Functional suppression of integrin beta 4-mediated adhesion caused by in vivo sequential selection for cancer cell intravasation

Intravasation is essential for hematogenous metastasis in cancer cells, but its cellular determinants have not been well elucidated because of a lack of suitable experimental cell systems. Int-3LL was originally developed by in vivo sequential selection for intravasation from Lewis lung carcinoma (3 LL) cells. Here, we found that these variant cells showed a highly penetrat ing ability in vitro as well as an augmented intravasating potential in viv o. In three-dimensional collagen-gel Int-3LL cells formed diffusive colonie s with less plating efficiency than their parental cells. Despite these pro perties, Int-3LL cells showed an ability of invasive migration in vitro sim ilar to parental cells. On the other hand a reduced adhesiveness and less s preading on extracellular matrices were revealed in Int-3LL cells. Analyses using anti-integrin antibodies indicated that the dysadhesion phenotype in Int-3LL cells was associated with integrin beta4 dysfunction, which is kno wn to produce epithelial detachment. Also, the types and the levels of inte grins were not indistinguishable between Int-3LL and parental 3LL cells. Th us, the impaired function of integrin beta4-mediated adhesion is considered to be an important factor in intravasation during metastasis.