Adhesion of cancer cells to endothelial monolayers: A study of initial attachment versus firm adhesion

For most cancer patients, the ultimate cause of death is not the primary tumor itself, but metastasis, or the spread of cancer from the primary tumor throughout the body. The formation of tumor foci at sites distant from the primary tumor is a multistep process which includes dissemination of the cancer cells through the blood stream and hence, interactions with the endothelium lining the blood vessels walls. At least two theories have been proposed for explaining the interaction between cancer cells and endothelium. According to one theory, the tumor cells roll along the endothelium and the rolling velocity decreases until the cells become firmly attached to the vessel wall. In another theory, the circulating cancer cells must first lodge inside small vessels before they attach to the endothelium. In the latter case, the cells would only metastasize in the smaller vessels where lodging can occur. To gain further insight into the process of metastasis, the adhesion of human breast cancer cells to human umbilical vein endothelial monolayers was investigated in terms of both initial attachment followed by firm adhesion and firm adhesion following incubation in a static environment. The parallel plate flow chamber was employed to perform two different adhesion assays that would simulate these two adhesion mechanisms. Adhesion assays were carried out at a variety of physiological shear stresses found in the microvasculature and both highly metastatic and nonmetastatic cells were investigated. Results showed that initial attachment was only observed at very low shear stresses whereas firm adhesion occurred at a number of physiological shear stresses. These results suggest that the adhesion of the human breast cancer cells used in this study to endothelium most likely takes place via a lodging-firm adhesion mechanism in the capillaries and venules. However, it is important to note that other factors such as pulsatility and vessel compliance may contribute to the attachment. It was also shown that, for these specific breast cancer cells, adhesion did not correlate with metastatic potential. This suggests that while blocking the adhesion of highly metastatic cells may inhibit their ability to metastasize, adhesion properties alone do not provide an indication as to whether a cell is metastatic or nonmetastatic under the conditions studied here.