Integrin alpha 6 beta 4 plays an important role in the interaction of epithelia with basement membranes, and its expression appears to be profoundly altered during tumor progression. Using a quantitative immunochemical assay, we investigated the expression of the beta 4 subunit associated with alpha 6 in 25 primary carcinomas, and in matching normal mucosae. alpha 6 beta 4 was expressed in all the carcinoma and mucosa samples. The highest beta 4 levels were detected in tumors at high clinical stage (Dukes' stage C). Furthermore, beta 4 reactivity inversely correlated with the degree of differentiation. By immunohistochemistry,beta 4 expression was particularly strong in the epithelium lining the upper third of the crypts and the absorbing surface of normal mucosa. In villous adenomas, beta 4 immunostaining tended to be enhanced in the epithelium lining the outer surfaces of neoplastic villi, but only 5 of 8 samples tested scored positive. In carcinomas, beta 4 expression was detected in 18 of 21 samples tested, and was strongly influenced by the pattern of tumor growth and by the type and level of differentiation. Carcinomas, or areas of carcinomas, with cohesive and differentiated growth pattern demonstrated weak beta 4 expression at the tumor-stroma interface. Carcinoma cells at the lumenal surface of the intestine, and carcinomas, or areas of carcinomas, composed of small clusters of cells surrounded by stroma, demonstrated strong beta 4 expression. Altogether, our observations indicate that in colorectal tumors the expression of the beta 4 subunit is strongly influenced by microenvironmental factors and tends to increase in high stage, poorly differentiated lesions.