We characterized a natural human antibody to adenocarcinomas and investigated the biological role of this Ab/Ag complex in cancer expansion. Human monoclonal antibodies (HuMAbs) were generated with hybridoma fusion methods using regional nodal lymphocytes of colon carcinoma patients. Among 1036 HuMAbs, only one, termed SK1, an IgM, was adenocarcinoma specific in the immunohistochemical study. The antigen recognized by SK1 (Ag-SK1) was a glycoprotein with a molecular weight of 42-46 kDa. The expression of Ag-SK1 on carcinoma cells varied according to the cell growth periods but was independent of cell cycle state as elucidated by two-colour fluorescence-activated cell sorter (FACS) analysis. A dot-blot analysis showed that the concentration of Ag-SK1 per total protein differed considerably among eight colon carcinoma cells examined and that the difference was closely correlated with the invasion capacity of the cells as assessed by a microchemotaxis assay. Furthermore, up to 87% of cell migration was inhibited by SK1 in a dose-dependent manner. These data suggested that Ag-SK1 is metabolized and expressed on highly invasive carcinoma cells. In addition, it appears that, although rare, some patients do mount an anti-cancer antigen response in their draining lymph nodes. A HuMAb such as SK1 may be a good candidate for the treatment of cancer invasion and metastasis.