Extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN, CD147) is a multifunctional protein that has been implicated in cancer invasion and metastasis by the induction of MMPs. To address its role in primary tumors of human non-small-cell lung cancer we assessed whether EMMPRIN expression is associated with the expression of MMP-2 and MMP-9 and with patient survival. Primary tumors of 150 patients (65 adenocarcinomas, 58 squamous cell carcinomas, and 27 of other subtypes) with completely resected lung cancers were stained by immunohistochemistry. We assessed intensity, extent, and cellular localization of EMMPRIN staining and determined MMP-2 and MMP-9 expression. 145 tumors expressed EMMPRIN (strong expression in 61 tumors), which was predominantly localized at the tumor cell membranes in 102 (68%) patients. We could not determine any correlation between EMMPRIN expression and MMP-2 or MMP-9 expression. The prognostic relevance of EMMPRIN was evaluated by Kaplan-Meier and multivariate Cox regression analysis in patients with adenocarcinoma (n ¼ 57) and squamous cell carcinoma of the lung (n ¼ 56). The median follow-up period was 36.0 months (range 4-156 months). Staining scores for EMMPRIN and MMP-2 and MMP-9 derived from staining intensities and percentages of positive cells did not predict outcome of patients. In contrast, univariate survival analysis demonstrated that membranous localization of EMMPRIN was associated with shortened survival in patients with adenocarcinoma (P ¼ 0.03; log-rank test), but not in squamous cell carcinoma. For the former patients, membranous EMMPRIN expression was also an independent predictor of patient survival (P ¼ 0.04; Cox regression analysis). The findings point to a role of EMMPRIN for the progression of adenocarcinoma of the lung that is unrelated to its function as inducer of MMPs. Modern Pathology (2008) 21, 1130-1138 doi:10.1038/modpathol.2008 published online 20 June 2008 Keywords: extracellular matrix; matrix metalloproteases; lung cancer; survival analysis; prognosis Lung cancer is still the most common cause of cancer-related death in Europe and in the United States 1,2 with non-small-cell lung cancer affecting approximately 80% of all lung cancer patients. 1,3 In stage I, only 60-65% of non-small-cell lung cancer patients, whose tumors were completely resected, are still alive 5 years after surgery. 4,5 This obvious aggressiveness is poorly understood and prompted us to search for potential molecular markers and mechanisms for early systemic spread of nonsmall-cell lung cancer.We previously found that disseminated cancer cells from non-small-cell lung cancer can be detected in bone marrow and lymph nodes and that the detection of such cells is specifically associated with poor survival in early stage patients. Moreover, we observed that one of the most frequently
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