ABSTRACT
To investigate the association between the expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) and the clinicopathological features in lepidic and invasive components of adenocarcinoma of the lung, we performed immunostaining for type IV collagen, various MMPs, and TIMPs in 27 cases of invasive adenocarcinomas and 5 cases of atypical adenomatous hyperplasia of alveolar epithelial cells (AAH). Mean extent of lepidic growth was 61% and the survival was significantly better in cases with 50% or more lepidic component. The preservation of type IV collagen in lepidic areas correlated inversely with lymphatic or vascular invasion (P = 0.02 and 0.002, respectively). Five-year survival was reduced in cases showing destruction of type IV collagen (P = 0.004) or expression of MMP-2 (P = 0.008) in lepidic areas. MMP-2 co-localized with MT-1-MMP (its activating enzyme) and TIMP-2 in neoplastic cells. Reactivity for other MMPs and TIMPs did not correlate with destruction of type IV collagen or prognosis. Type IV collagen was preserved in all cases of AAH. MMP-2, but not MT-1-MMP, was expressed in two of the five cases of AAH. Immunostaining for type IV collagen MMP-2 is useful in evaluating the prognosis of the lung.
Subject(s)
Adenocarcinoma, Bronchiolo-Alveolar/pathology , Adenoma/pathology , Lung Neoplasms/pathology , Lung/pathology , Matrix Metalloproteinases/biosynthesis , Adenocarcinoma, Bronchiolo-Alveolar/metabolism , Aged , Collagen Type IV/analysis , Female , Humans , Hyperplasia , Immunohistochemistry , Lung/chemistry , Lung Neoplasms/metabolism , Male , Matrix Metalloproteinase 2/analysis , Matrix Metalloproteinases, Membrane-Associated , Metalloendopeptidases/analysis , Microscopy, Confocal , Middle Aged , Neoplasm Invasiveness , Prognosis , Survival Analysis , Tissue Inhibitor of Metalloproteinase-1/analysis , Tissue Inhibitor of Metalloproteinase-2/analysisABSTRACT
The aim of this study was to evaluate the usefulness of determination of telomerase activity and expression of human telomerase RNA component (hTERC) and human telomerase reverse transcriptase (hTERT) for the diagnosis of lung carcinomas. The tissues studied consisted of 115 carcinomas and adjacent nonneoplastic lung, which were removed surgically without previous chemotherapy or radiotherapy. Telomerase activity was determined using a semiquantitative polymerase chain reaction-based telomeric repeat amplification protocol (TRAP) assay. The results obtained were classified into high and low telomerase groups. Localization of expression was examined by using in situ hybridization and immunohistochemistry. The correlation between telomerase activity in lung carcinoma and clinicopathologic features, including prognosis, was investigated. Telomerase activity in lung carcinomas was detected in 107 of 115 (93%) lung carcinomas, but not in any adjacent noncancerous tissues, and was significantly higher in small cell carcinoma than in any other histologic type. This activity also was significantly higher in poorly differentiated than in well-differentiated squamous cell carcinomas and adenocarcinomas. The overall survival rate (P =.020) was significantly lower in the high telomerase group. Messenger RNAs for hTERC and hTERT were mainly detected in the cytoplasm of cancer cells by in situ hybridization, and TERT protein was localized in the nuclei of these cells by immunohistochemical staining. Determinations of telomerase activity by in situ hybridization, immunohistochemistry, and TRAP assay are useful for evaluating the diagnosis and prognosis of lung carcinomas.
Subject(s)
Adenocarcinoma/enzymology , Lung Neoplasms/enzymology , RNA, Messenger/metabolism , RNA , Telomerase/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , Base Sequence , DNA-Binding Proteins , Female , Humans , Immunohistochemistry , In Situ Hybridization , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Lymph Nodes/pathology , Lymphatic Metastasis/genetics , Lymphatic Metastasis/pathology , Male , Middle Aged , Molecular Sequence Data , Neoplasm Staging , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Telomerase/geneticsABSTRACT
BACKGROUND: Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric repeats onto chromosomal ends using a segment of its RNA component as a template. Its activity has become an established indicator of the diagnosis, biologic behavior, and prognosis of several tumors. However, to the authors' knowledge, no previous study has investigated the diagnostic and prognostic importance of the expression of telomerase RNA component (hTR) in transitional cell carcinoma of the upper urinary tract (TCC-UUT). METHODS: The authors investigated hTR expression using in situ hybridization in 130 cases of TCC-UUT, and also its relation to proliferating cell nuclear antigen (PCNA) immunoreactivity, immunoreactivity for p53 oncoprotein, clinicopathologic parameters, and clinical outcome. RESULTS: Positive hTR expression was recognized in 98.4% of the samples and was apparent within the cytoplasm of tumor cells. In normal urothelium, its expression was restricted to the basal cell layers, whereas in the dysplastic lesions of TCC-UUT it was detected with the same intensity and distribution as in the tumor itself. No correlation was found between hTR expression and clinicopathologic findings, PCNA index, or the expression of p53 oncoprotein, although hTR score did tend to increase with disease stage. In univariate and multivariate analyses of disease free and overall survival rates, high hTR expression was associated with significant decreases in both rates. CONCLUSIONS: The expression of hTR appears to be a useful indicator of prognosis for patients with TCC-UUT. In addition, evidence of up-regulation of hTR may also be useful in the diagnosis of this disease.
