The c-ets-1 transcription factor has been involved in the in vitro transactivation of matrix-degrading protease genes that might play an important role in tumor invasion. Using in situ hybridization, we analyzed serial frozen sections for c-ets-1, collagenase 1, and urokinase-type plasminogen activator gene expression in 54 lung carcinomas including 34 non-neuroendocrine carcinomas (18 squamous carcinomas, 10 adenocarcinomas, 3 large cell carcinomas, and 3 basaloids) and 20 neuroendocrine carcinomas (7 small cell lung carcinomas, 4 large cell neuroendocrine carcinomas, 4 well differentiated neuroendocrine carcinomas, and 5 carcinoids). c-ets-1 gene was expressed in stromal cells in 44/54 lung carcinomas including one metastasizing carcinoid. c-ets-1 transcripts were also detected in cancer cells more frequently in neuroendocrine than in non-neuroendocrine carcinomas (P = 0.0059) and in stages III and IV and metastasis more frequently than in stages I and II ( P = 0.0065). Collagenase 1 gene was expressed in 16/34 non-neuroendocrine tumors and in 1/20 neuroendocrine tumors, either in stromal (12/17) or in cancer cells (6/17). Urokinase-type plasminogen activator mRNAs were expressed in 45/54 lung carcinomas in stromal and/or cancer cells. In non-neuroendocrine tumors, c-ets-1 and collagenase 1 gene expressions in stromal cells were correlated. These results demonstrate that the transcription factor c-ets-1, collagenase 1, and urokinase-type plasminogen activator are involved in lung cancer invasion and suggest that c-ets-1 protein might transactivate collagenase 1 gene during tumor invasion.