Thomas Fixemer

Estrogen Receptor Expression in Prostate Cancer and Premalignant Prostatic Lesions

Estrogens have been implicated in prostatic cancerogenesis and tumor progression. The mechanisms underlying estrogen signaling in human prostate tissue, however, remain poorly understood. Using immunohistochemical and in situ hybridization (ISH) techniques, the present study demonstrates the classical estrogen receptor (ERalpha) in premalignant lesions and prostatic adenocarcinoma through the various stages of the disease. Conversely, the novel characterized ERbeta subtype was undetectable in human prostate tissue. High-grade prostatic intraepithelial neoplasia revealed ERalpha mRNA and protein expression in 28% and 11% of cases evaluated. Focal ER immunoreactivity was detected in a minority of low- to intermediate-grade adenocarcinoma. High-grade (primary Gleason grade 4 and 5) tumors revealed ER protein expression in 43% (62% respectively) of cases. The most significant ERalpha gene expression on mRNA and protein levels was observed in hormone refractory tumors and metastatic lesions, including lymph node and bone metastases. Results of the current study suggest that estrogens can affect prostatic cancerogenesis and neoplastic progression through an ER-mediated process in human prostate tissue.

Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression.

Members of the TRP superfamily of cation channels have homeostatic and regulatory functions in cells and changes in their expression may contribute to malignant growth. Previously, we have demonstrated that the gene of the Ca2+-selective cation channel CaT-L or TRPV6 is not expressed in benign prostate tissues including benign prostate hyperplasia, but is upregulated in prostate cancer. Here, we report on the differential expression of TRPV6 mRNA in prostate tissue obtained from 140 patients with prostate cancer. Using in situ hybridization, TRPV6 transcripts were undetectable in benign prostate tissue, high-grade prostatic intraepithelial neoplasia (n=57), incidental adenocarcinoma and all tumors less than 2.3 cubic centimeter (cc). In prostatectomy specimens from 97 clinically organ-confined tumors, TRPV6 expression correlated significantly with the Gleason score (P=0.032), pathological stage (P<0.001) and extraprostatic extension (P=0.025). Lymph node metastasis (n=17) and androgen-insensitive tumors (n=27) revealed TRPV6 expression in 63 and 67% of cases, respectively. The latter, however, revealed markedly and significantly decreased levels when compared with untreated tumors (P=0.044). In summary, the data demonstrate that TRPV6 expression is associated with prostate cancer progression. Accordingly, TRPV6 represents a prognostic marker and, as a plasma membrane Ca2+ channel, a promising target for new therapeutic strategies to treat advanced prostate cancer.

Relation between Bcl-2, cell proliferation, and the androgen receptor status in prostate tissue and precursors of prostate cancer

Several recent studies have suggested an important role of the apoptosis suppressing Bcl‐2 gene product in prostate cancer progression to an androgen‐insensitive disease.

Estrogen receptor gene expression and its relation to the estrogen‐inducible HSP27 heat shock protein in hormone refractory prostate cancer

The recent discovery of the classical estrogen receptor α (ERα) in androgen‐insensitive prostate cancer has shed new light on the role of estrogens in endocrine therapy failure. To get more information on downstream events of estrogen signaling in these tumors, we investigated the relation between ERα gene expression, and the estrogen‐inducible heat shock protein HSP27 in recurrent prostatic adenocarcinomas.

In situ hybridization analysis of genes coding collagen IV α1 chain, laminin β1 chain, and s‐laminin in prostate tissue and prostate cancer: Increased basement membrane gene expression in high‐grade and metastatic lesions

Recent immunohistochemical data have shown that invasive prostate cancer cells are separated from the host tissue by basement membranes (BM), and express associated adhesive molecules that bind to these de novo synthesized extracellular matrices.

Telomerase Activity and Telomerase Subunit Gene Expression Levels Are Not Related in Prostate Cancer: A Real-Time Quantification and In Situ Hybridization Study

Because the mechanisms of telomerase activation in prostate cancer are mainly unknown, we investigated the relationships between telomerase activity and expression levels of human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) mRNA in benign and malignant alterations of the human prostate gland. Using the LightCycler technology, hTERT mRNA expression was quantified in 46 radical prostatectomy and 10 benign prostatic hyperplasia (BPH) cases; hTR expression was quantified in a subset of these tissue samples. Telomerase activity was measured using a quantitative telomeric repeat amplification protocol ELISA assay. Similar to hTR, which was expressed in all tissue samples tested, hTERT mRNA was detected in 98% of the prostate cancer samples and in 30% of the BPH samples. Regarding clinicopathologic variables, telomerase activity was significantly correlated with Gleason score (<7 vs ≥7, p = 0.02). No relationships emerged between normalized hTR or hTERT expression levels and tumor stage, Gleason score, lymph node status, or preoperative serum prostate-specific antigen. Remarkably, one third of all cancer and BPH tissue samples with hTR and hTERT expression lack telomerase activity. Quantitative analyses contradict the assumption that a certain threshold level of hTR or hTERT mRNA is required for telomerase activation, thus indicating that telomerase regulation in prostate cancer occurs more likely on a posttranscriptional level. Nevertheless, the observation that hTR and hTERT mRNA levels are significantly (p < 0.002) correlated suggests some common mechanisms in the up-regulation of hTR and hTERT expression. Because in situ hybridization revealed strong hTERT expression in all cells of the tumor glands but also in high-grade prostatic intraepithelial neoplasia foci, this up-regulation seems to occur early in prostate carcinogenesis.

4 In situ hybridization of human telomerase reverse transcriptase mRNA in prostate carcinoma

Publisher Summary In prostate cancer, the most common malignancy in elderly men in Western countries, increased telomerase activity is already evident at the very early stages of the disease—namely, high-grade prostatic intraepithelial neoplasia (HGPIN). Because it is found in almost all prostate cancers, telomerase is a candidate for improved diagnostic and therapeutic strategies. However, its clinical use is still limited because of several reasons. The telomerase regulatory mechanisms during cancer development are still largely undefined based on both transcriptional and posttranscriptional mechanisms. The existence of different regulatory mechanisms possibly occurring in either a tissue-specific or tumor-specific manner is likely. Using in situ hybridization, it has been demonstrated that strong human telomerase reverse transcriptase (hTERT) mRNA expression in the tumor glands. A homogeneous staining distribution pattern is observed irrespective of varying Gleason grades among different tumor areas. At the cellular level, positive staining of hTERT is localized almost exclusively in the cytoplasm.