Lu-ECAM-1-mediated adhesion of melanoma cells to endothelium under conditions of flow

Abstract

Metastasis is thc proccss hy which primary cancer cclls establish new tumor colonies in select, secondary organ sites.Selection of a target organ for metastasis occurs in nonrandom fashion and is dictated by compatible tumor-cell and host-cell characteristics. A primary step in this selection process is adhesion of blood-borne tumor cells to distinct, organ-specific adhesion molecules, constitutively expressed on the luniinal surface of endothelial cells of the target site (reviewed by Albclda, 1993; Lafrcnic ct a/., 1993; Pauli et ul., 1995). Thcsc adhesion molcculcs arc generally restrictcd in their expression to endothelia of select vascular branches and exhibit adhesion preferences for specific cancer types. This premise is supported by studies in our laboratory detailing the isolation and characterization of the lung-derived, melanoma cell-binding endothelial cell adhesion molecule Lu-ECAM-1 (Zhu et al., 1991(Zhu et al., , 1992. This adhesion molecule is a 90-kDa integral mcmhranc protein that is cxpresscd on endothelia of lung pleural, suhplcural and, to a lcsscr extcnt, peribronchial vcnules. Its prcfcrred expression in these blood vesscls is topographically correlated with the formation of experimental B16 melanoma metastases (Zhu and Pauli, 1993). In vitro, Lu-ECAM-1 promotes the selective, Ca2+-dependent adhesion of lung-metastatic B16 melanoma cells to endothelium but fails to support adhesion of other murine lung-metastatic tumor cells, including KLN205 squamous carcinoma cells and RAW117-P large cell lymphoma cells (Zhu el a/., 1992). Correspondingly, anti-adhesive, anti-Lu-ECAM-1 monoclonal antibodies (MAbs) prepared against lung matrix-modulated bovine aortic endothelial cells (BAEC) (Zhu and Pauli, 1993) cause rapid clearance of i.v.-inoculated B16-Fl0 melanoma cells from mouse lungs and are effective in preventing colonization of the lungs. A similar anti-metastatic effect is observed in mice that are actively immunized with the bovine homolog of ImECAM-I . These mice are protected from lung colonization with melanoma cells in an antibody titer-dependent manner (Zhu et al., 1992).Our adhesion and anti-metastasis studies strongly suggest that Lu-ECAM-I plays a primary role in the colonization of mouse lungs by Bl6 mclanoma cclls (Zhu el a/., 1992).However, they provide no unequivocal proof that the Lu-ECAM-1 adhesion receptor acts by itself in causing vascular arrest of lung-metastatic B16 melanoma cells. It is possible that Lu-ECAM-1 adhesion follows physical entrapment of blood-borne melanoma cells in the microvasculature or is part of a cascade adhesion event that involves multiple adhesion molecules acting in a timely and coordinated fashion to facilitate cancer cell arrest. To answer these questions, wc investigated the adhesion of lung-metastatic B16-Fl0 melanoma cells to endothelial cell monolayers that express different amounts of Lu-ECAM-1 in a radial flow chamber where the forces and time scales of adhesion mimic those in vivo. At physiological shear stresses between 0.32 and 1.0 dynes...

A Novel Consensus Motif in Fibronectin Mediates Dipeptidyl Peptidase IV Adhesion and Metastasis

“…Because all lung-metastatic cancer cells tested in our laboratory, including MDA-MB-231, B16-F10, 4T1, MTF7, LLC1, and K7M2, exhibit high message and protein levels for both FN and integrin ␤ 4 and adhere to both of the respective pulmonary addressins (DPPIV and CLCA), it is conceivable that pulmonary vascular arrest of blood-borne cancer cells is initiated by the DPPIV/poly-FN adhesion and is stabilized by the CLCA/ integrin ␤ 4 adhesion discovered in this laboratory (42,56). Circumstantial support for this notion came from studies of the CLCA/integrin ␤ 4 adhesion under flow conditions (57). These experiments showed that integrin ␤ 4 -expressing tumor cells adhere to CLCA-coated dishes only at low shear stresses.…”

Structure and Function of CLCA Proteins

“…The bCLCA2 (Lu-ECAM-1) ortholog was cloned using antibody that blocked the adhesion-receptor/ligand pair that mediates binding of lung metastatic melanoma cells to bovine aortic endothelial cells (50,70,212,214). The origins of the clone identify bCLCA2 as the endothelial adhesion molecule that binds hematogeneous tumor cells, causing vascular arrest before tumor growth and invasion.…”

Cloning and Characterization of Lung-Endothelial Cell Adhesion Molecule-1 Suggest It Is an Endothelial Chloride Channel

“…11). The purified molecule promotes strong adhesion of B16-F10 cells under static and hydrodynamic conditions (14) and, in soluble form, competi-tively inhibits adhesion of these tumor cells to immobilized Lu-ECAM-1 (11,13). Here, we identify other components of the Lu-ECAM-1 complex and define their interrelationships.…”