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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
Androgen withdrawal inhibits tumor growth and is associated with decrease in angiogenesis and VEGF expression in
Liang Cheng1, Shaobo Zhang, Christopher J Sweeney
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. lcheng@iupui.edu
Abstract:
Recent evidence suggests that androgens stimulate growth of human prostate cancer partly by regulating expression of growth factors such as vascular endothelial growth factor (VEGF) in vitro and in vivo. In this study, we used CWR22Rv1, a novel androgen-responsive but androgen-independent human prostate cancer model, to evaluate the effect of androgen withdrawal on tumor growth, expression of VEGF and the cell proliferation marker Ki-67, and angiogenesis. A time-release testosterone pellet was implanted three days before inoculation of CWR22Rv1 cells in the mice. The tumor volumes were measured every three days. Serum PSA was measured on days 1, 12, 20, 27 and 34 post inoculation. Castration was performed on the 20th day post inoculation. Immunohistochemical assays were used to evaluate cell proliferation and microvessel density. Enzyme-linked immunosorbent assay (ELISA) was used to quantify VEGF expression. The average tumor volumes in the castration group on the 27th and 34th days were 122 and 168 mm3, respectively, compared to 156 and 210 mm3 in the non-castration group (p<0.01). Serum PSA level in the castration group decreased to about 41% of the level of the non-castration group (p<0.01). The VEGF protein levels in the tumors of castrated and non-castrated mice on day 34 were 0.62 pg and 1.36 pg/100 microg total protein, respectively (p<0.001). The mean percentage of Ki-67-positive tumor cells in the castrated and non-castrated groups were 1.8% and 2.8%, respectively (p=0.015). The mean microvessel densities in the castrated and non-castrated groups were 15 and 22 vessels/field, respectively (p<0.01) We conclude androgen withdrawal reduced both VEGF and microvessel density, and this was associated with decreased cellular proliferation in androgen-independent CWR22Rv1 human prostate cancer tumor in vivo.
Insights
Androgen withdrawal significantly reduced tumor growth, vascular endothelial growth factor (VEGF), and angiogenesis in an androgen-independent prostate cancer model. This indicates a potential therapeutic strategy for advanced prostate cancer.
Area of Science:
- Oncology
- Endocrinology
- Cancer Biology
Background:
- Androgens are known to stimulate prostate cancer growth by regulating growth factors like vascular endothelial growth factor (VEGF).
- Understanding androgen's role in advanced, potentially androgen-independent prostate cancer is crucial for effective treatment strategies.
- The CWR22Rv1 cell line provides a novel model for studying androgen-responsive yet androgen-independent human prostate cancer.
Purpose of the Study:
- To investigate the impact of androgen withdrawal on tumor growth in an androgen-independent prostate cancer model.
- To evaluate the effects of androgen withdrawal on VEGF expression, cell proliferation (Ki-67), and angiogenesis.
- To assess the correlation between androgen suppression and key markers of tumor progression in vivo.
Main Methods:
- Utilized the CWR22Rv1 human prostate cancer cell line in a mouse model with time-release testosterone pellets.
- Performed castration on day 20 post-inoculation to induce androgen withdrawal.
- Measured tumor volume, serum PSA, VEGF protein levels (ELISA), cell proliferation (Ki-67 IHC), and microvessel density (IHC).
Main Results:
- Androgen withdrawal significantly reduced tumor volumes (168 mm³ vs. 210 mm³ at day 34, p<0.01).
- Castration led to a substantial decrease in serum PSA levels (41% of control, p<0.01) and VEGF protein (0.62 pg vs. 1.36 pg/100 µg, p<0.001).
- Reduced cell proliferation (1.8% vs. 2.8% Ki-67 positive cells, p=0.015) and microvessel density (15 vs. 22 vessels/field, p<0.01) were observed following androgen withdrawal.
Conclusions:
- Androgen withdrawal effectively suppressed tumor growth in this androgen-independent prostate cancer model.
- The reduction in tumor growth was associated with decreased VEGF expression and angiogenesis.
- These findings suggest that targeting androgen signaling may be a viable therapeutic approach even in advanced prostate cancers.
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