Distinct patterns of endothelin axis expression in primary prostate cancer
Geeta Godara1, Stefana Pecher, Drazen M Jukic
1Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15232, USA.
Objectives:
Emerging evidence supports a role for endothelin-1 (ET-1), endothelin A and B receptors (ET(A) and ET(B), respectively), and neutral endopeptidase (NEP) in the progression of prostate carcinoma. In clinical trials for advanced prostate cancer, ET axis blockade significantly delayed the time to disease progression in a subset of patients. We examined ET axis expression in prostate cancer, prostatic intraepithelial neoplasia, and normal adjacent tissue and then analyzed the relationship of the protein levels with disease progression.
Methods:
The expression levels of ET(A), ET(B), and NEP were determined in 120 prostate cancer specimens obtained at surgery or biopsy by immunohistochemistry. In situ hybridization on a subset of the specimens was used to confirm the immunohistochemistry findings.
Results:
In regions of adenocarcinoma, immunohistochemistry analysis demonstrated high ET(A) expression in 72% of the specimens. ET(A) expression was significantly elevated with increased pathologic stage and grade. ET(B) and NEP levels were significantly decreased in adenocarcinoma compared with normal adjacent tissue and prostatic intraepithelial neoplasia; however, reduced expression did not correlate with tumor grade or stage. Patients with prostate-specific antigen recurrence had significantly greater ET(A) levels in their primary tumors than did patients who were disease free 5 years after prostatectomy. Patients with high ET(A) expression in the adenocarcinoma regions with low ET(B) and NEP had a significantly decreased interval to prostate-specific antigen progression compared with patients with low ET(A) or high ET(B)/NEP expression.
Conclusions:
These data suggest two patterns of ET(A) expression in primary prostate cancer, with increased expression correlating with more advanced disease. The use of these expression patterns to identify patients more likely to respond to ET axis blockade might enhance treatment outcomes.
Insights
High endothelin A receptor (ET(A)) expression in prostate cancer correlates with advanced disease and faster progression. Targeting the endothelin axis may benefit patients with specific ET(A) expression patterns.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Emerging evidence implicates the endothelin-1 (ET-1) system, including endothelin A (ET(A)) and B (ET(B)) receptors and neutral endopeptidase (NEP), in prostate cancer progression.
- Clinical trials indicate that ET axis blockade can delay disease progression in advanced prostate cancer patients.
Purpose of the Study:
- To investigate the expression patterns of ET(A), ET(B), and NEP in prostate cancer, prostatic intraepithelial neoplasia, and normal adjacent tissues.
- To analyze the correlation between these protein levels and prostate cancer progression, including pathologic stage, grade, and recurrence.
Main Methods:
- Immunohistochemistry was used to quantify ET(A), ET(B), and NEP expression in 120 prostate cancer specimens.
- In situ hybridization confirmed immunohistochemistry findings in a subset of samples.
- Protein levels were correlated with clinical parameters such as stage, grade, and prostate-specific antigen recurrence.
Main Results:
- High ET(A) expression was observed in 72% of adenocarcinoma specimens and significantly correlated with increased pathologic stage and grade.
- ET(B) and NEP levels were decreased in adenocarcinoma compared to normal and pre-neoplastic tissues, but did not correlate with tumor stage or grade.
- Elevated ET(A) levels in primary tumors were associated with prostate-specific antigen recurrence.
- Patients with high ET(A) and low ET(B)/NEP expression showed a significantly shorter interval to PSA progression.
Conclusions:
- Two distinct ET(A) expression patterns in primary prostate cancer are suggested, with higher expression linked to more aggressive disease.
- Identifying patients based on these ET(A) expression patterns could optimize response to ET axis blockade therapies.
- This approach may enhance treatment outcomes for prostate cancer patients.
