Loss of tissue transglutaminase as a biomarker for prostate adenocarcinoma

Abstract

BACKGROUND Additional molecular tissue biomarkers for prostate carcinoma are needed to stratify patients with clinically suspicious findings, such as an elevated prostate specific antigen (PSA) with a negative biopsy, according to risk. METHODS Prostate tissues from 43 cancer cases and 47 controls with no evidence of cancer were labeled for transglutaminase by immunohistochemistry. Immunoreactivity was quantified using the Autocyte Pathology Workstation. In addition, quantitative fluorescence image analysis was used to compare transglutaminase concentrations in cells obtained by fine‐needle aspiration from excised prostates. Loss of gene expression was evaluated by reverse transcriptase–polymerase chain reaction and growth with 5‐azacytidine. RESULTS Visually, benign glands from controls generally expressed tissue transglutaminase, whereas regions with adenocarcinoma generally were negative. With quantitative immunohistochemistry, 41 of 43 adenocarcinoma of the prostate (CaP) cases expressed lower mean percentage areas positive for transglutaminase than did 30 of 30 benign prostatic hyperplasia (BPH) and 17 of 17 prostatitis cases (P < 0.0001; odds ratio [OR], 1577; 95% confidence interval (CI), 74–33,820; relative risk [RR], 25; 95% CI, 6–95). Quantitative immunofluorescence of 3277 cells collected by FNA from 19 CaP cases and 645 cells from 5 cases of BPH showed that the mean content of transglutaminase was 93 femtograms (fg) for the CaP‐derived cells and 138 fg for the BPH cells (P < 0.0001). Receiver operating curve analysis of the immunohistochemistry data showed an optimized threshold produced 95% sensitivity with 100% specificity. Growth of LNCaP cells with 5‐azacytidine failed to stimulate transglutaminase expression, suggesting that loss of expression was likely not attributable to promoter methylation. CONCLUSIONS Measurements of transglutaminase on tissue sections provides additional diagnostic information that is potentially useful for risk assessment of patients with suspicious clinical findings, such as nodules or positive PSA and negative biopsies, without overdetecting disease. Cancer 2000;89:412–23. © 2000 American Cancer Society.

Augmentation of Tissue Transglutaminase Expression and Activation by Epidermal Growth Factor Inhibit Doxorubicin-induced Apoptosis in Human Breast Cancer Cells

“…Conversely, RA-mediated TGase expression was suppressed in fibroblasts expressing an oncogenic form of Ras (16,17), implying that retinoid-stimulated TGase expression was inconsistent with the Ras-transformed phenotype. As a result of these and similar findings, such as the proposed use of TGase hypoexpression as a biomarker for prostate cancer (18), it has become generally accepted that TGase promotes cellular processes that limit cell number. However, recent evidence suggests that TGase may not be detrimental to the growth of all cell types.…”

Proteomic Profiling of Potential Molecular Targets of Methyl-Selenium Compounds in the Transgenic Adenocarcinoma of Mouse Prostate Model

“…With immunohistochemistry staining and immunofluorescence assays, Birckbichler et al (30) showed that expression and activity of TGM4 in prostate adenocarcinoma was significantly lower than normal prostate, benign prostatic hyperplasia, and inflammation tissues. The tumor suppressor PTEN induces TGM4 expression.…”

GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis

“…Upon secretion, TG2 is activated by the high level of Ca 2ϩ in the extracellular space and functions as a cross-linking enzyme in the matrix (28). There are numerous reports of downregulation of TG2 in aggressive tumors and metastases (30)(31)(32)(33). Recombinant TG2 applied to rat mammary adenocarcinomas implanted in dorsal skin window chambers produced significant growth delay in the tumors (34), and transfection of TG2 into a highly malignant hamster fibrosarcoma cell line led to significant reduction of tumor incidence (35).…”