Integrins are a family of transmembrane glycoproteins that serve as cell-cell and cell-substratum adhesion molecules and help regulate cellular differentiation and proliferation. In malignant cells, which exhibit abnormal differentiation and growth properties, the expression of an altered integrin repertoire could therefore be expected. From a tumorigenic human fibrosarcoma cell line we isolated a unique complementary DNA corresponding to the alpha 6 integrin subunit. Northern blot analysis using this complementary DNA as probe indicated that alpha 6 integrin mRNA was abundantly expressed in all neoplastically transformed fibroblast cell lines but not in normal diploid fibroblasts. In addition to its potential as a marker for the neoplastic transformation of human fibroblasts, the alpha 6 integrin mRNA was also found to be consistently expressed at higher levels in tumorigenic fibroblasts than in immortalized but nontumorigenic fibroblasts. This differential expression of alpha 6 integrin was reflected at the cell surface protein level using cytofluorometric analysis with specific monoclonal antibody. In contrast, the levels of cell surface expression of other integrins were unchanged (such as alpha 3 and beta 1) or down-regulated (such as alpha 5) when transformed cells were compared with normal fibroblasts. The incremental up-regulation of alpha 6 integrin was selective and paralleled the progression of normal cells to immortalized cells and finally to tumorigenic cells. This elevated alpha 6 subunit associated with the beta 1 subunit to form a heterodimer receptor for laminin. Since fibrosarcoma cell invasion of basement membrane has been shown to involve alpha 6 beta 1 integrin, then the induction or up-regulation of alpha 6 expression is an important step in tumor progression and evolution to the invasive phenotype in fibrosarcoma.