Race-associated expression of MHC class I polypeptide-related sequence A (MICA) in prostate cancer.

Despite the lack of a complete understanding of the disparities involved, prostate cancer (PCa) has both higher incidence and death rates in African American Men (AAM) relative to those of Caucasian American Men (CAM). MHC class I polypeptide related sequence A (MICA) is an innate immunity protein involved in tumor immunoevasion. Due to a lack of reports of race-specific expression of MICA in PCa, we evaluated MICA expression in patients' tumors and in cell lines from a racially diverse origin. Immunohistochemistry was done on a tissue microarray (TMA) with antibodies against MICA. Tumor MICA mRNA was assessed by data mining using Oncomine and PROGeneV2. Surface MICA and release rate of soluble (s) MICA was evaluated in PCa cell lines originally derived from African American (MDA-PCa-2b) or Caucasian (LNCaP and DU-145) PCa patients. Prostate tumor tissue had a 1.7-fold higher MICA expression relative to normal tissue (p < .0001). MICA immunoreactivity in PCa tissue from AAM was 24% lower (p = .002) compared to CAM. Survival analysis revealed a marginal association of low MICA with poor overall survival (OS) (p = .058). By data mining analysis, a 2.9-fold higher level of MICA mRNA was evidenced in tumor compared to normal tissue (p < .0001). Tumors from AAM had 24% lower levels of MICA mRNA compared to tumors from CAM (p = .038), and poor prognosis was found for patients with lower MICA mRNA (p = .028). By flow cytometry analysis, cell fraction positive for surface MICA was of 3% in MDA-PCa-2b cells, 54% in DU-145 cells, and 67% in LNCaP cells (p < .0001). sMICA was detected in DU-145 and LNCaP cells, but was not detected in MDA-PCa-2b cells. Both LNCaP and DU-145 cells were sensitive to cytolysis mediated by Natural killer (NK) cells. MDA-PCa-2b cells, however were between 1.3-fold at 10:1 Effector:Target (E:T) ratio (p < .0001) and 2-fold at 50:1 E:T ratio (p < .0001) more resistant to NK-mediated cytolysis relative to cells from Caucasian origin. These results suggest that MICA expression may be related to the aggressive nature of PCa. Our findings also demonstrate for the first time that there are variations in MICA expression in the context of racial differences. This study establishes a rationale for further investigation of MICA as a potential race-specific prognostic marker in PCa.

The expression level of lysophosphatidylcholine acyltransferase 1 (LPCAT1) correlates to the progression of prostate cancer.

BACKGROUND: Lysophosphatidylcholine acyltransferase 1 (LPCAT1), the enzyme catalyzing the reaction in remodeling of phosphatidylcholine (PC) has been reported to express in prostate. However, its diagnostic and prognostic values remain unclear. METHODS: Immunohistochemistry (IHC) for LPCAT1 was performed on the tissue microarray (TMA) slides containing 251 samples from 148 patients with various prostatic disorders. The association of expression level of LPCAT1 with the progression of prostate cancer was analyzed. RESULTS: LPCAT1 IHC mean score was the highest in metastatic prostate cancer (8.00±1.28), which was significantly higher than that in primary prostate cancer (4.63±3.00, p=9.73E-07), in high grade prostatic intraepithelial neoplasia (HGPIN, 2.72±2.47, p=1.02E-12), and in benign prostate (2.68, p=6.17E-12). The mean score in primary prostate cancer was significantly higher than that in HGPIN (p=4.09E-04) and in benign prostate (p=2.74E-04). There was no significant difference in the mean score between HGPIN and benign prostate (p=0.951). LPCAT1 IHC score also correlated to the tumor grade and stage of prostate cancer. Patients who underwent prostatectomy for prostate cancer and developed biochemical recurrence or clinical metastasis had higher LPCAT1 IHC score than those who underwent prostatectomy for prostate cancer and did not develop biochemical recurrence and clinical metastasis. The association of LPCAT1 with the progression of prostate cancer was independent of patient race and age, PSA level and positivity of surgical resection margins. CONCLUSIONS: LPCAT1 correlates with the progression of prostate cancer and could be a new biomarker in diagnosis, prognosis and studying the pathogenesis of prostate cancer.

MTA1-activated Epi-microRNA-22 regulates E-cadherin and prostate cancer invasiveness.

We have previously shown that metastasis-associated protein 1 (MTA1), a chromatin remodeler, plays an important role in prostate cancer invasiveness, likely through regulation of epithelial-to-mesenchymal transition. Here, we identified miR-22 as an epigenetic-microRNA (Epi-miR) directly induced by MTA1 and predicted to target E-cadherin. Loss-of-function and overexpression studies of MTA1 reinforced its regulatory role in miR-22 expression. MiR-22 directly targets the 3'-untranslated region of E-cadherin, and ectopic overexpression of miR-22 diminishes E-cadherin expression. Overexpression of miR-22 in prostate cancer cells promotes cell invasiveness and migration. Meta-analysis of patient tumor samples indicates a positive correlation between MTA1 and miR-22, supporting their inhibitory effect on E-cadherin expression. Our findings implicate the MTA1/Epi-miR-22/E-cadherin axis as a new epigenetic signaling pathway that promotes tumor invasion in prostate cancer.

Targeting MTA1/HIF-1α signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression.

The metastasis-associated protein 1(MTA1)/histone deacetylase (HDAC) unit is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific Pten-null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene (Pter), affect MTA1/HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1/HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamic acid, vorinostat), which also downregulates MTA1, could block prostate tumor progression in vivo. We generated and utilized a luciferase reporter in a prostate-specific Pten-null mouse model (Pb-Cre+ ; Ptenf/f ; Rosa26Luc/+ ) to evaluate the anticancer efficacy of Pter/SAHA combinatorial approach. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA1-associated proangiogenic factors HIF-1α, VEGF, and IL-1ß leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA1/HIF-1α than by high dose SAHA alone. Our study provides preclinical evidence that Pter/SAHA combination treatment inhibits MTA1/HIF-1α tumor-promoting signaling in PCa. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1-targeted therapies in PCa.

Cardiac murmur prompting diagnosis of metastatic nonseminomatous germ cell testicular neoplasia in an 18-year-old patient.

Most retroperitoneal tumors such as renal cell carcinoma have been associated with tumor thrombus extending into the renal vein, inferior vena cava (IVC), and heart. The retroperitoneal metastatic potential of testicular tumors is well known. We report here the first instance of a cardiac murmur prompting diagnosis of metastatic testicular neoplasia in an 18-year-old patient. Chemotherapy was delayed and after successful surgical resection of the ventricular mass, the patient recovered uneventfully. This case underscores the need to pursue abnormal cardiac exams in newly diagnosed testicular cancer patients.

A retrospective study on pathologic features and racial disparities in prostate cancer.

We reviewed more than 3,000 pathology reports on prostate cancer-related surgical specimens and analyzed racial disparities in histological and clinical features at the time of initial biopsy, diagnosis of prostate cancer, and prostatectomy, as well as in characteristics of tumor evolution between African American and Caucasian patients. As compared to Caucasians, African American patients had younger age, higher cancer detection rate, higher Gleason score of prostate cancer, and more bilateral involvement of the prostate. African Americans also had larger prostates, greater volume of tumor, and more positive margins. The diagnosis of HGPIN or ASAP in prostate biopsies and African American race conferred an increased risk of diagnosis of prostate cancer. The interval between prior noncancerous biopsy and the subsequent biopsy with diagnosis of prostate cancer was shorter in men with HGPIN, with ASAP, or of African American race.

Perineural invasion in prostate cancer biopsies is not associated with higher rates of positive surgical margins.

PURPOSE: High rates of extracapsular tumor extension have been reported with biopsy perineural invasion (PNI), leading some to advocate routine resection of the ipsilateral neurovascular bundle (NVB) with radical retropubic prostatectomy (RRP) to assure negative surgical margins. The contemporary rates of extracapsular tumor extension (ECE) and margin status associated with biopsy PNI were investigated. MATERIALS AND METHODS: The prostate needle biopsies, RRP specimens, and operative reports of 452 consecutive patients undergoing RRP by a single surgeon were reviewed to determine the presence of PNI invasion, presence of ECE, margin status, and preservation of NVB. Patients were excluded from the analysis if they underwent preoperative hormonal ablation or if their original biopsy was not reviewed by the pathologists at our institution. Both univariate and multivariate analyses were performed to determine the effect of PNI on extracapsular extension, the likelihood of performing a bilateral nerve-sparing technique, and the result of a positive surgical margin. RESULTS: In the 402 evaluable cases, based on multivariate models PNI showed only a marginal association with positive surgical margin (+SM) (P = 0.10) and bilateral nerve-sparing (B-NS) (P = 0.07), but was significantly associated with organ confinement (P = 0.03). The odds ratio (OR) of PNI for +SM, although not statistically significant, was 0.36. Although showing a higher level of statistical significance, PNI for OC had an odds ratio of 0.50. Similarly, the odds ratio was 0.54 for B-NS. CONCLUSIONS: Although biopsy PNI alone was associated with a higher probability of ECE, it is not predictive of bilateral nerve-sparing technique or a positive surgical margin in an individual patient.

Prostate-specific antigen doubling time in the identification of patients at risk for progression after treatment and biochemical recurrence for prostate cancer.

After primary treatment for clinically localized prostate cancer, biochemical recurrence is usually the first evidence of either local recurrence or metastatic progression. This poses a diagnostic dilemma for both the patient and the physician regarding future therapy. Prostate-specific antigen doubling time (PSADT) is a useful tool in this clinical setting. There have been multiple reports of the utility of PSADT in men with isolated biochemical recurrence after either radical prostatectomy or external-beam radiation therapy. Early observations of PSADT in men with recurrence are reviewed and the current literature is summarized to allow physicians to make an accurate assessment of a patient's risk of progression after isolated biochemical recurrence.

Influence of biopsy perineural invasion on long-term biochemical disease-free survival after radical prostatectomy.

OBJECTIVES: To investigate the influence of biopsy perineural invasion (PNI) on long-term prostate-specific antigen recurrence rates, final pathologic stage, and surgical margin status of men treated with radical prostatectomy. Radical prostatectomy offers the best chance for surgical cure when performed for organ-confined disease. However, the histologic identification of PNI on prostate biopsy has been associated with a decreased likelihood of pathologically organ-confined disease. METHODS: Seventy-eight men with histologic evidence of PNI on biopsy underwent radical prostatectomy by a single surgeon between April 1984 and February 1995 and were compared with 78 contemporary matched (biopsy Gleason score, prostate-specific antigen level, clinical stage, age) controls without PNI. Biochemical disease-free survival and pathologic findings were compared. RESULTS: After a mean follow-up of 7.05 +/- 2.2 years and 7.88 +/- 2.7 years (P = 0.04) for patients with biopsy PNI and controls, respectively, no significant difference in the long-term prostate-specific antigen recurrence rates was observed (P = 0.13). The final Gleason score and pathologic staging were also similar in this matched cohort. Although the numbers of neurovascular bundles resected were comparable between the groups, no difference was found in the rate of positive surgical margins identified (13% versus 10%, P = 0.62). CONCLUSIONS: We were unable to show that PNI on needle biopsy influences long-term tumor-free survival.

Substratification of stage T1C prostate cancer based on the probability of biochemical recurrence.

OBJECTIVES: To evaluate the influence of preoperative prostate-specific antigen (PSA), biopsy Gleason sum, and prostate biopsy quantitative histologic findings on the probability of biochemical failure in an attempt to identify criteria to substratify Stage T1c prostate cancer more accurately. METHODS: We reviewed the records of 1149 patients who underwent prostatectomy for T1c disease between 1988 and 2000. Biochemical recurrence (PSA 0.2 ng/mL or greater) defined the endpoint in this study. Recursive partitioning analysis was used to establish cutpoints for preoperative PSA level, biopsy Gleason sum, number of positive biopsy cores, and maximal percentage of any single biopsy core involved with cancer. These cutoff values were then evaluated using Kaplan-Meier estimations to determine the probability of remaining biochemically recurrence free. RESULTS: Using a PSA cutpoint of 10 ng/mL or a biopsy Gleason sum of 7, two groups of patients were identified (T1cI and T1cII). The rate of freedom from PSA recurrence at 3, 5, and 10 years after surgery for T1cI was 98%, 96%, and 96%, respectively, and for T1cII was 86%, 83%, and 73%, respectively (P <0.001). For T1cII patients, the greatest percentage of cancer in a single biopsy core was found to be a predictor of biochemical failure on multivariate analysis and, using a cutoff value of 50%, further stratified the PSA recurrence-free rates for the men in group T1cII (90% and 85% versus 75% and 56% at 5 and 10 years after surgery, respectively, P = 0.03). CONCLUSIONS: The results of this study demonstrate that within Stage T1c there are two populations of patients with significantly different recurrence probabilities: T1cI (Gleason sum less than 7 and PSA 10 ng/mL or less) and T1cII (Gleason sum 7 or greater or PSA greater than 10 ng/mL). Furthermore, using a cutpoint of 50% of cancer in a single core of biopsy tissue, additional risk stratification is afforded to men with higher risk "T1cII" cancer.