TRANSITION FROM THE NONINVASIVE TO THE INVASIVE PHENOTYPE AND LOSS OFALPHA-CATENIN IN HUMAN COLON-CANCER CELLS

Loss of epithelioid organization in carcinoma cell lines has been rela ted to invasiveness and poor differentiation of tumors. We investigate d the invasion in vitro of various human colon cancer cell lines. Most cell lines were noninvasive into chick heart fragments, and this corr elated with an epithelioid morphotype, Only cell lines COLO320DM, SW62 0, and variants of HCT-8 and DLD-1 were invasive and nonepithelioid. W e examined in these cell lines whether invasiveness was related to cha nges in the structure and function of the E-cadherin/catenin complex, E-cadherin functions as an invasion suppressor and as a cell-cell adhe sion molecule when Linked to the cytoskeleton via alpha-catenin plus b eta- or gamma-catenin, All noninvasive cell lines showed E-cadherin li nked to these catenins. The E-cadherin-dependent cell-cell adhesion fu nction in these cell lines was demonstrated by two assays ill vitro. I t was interesting that all invasive cell lines showed a dysfunctional E-cadherin/catenin complex. COLO320DM, SW480, and SW620 cells were def ective in E-cadherin expression, whereas the invasive variants of HCT- 8 and DLD-1 lacked the alpha-catenin protein, From clonal epithelioid HCT-8 cultures with functional E-cadherin/catenin complexes, we subclo ned, repeatedly, round cell variants that were again invasive and expr essed no alpha-catenin protein. Our data suggest that reproducible tra nsformations toward a more invasive phenotype in HCT-8 cells are assoc iated with down-regulation of alpha-catenin. The mechanisms of this tr ansformation and the level of alpha-catenin down-regulation are curren tly investigated.