The breast cancer beta(4) integrin and endothelial human CLCA2 mediate lung metastasis

Adhesion of blood-borne cancer cells to the endothelium is a critical deter minant of organ-specific metastasis. Here we show that colonization of the lungs by human breast cancer cells is correlated with cell surface expressi on of the alpha (6)beta (4) integrin and adhesion to human CLCA2 (hCLCA2), a Ca2+-sensitive chloride channel protein that is expressed on the endothel ial cell luminal surface of pulmonary arteries, arterioles, and venules, Tu mor cell adhesion to endothelial hCLCA2 is mediated by the beta (4) integri n, establishing for the first time a cell-cell adhesion property for this i ntegrin that involves an entirely new adhesion partner. This adhesion is au gmented by an increased surface expression of the alpha (6)beta (4) integri n in breast cancer cells selected in vivo for enhanced lung colonization bu t abolished by the specific cleavage of the beta (4) integrin with matrilys in. beta (4) integrin/hCLCA2 adhesion-blocking antibodies directed against either of the two interacting adhesion molecules inhibit lung colonization, while overexpression of the beta (4) integrin in a model murine tumor cell line of modest lung colonization potential significantly increases the lun g metastatic performance. Our data clearly show that the beta (4)/hCLCA2 ad hesion is critical for lung metastasis, yet expression of the beta (4) inte grin in many benign breast tumors shows that this integrin is insufficient to bestow metastatic competence on cells that lack invasiveness and other e stablished properties of metastatic cells.