BERKELEY, CA (UroToday.com) - Advanced prostate adenocarcinoma (PCa) is initially responsive to androgen-deprivation therapy (ADT). Over time, several mutations occur and PCa progressively becomes castration resistant. Castration-resistant prostate cancer (CRPC) is associated with high mortality and morbidity. The development of CRPC is mediated through two overlapping androgen receptor- (AR) independent and AR-dependent mechanisms. Hyaluronic acid and its receptors (CD44 and RHAMM) are closely associated with development of androgen independence in PCa.
To better understand RHAMM involvement in the PCa to CRPC process (also in the perspective of current tests with RHAMM vaccines) we have conducted the present study. The aim of our study was to evaluate RHAMM expression in prostate tissue samples that underwent distinctive exposure to ADT. We have evaluated normal peri-tumoral prostate, hyperplasic prostate, PCa and CRPC. These samples were obtained from 367 men divided into 6 groups:
Group 1: BPH (n=34)
Group 2: BPH using finasteride for more than 6 months (n=20)
Group 3: PCa, obtained after radical prostatectomy (n=202)
Group 4: PCa after ADT, obtained from men who entered into a trial of neoadjuvant ADT with cyproterone acetate prior to radical prostatectomy (n=78)
Group 5: CRPC, men who underwent TURP and had CRPC (n=15)
Group 6: peritumoral tissue, normal tissue adjacent to PCa in radical prostatectomy specimens (n=18)
Clinical and laboratory data were obtained from patients’ files, and patients were also contacted to assess follow-up. Tissue microarray was performed to evaluate RHAMM expression (additionally PSA and CD68 were also evaluated).
There was no RHAMM expression in any core samples from patients with BPH (with or without finasteride) or normal peri-tumoral tissue cores (18 cores). Similarly, none of the 202 prostate cancer tissue samples (222 cores) from men without prior ADT expressed RHAMM. RHAMM was expressed in samples from 28 patients with prostate cancer (39.4%) with ADT. Among the CRPC samples, RHAMM was positive in six cases (46.2%). RHAMM expression was significantly higher in prostate cancer with ADT and CRPC than in the other groups (P < 0.001). When evaluating samples from patients with prostate cancer undergoing ADT, there was a clear trend toward progressive RHAMM expression according to ADT duration.
In the present study there were some important findings. First, there was a strong association between prostate cancer exposure to ADT and RHAMM expression. Normal peri-tumoral prostatic tissue and BPH samples, and even prostate cancer samples without ADT, did not express RHAMM in any of the 265 cases (403 TMA cores). Importantly, BPH samples did not express RHAMM even after testosterone suppression therapy with finasteride, suggesting that androgen suppression is only associated with RHAMM expression in PCa. By contrast, PCa tissue samples from patients exposed to ADT, and many CRPC samples, expressed RHAMM. As RHAMM expression is also associated with inflammatory conditions, further IHC assays with PSA and CD68 were conducted to confirm our results.
Second, there was an association between RHAMM protein expression and ADT in prostate cancer that had already begun after the first month of ADT. Previous studies have shown that CRPC overexpresses RHAMM and exhibits excessive RHAMM signaling, stimulated by HA, which results in cell trafficking and prostate cancer metastasis. By contrast, normal prostatic tissue does not express HA or RHAMM, and androgen-dependent prostate cancer has very limited RHAMM expression and limited HA expression. However, the moment when this expression becomes more evident during the development of castration resistance is unknown. According to the present findings, RHAMM overexpression begins in the early stages of ADT, before prostate cancer becomes CRPC. Additionally, RHAMM overexpression develops progressively with the duration of ADT. RHAMM overexpression is essential for RAS-mediated oncogenic transformation and is linked to metastasis development.
We have not found any association between RHAMM expression in PCa samples and prognostic factors in PCa Kaplan-Meyer curves are shown (Figure 3).
In conclusion, RHAMM protein expression in prostate cancer is directly associated with ADT. Significant RHAMM expression occurs as early as after 1 month of ADT and progressively increases according to ADT duration. When prostate cancer becomes CRPC, RHAMM expression is even higher. RHAMM expression was not associated with prognostic factors for prostate cancer in men who underwent neoadjuvant ADT before radical prostatectomy. RHAMM overexpression may participate in hormonal resistance in prostate cancer.
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| Figure 1: Histological findings of four consecutive TMA cores representing the same region of each case, through H&E, IHC with RHAMM, PSA and CD68 (x400), showing: A2-) absent RHAMM expression in BPH; B2-) absent RHAMM expression in prostate cancer without ADT (CaP w/o); C2-) RHAMM expression in prostate cancer with 8 months of neoadjuvant ADT (CaP + ADT); D2-) RHAMM expression in CRPC. Line 1 shows H&E slides for each case; line 3 shows prostate glands through IHC with PSA; line 4 shows absence of macrophages as confounding factors through IHC with CD68 |
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| Figure 2: Association between ADT duration (months) and RHAMM expression in prostate cancer (n = 280), Brasil, 1989 - 2010. |
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| Figure 3: K-M curve for RHAMM expression and biochemical recurrence after radical prostatectomy. |
Written by:
Fernando Korkes, MD, PhD, et al. as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Division of Urology, ABC Medical School, São Paulo, Brazil
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