Beyond the Abstract - Elevated expression of cancer-associated proliferating cell nuclear antigen in high-grade prostatic intraepithelial neoplasia and prostate cancer, by George E. Sandusky, DVM, PhD

BERKELEY, CA ( - Prostate cancer is one of the leading forms of cancer in industrial countries.

Critical determinants of prostate cancer progression affecting patient prognosis include: histologic Gleason tumor cell scoring, high serum PSA values, and bone scans for monitoring tumor cell migration and metastasis. While identifying prostate cancer in gross surgical specimens is relatively straight-forward, diagnosis of the disease can remain challenging for specimens associated with certain borderline lesions due to inadequate biopsy material submitted for evaluation or confounding morphological features that do not facilitate a ready diagnosis.

In an effort to reduce the degree of ambiguity associated with these types of lesions we evaluated a new biomarker in development called cancer associated proliferating cell nuclear antigen as a potential diagnostic tool. The expression of a cancer-associated isoform of PCNA (i.e. caPCNA) was first reported by Bechtel et al. (1998). In the Bechtel study, caPCNA was observed to be a unique acidic isoform of the protein that was absent from the nuclei of non-malignant proliferating breast epithelia cells. Non-malignant breast epithelial appeared to express a basic isoform of PCNA (i.e. nmPCNA) that arose as a result of differential post-translational modification of the PCNA primary sequence, and was not the result of a discrete genetic mutation or alternate splice variant of the PCNA gene. Structural analysis of the caPCNA isoform led to the development of an antibody that selectively recognizes the caPCNA isoform and not the nmPCNA isoform. Recognition of the caPCNA isoform by this antibody occurs with high sensitivity and specificity for cancer cells. Additional studies with the antibody indicated that caPCNA is expressed in a large variety of cancer cell types and is present at all stages (1-4) of the disease. In contrast, caPCNA is not consistently observed in most normal tissues adjacent to the cancer, and the caPCNA antibody is reactive with breast, cervical, colon, gastric, lung, ovary, prostate, and thyroid adenocarcinoma.

Based on this association, Wang and colleagues explored the hypothesis that expression of the caPCNA isoform in whole mount prostate sections in 94 individual clinical patient cases might be a useful biomarker for identifying the presence of prostate cancer in “tough-to-call” cancer cases when immunostaining is used to identify localized prostate adenocarcinoma clusters in whole mount prostate sections. Using immunohistochemical analyses, they found that immunostaining of caPCNA within the prostate revealed a strongly positive expression pattern in prostate cancer cells as compared to low or negative expression levels in normal prostatic epithelium. Furthermore, the fraction of cells staining positively with caPCNA antibody in prostatic adenocarcinoma (mean, 23%) was significantly higher than that in benign prostatic epithelium (mean, 2%; P <0.001) or high-grade prostatic intraepithelial neoplasia (PIN) (mean, 6%; P <0.05). Moreover, the intensity of caPCNA expression in prostatic adenocarcinoma (mean, 2.9) was significantly higher than that in benign prostatic tissue (mean, 0.7; P <0.001) or high-grade PIN (mean, 2.0; P <0.001). Benign prostatic epithelium showed only minimal or negative reactivity. There was significant correlation between the percentage of caPCNA expression and primary Gleason grade (P = 0.01), and with Gleason score (P = 0.02). Adenocarcinomas with positive vascular invasion had a significantly higher percentage of cells staining with caPCNA antibody (P < 0.0001) and a higher intensity of caPCNA expression (P = 0.04). The clinical sample studies were consistent with the results from cell culture model systems showing that the caPCNA isoform was negatively (not) expressed in many normal cell lines derived from a variety of tissues, and that caPCNA expression was highly expressed in many cancer cell lines representing a comparable variety of tissues.

These findings indicate that monitoring caPCNA expression may have diagnostic applications for prostate cancer. With further validation studies and additional experimentation, caPCNA immunostaining may become a valuable adjunctive diagnostic tool that can facilitate the accurate and timely evaluation of “difficult-to-call” clinical specimens and as a result, potentially improve the frequency of positive outcomes for patients with prostate cancer.



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George E. Sandusky as part of Beyond the Abstract on 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.

Elevated expression of cancer-associated proliferating cell nuclear antigen in high-grade prostatic intraepithelial neoplasia and prostate cancer - Abstract Prostate Cancer Section

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