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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model
Anna Johansson1, Jonathan Jones, Kristian Pietras
1Department of Medical Bioscience, Pathology, Umeå University, Sweden. anna.johansson@medbio.umu.se
Background:
Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration-induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma.
Methods:
Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies.
Results:
In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF-Rbeta were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF-Rbeta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone.
Conclusions:
The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced.
Insights
Castration’s effect on prostate cancer regression is limited by an androgen-insensitive tumor stroma. Targeting this stroma alongside castration enhances anti-tumor effects, improving outcomes for advanced prostate cancer patients.
Area of Science:
- Urology
- Oncology
- Molecular Biology
Background:
- Castration causes significant involution of the normal prostate gland, driven by stromal and vascular changes.
- Androgen-sensitive prostate tumors show less regression after castration, potentially due to a limited stromal/vascular response.
- Animal models were used to investigate the role of stroma and vasculature in castration resistance.
Purpose of the Study:
- To explore the importance of stroma and vascular effects in castration-resistant prostate tumors.
- To determine if combining castration with stroma-targeted therapy can enhance anti-tumor effects.
Main Methods:
- Utilized Dunning PAP and H rat tumor models.
- Employed stereological methods, immunohistochemistry, and Western blotting.
- Assessed tumor response 7 and 28 days post-castration, with and without stroma-targeted therapies.
Main Results:
- Normal prostate epithelium showed rapid androgen receptor (AR) downregulation post-castration; Dunning tumors did not downregulate AR in the stroma.
- Vascular regulators (angiopoietins, tie 2, PDGF-Rbeta) remained unchanged in tumor stroma, unlike in the normal prostate, preventing vascular involution.
- Combined castration and stroma-targeted therapy (inhibiting tie 2 and PDGF-Rbeta) reduced vascular density, increased tumor cell apoptosis, and decreased tumor growth compared to castration alone.
Conclusions:
- The stroma of highly differentiated, androgen-sensitive Dunning tumors appears androgen-insensitive.
- Targeting this unresponsive tumor stroma can significantly enhance the efficacy of castration therapy.
- This suggests a potential therapeutic strategy for improving outcomes in advanced prostate cancer.
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