Tumor cell surface alpha 4 beta 1 integrin mediates adhesion to vascular endothelium: demonstration of an interaction with the N-terminal domains of INCAM-110/VCAM-1.

Abstract

Hematogenous metastasis involves adhesive interactions between blood-borne tumor cells and the vessel wall. By the use of in vitro assays, the adhesion of human melanoma, osteosarcoma, and kidney carcinoma (but not colon carcinoma) cell lines was shown to involve the cytokine-inducible endothelial cell surface protein inducible cell adhesion molecule 110 (INCAM-110) and the alpha 4 beta 1 integrin, molecules normally involved in endothelial-leukocyte interactions. Tumor adhesion to human endothelial cell monolayers was increased 1.9- to 8.2-fold by endothelial activation with the cytokine tumor necrosis factor (TNF) and inhibited by the anti-INCAM-110 monoclonal antibody (mAb) E1/6. Each of these tumor cells expressed members of the beta 1 integrin family of adhesion molecules, and antibodies to the alpha 4 and beta 1 integrin subunits inhibited tumor-endothelial adhesion (48-87% inhibition). A cDNA encompassing the three N-terminal Ig-like domains of vascular cell adhesion molecule 1 (VCAM-1) encoded a protein recognized by the anti-INCAM-110 mAb E1/6 and, when captured onto plastic, supported melanoma cell adhesion by an alpha 4 integrin-dependent mechanism. In contrast to mAb E1/6, a second anti-INCAM-110 mAb Hu8/4 neither inhibited adhesion to activated endothelium nor bound the first three Ig-like domains of INCAM-110/VCAM-1. These data indicate that the adherence of several human tumors to activated endothelium is mediated by an interaction of alpha 4 beta 1 integrin and the N-terminal Ig-like domains of endothelial INCAM-110/VCAM-1. Tumor acquisition of the alpha 4 integrin subunit and endothelial expression of INCAM-110 may affect the frequency and distribution of metastasis.

Adhesion of T and B lymphocytes to extracellular matrix and endothelial cells can be regulated through the beta subunit of VLA

“…Recently, it has been observed that VLA-4 is also able to interact with glycoproteins expressed at the surface of various types of ceils including endothelium. One of these ligands has been identified as the vascular cellular adhesion molecule-1 (VCAM-1) (Elices et al, 1990;Taichman et al, 1991).…”

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

“…In interpreting our findings, several factors, particularly epidemiology of melanoma, natalizumab‐associated progressive multifocal leukoencephalopathy (PML), various aspects of the TOUCH Risk Management (RiskMAP) Action Plan, and the Safety Surveillance Program in this RiskMAP (Table 3), potential pathophysiology, and an overview of pharmacovigilance efforts for opportunistic complications of medications, should be considered 6, 7, 8, 9, 10, 11, 13, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47.…”

“…Blocking α 4 integrins on the surface of lymphocytes prevents their adhesion to vascular‐cell adhesion molecule 1 (VCAM‐1), which is expressed on the surface of vascular endothelial cells in brain and spinal cord blood vessels (the acknowledged mechanism of action for the favorable effect on MS). Studies of α 4 integrin expression show that it has different roles in melanoma 30, 31, 32, 33. The underlying pathophysiology of a potential causal relationship is uncertain.…”

“…2) Normal melanocytes and early stage melanomas do not express α 4 integrin, whereas metastatic melanomas do 30, 31, 32, 33, 34, 35, 36. Expression of α 4 β 1 integrin shows an inverse correlation with invasive potential of an aggressive melanoma cell line (B16) 30, 33. Expression of the integrin α 4 β 1 on melanoma cells can inhibit the invasive stage of melanoma 34, 37.…”

The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin

“…However, the exact role of integrins in this process remains under investigation. One member of this family is the very late activation antigen-4 (VLA-4, α 4 β 1 ) expressed under physiological conditions on different subtypes of leukocytes, but is also found on melanoma, osteosarcoma, and rhabdomyosarcoma cells [8][9][10][11]. VLA-4 is able to bind to its ligand vascular cell adhesion molecule-1 (VCAM-1) expressed by activated endothelium thereby mediating adhesion and a subsequent transmigration of tumour cells [8,12].…”