Endothelial Cell Adhesion Molecules and Their Role in Organ Preference of Metastasis

Abstract

Endothelial cell adhesion molecules expressed in distinct vascular branches of select organs are implicated in organ preference of metastasis. Two constitutively expressed adhesion molecules of the lung vasculature are described here. The first is the murine B 16 melanoma cell-binding endothelial cell adhesion molecule Lu-ECAM-1. The 90kDa Lu-ECAM-1 selectively promotes adhesion and lung metastasis of B 16 melanoma cells. Melanoma cell attachment to immobilized Lu-ECAM-1 is inhibited in a dose dependant manner by anti-Lu-ECAM-1 mAb 6D3, soluble Lu-ECAM-1, and lacto-N-fucopentose. In vivo blocking of Lu-ECAM-1 by its mAb 6D3 prevents lung colonization of B16-F10. However, Lu-ECAM-1 either binds nor affects metastasis of other lung colonizing tumor cells (e.g., KLN205 carcinoma cells), or tumor cell lines that metastasize to other organs than the lung (e.g., liver-metastatic B16-L8-F10, RAW117-H10), and does not bind lymphocytes and neutrophils. The second adhesion molecule is rat dipeptidyl peptidase IV(DPP IV). This sialoglycoprotein binds lung-metastatic rat prostate and breast carcinoma cells via fibronectin which is expressed in significantly higher amounts on the surface of metastatic than non-metastatic tumor cells. Increased fibronectin expression is associated with increases in tumor cell β₁ and β₃ integrins. DPP IV binding is mediated by a fibronectin sequence other than RGD and is independent of its peptidase domain. These constitutively expressed adhesion molecules are believed to be responsible for site-specific vascular arrest of blood-borne cancer cells and, through as yet unknown signaling events, may cause upregulation of other (transiently expressed) adhesion molecules to enhance tumor cell binding to endothelium and/or initiate gap junctional communication to promote extravasation and secondary tumor growth.