EXPRESSION OF THE ALPHA-6, BETA-1 AND BETA-4 INTEGRIN SUBUNITS, BASEMENT-MEMBRANE ORGANIZATION AND PROTEOLYTIC CAPACITIES IN LOW AND HIGH METASTATIC HUMAN COLON-CARCINOMA XENOGRAFTS

Malignant transformation is associated with alterations in both cell-c ell and cell-matrix interactions. The E2 and C5 clones, derived from t he human colon adenocarcinoma LoVo cell line, show, respectively, low and high metastatic capacity as experimental xenografts in vivo In thi s study, we have assessed the adhesion and spreading of E2 and C5 cell s on basement membrane laminin, expression of the laminin receptor int egrins alpha 6 beta 1 and alpha 6 beta 4 and expression of gelatinolyt ic and plasminogen-dependent activities. On days 5 and 7 after subcuta neous grafting to immunosuppressed newborn rats, well-differentiated E 2 tumors displayed a polarized expression of these integrin subunits, with the exception of the beta 1 subunit which remained pericellular. In contrast, C5 tumors were unorganized and the three integrin subunit s remained nonpolarized and pericellular. Row cytometry results showed that the expression of alpha 6 beta 1 and alpha 6 beta 4 integrins wa s weaker in the highly metastatic C5 clone than in the E2 clone wherea s laminin expression was not significantly different. Underexpression and pericellular localization of these integrin receptors in C5 cells as compared to E2 cells may explain the difference in their binding an d spreading capacity on laminin, organization of peritumoral basement membrane and the maintenance of a differentiated phenotype. Whereas si milar levels of gelatinolytic and plasminogen activator activities hav e been detected in the culture supernatant of the two clones, histozym ograms showed that plasminogen-dependent caseinolysis appeared earlier in sections of C5 and parental tumors than in those of E2 xenografts. These results suggest that enhanced aggressiveness of C5 tumors in vi vo may be linked to both an impairment of basement membrane setting du e to integrin underexpression and distribution and of proteolytic acti vities modulated by tumor/host interactions.