Caveolin-1, a 21- to 24-kd integral membrane protein, is primarily implicated as a tumor suppressor gene. Transformed cells normally contain reduced or no caveolin-1. Re-expression of caveolin-1 is found in advanced human and mouse prostate adenocarcinomas. To explore its potential role in tumorigenesis and tumor progression of human lung cancers, we used the well-characterized cell line (CL) series of lung adenocarcinoma cells with increasing cellular invasiveness to show that expression of caveolin-1 mRNA and protein was up-regulated with enhanced invasion/metastatic capability of CL cells. Reintroducing the caveolin-1 gene into the less invasive, caveolin-1-negative CL cells enhanced their invasive capability at least by twofold, as revealed by an in vitro chamber invasion assay. Thus, a correlation exists for both constitutive and induced expression of caveolin-1 in CL cells. Immunohistochemical examination of caveolin-1 was performed in 95 specimens obtained retrospectively from patients who had lung adenocarcinoma either with (35 patients) or without (60 patients) ipsilateral hilar/peribronchial tumor-metastasized lymph nodes. Caveolin-1 immunoreactivity was either totally absent or just barely detectable in a few lung adenocarcinoma cells from cases diagnosed as lung adenocarcinoma without regional lymph node metastasis. In contrast, increased caveolin-1 immunoreactivity both in number and intensity was detected in primary lung adenocarcinoma cells as well as in cancer cells that metastasized to regional lymph nodes from the cases diagnosed as advanced lung adenocarcinoma with nodal metastases. Multivariate analysis considering caveolin-1 immunoreactivity in addition to the established prognostic parameters such as pT stage, pN in these patients confirmed that caveolin-1 is an independent functional predictor of poor survival. We further revealed that up-regulated caveolin-1 in CL cells is necessary for mediating filopodia formation, which may enhance the invasive ability of lung adenocarcinoma cells.