the Study:
- To investigate the role of TNF in prostate epithelial cell apoptosis after androgen withdrawal.
- To determine if TNF is a necessary mediator of castration-induced prostate regression in vivo.
- To explore potential therapeutic strategies for prostate cancer based on TNF signaling.
Main Methods:
- Utilized high-resolution serial magnetic resonance imaging to quantify prostate volume changes in mice over time.
- Employed gene knockout models (Tnf-/-, Tnfr1-/-) and blocking antibodies (soluble TNF receptor 2) to assess TNF signaling.
- Analyzed TNF and TNF mRNA levels in rat prostate tissue after castration.
Main Results:
- Mice lacking TNF or TNF receptor 1 (Tnfr1) exhibited significantly reduced prostate regression after castration.
- Blocking TNF signaling with soluble TNF receptor 2 mimicked the reduced regression phenotype.
- Increased membrane-bound TNF and stromal cell TNF mRNA were observed in rat prostates post-castration, suggesting a paracrine role.
- Administration of soluble TNF restored normal prostate regression in Tnf-/- mice during castration, but not in wild-type mice without castration.
Conclusions:
- TNF is a critical mediator of prostate epithelial cell apoptosis and regression following androgen withdrawal.
- TNF acts in conjunction with other castration-induced signals, rather than being sufficient alone.
- These findings highlight a novel physiological role for TNF in prostate involution and offer potential therapeutic targets for prostate cancer.
