Increased expression of integrins by heparin-binding EGF like growth factor in human esophageal cancer cells

The adhesion of cancer cells to vascular endothelium is an important step in the hematogenous metastasis of cancer. The authors investigated the alteration of integrin expression in human esophageal cancer cells, following the selectin-mediated initial adhesion to endothelial cells. The expression of α2β1 and α3β1 integrins in esophageal cancer cells (TE-1 and T.Tn), strongly expressing EGF-receptors, were markedly increased by the addition of the heparin-binding EGF like growth factor (HB-EGF). The increase of integrin expression in esophageal cancer cells was inhibited by the addition of the tyrosine kinase inhibitor, genistein. HB-EGF treatment of esophageal cancer cells resulted in the augmentation of cancer cell adhesion to immobilized collagen. When esophageal cancer cells were co-cultured with endothelial cells, similar levels of augmentation of cancer cell adhesion to collagen were observed. The augmentation of cancer cell adhesion to collagen was inhibited by the addition of an anti-HB-EGF neutralizing antibody. Our interpretation of the results described above is that the cancer cells receive stimulation from cytokines, such as HB-EGF, produced by endothelial cells, following initial adhesion of cancer cells via selectins. This results in a secondary increase in the expression of cell adhesion molecules, such as the β1 integrin family, and leads to augmentation in the adhesive activities of cancer cells at vessel walls. We postulate that this sequence of events involves the enhanced transmigration of cancer cells to extravascular tissues, following the selectin-mediated adhesion to the endothelium.