Amphiregulin expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 93 cases.

Amphiregulin (AMP) is a heparin-binding glycoprotein that is structurally and functionally related to epidermal growth factor. Its effects are mediated by the tyrosine kinase activity of the epidermal growth factor receptor (EGF-R), and specific nuclear targeting sequences. AMP induces cell proliferation after androgen stimulation of human prostate cancer cell lines. An autocrine proliferative loop involving AMP, androgen, and EGF-R may, therefore, play a role in prostatic carcinogenesis. The purpose of this study was to compare the expression of AMP in benign prostatic epithelium, high-grade prostatic intraepithelial neoplasia (PIN), and adenocarcinoma. We performed an immunohistochemical study of select sections from 93 radical prostatectomies performed at the Mayo Clinic between 1987 and 1991. All patients were previously untreated and found to have pathologic stage T2N0M0 adenocarcinoma after routine handling of surgical specimens. Affinity-purified polyclonal antibody directed against AMP was applied to tissue sections using the streptavidin-biotin method. For each case, the percentage of immunoreactive cells in benign epithelium, PIN, and adenocarcinoma was estimated in 10% increments. Intensity on a scale from 0 (negative) to 3 (strongly immunoreactive) and pattern of expression (nuclear versus cytoplasmic) also were recorded. AMP immunoreactivity was present in benign prostatic epithelium, PIN, and prostatic adenocarcinoma in all cases. The mean percentage of AMP-immunoreactive cells was 53.8% in benign epithelium, 65.9% in PIN, and 74.3% in cancer. Intensity was moderate in all cases. The pattern of expression was usually nuclear in benign epithelium (secretory and basal cells), and usually cytoplasmic or nuclear and cytoplasmic in PIN and adenocarcinoma. There were rare scattered immunoreactive cells in the stroma, ejaculatory duct epithelium, and urethral urothelium. Endothelial cells were invariably unstained. AMP expression in prostate increases progressively from benign epithelium to PIN and cancer. Increased expression of AMP may contribute to the development of prostatic adenocarcinoma. Predominantly nuclear staining was observed in benign epithelium, whereas cytoplasmic or nuclear and cytoplasmic staining was observed in PIN and adenocarcinoma. The differences in nuclear and cytoplasmic localization of immunoreactivity may reflect the presence of two pathways of activation, and hence varying biological functions of AMP.

Bostwick DG ，Qian J ，Maihle NJ 《PROSTATE》

Androgen receptor expression in prostatic intraepithelial neoplasia and cancer.

Sweat SD ，Pacelli A ，Bergstralh EJ ，Slezak JM ，Bostwick DG ... -  《JOURNAL OF UROLOGY》

Immunohistochemical expression of retinoblastoma and p53 tumor suppressor genes in prostatic intraepithelial neoplasia: comparison with prostatic adenocarcinoma and benign prostate.

Tamboli P ，Amin MB ，Xu HJ ，Linden MD ... -  《-》

Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer.

Oxidative stress results in damage to cellular structures and has been linked to many diseases, including cancer. The authors sought to determine whether the expression of three major antioxidant enzymes, copper-zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), and catalase, was altered in human prostate carcinoma and its likely precursor, high grade prostatic intraepithelial neoplasia (PIN). The level of reactive oxygen species damage was evaluated by measuring the expression of the DNA adduct 8-hydroxydeoxyguanosine. The authors evaluated the tissue expression of the antioxidant enzymes in prostate carcinoma by immunohistochemistry, immunogold electron microscopy, and enzymatic assay. The polymerase chain reaction was used to amplify and screen tissue specimens for the genes of SOD1, SOD2, and extracellular SOD (SOD3). Matched paraffin embedded tissue sections were evaluated by RNA in situ hybridization for expression of SOD1 and immunohistochemically for the DNA adduct 8-hydroxydeoxyguanosine. All prostatic tissues, including cancer, displayed immunoreactivity for the three antioxidant enzymes in epithelial cells, with no staining of the stroma, inflammatory cells, or endothelial cells. The number of immunoreactive cells was greater in benign epithelium than in PIN and cancer for each enzyme. The mean percentage and intensity of immunoreactive cells was greatest for SOD2, intermediate for SOD1, and lower for catalase. Staining in cancer was heterogeneous. Immunogold ultrasound studies revealed strong mitochondrial labeling for SOD2, which was greater in benign epithelium than in cancer; SOD1 labeling was invariably weaker, with nuclear labeling in benign epithelium and cytoplasmic labeling in cancer cells. There was no difference in enzyme activity for the three antioxidant enzymes between benign epithelium and cancer. No mutations were found in the 5 exons of SOD1, 5 exons of SOD2, and 3 exons of SOD3, except for 3 of 20 cases with polymorphisms for exon 3 of SOD1. Intense nuclear immunoreactivity for 8-hydroxydeoxyguanosine was present in fewer than 3% of epithelial cells, with no apparent differences among benign epithelium, PIN, and cancer. SOD1, SOD2, and catalase had lower expression in PIN and prostate carcinoma than in benign epithelium. The number of immunoreactive cells in PIN was similar to cancer, indicating that these are closely related. Enzyme activities were variable, with no difference between benign epithelial cells and cancer, although this lack of change in enzyme activity could have been due to the presence of contaminating benign cells within the cancer specimens. The results of reactive oxygen species damage were found only in the epithelium and not in the stroma. Expression of the DNA adduct 8-hydroxydeoxyguanosine was present in fewer than 3% of cells, with no apparent differences among benign epithelium, PIN, and cancer. These findings suggest that oxidative stress is an early event in carcinogenesis.

Bostwick DG ，Alexander EE ，Singh R ，Shan A ，Qian J ，Santella RM ，Oberley LW ，Yan T ，Zhong W ，Jiang X ，Oberley TD ... -  《CANCER》

Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases.

Bostwick DG ，Pacelli A ，Blute M ，Roche P ，Murphy GP ... -  《CANCER》