Cancer cell interactions with injured or activated endothelium.
Blood vessels and lymphatics are the most important pathways for dissemination of cancer cells but the entry and exit of these cells into and from the vasculature requires that they pass through barriers formed by the endothelium and its basement membrane. This review summarizes evidence that this step in metastasis can be regulated by microenvironmental influences which alter the properties of this barrier. These phenomena can be attributed to both 'passive' and 'active' responses of the endothelium. The microvasculature is susceptible to perturbation from environmental agents, host cells and cancer cells. There is clinical and experimental evidence that this can upregulate the metastatic process. Using established animal models of pulmonary microvascular injury it has been shown that endothelial damage promotes the localization and metastasis of circulating cancer cells to the lung and that this effect is lost after endothelial repair. Oxidative stress is an effector of vascular damage in several of the experimental models. While endothelial cells appear to be directly susceptible to free radical attack, basement membranes are not. However, oxidative injury of endothelial cells causes release of proteases which can then degrade the basement membrane. This event is associated with generation of tumor cell chemoattractants and enhances cancer cell invasion of vascular basement membranes in vitro. Vascular endothelial cells are also susceptible to stimulation by systemic mediators including cytokines, thrombin, or endotoxin which induce a series of active responses in the vessel wall. These perturbed endothelial cells synthesize and express cell surface adhesion molecules which can interact with cancer cells. They also release chemoattractants which stimulate cancer cell motility. We postulate that such responses endow the vessel wall with the potential to act as a determinant of metastatic rate.
Lafrenie
R
R
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Shaughnessy
S G
SG
Orr
F W
FW
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005609:Free Radicals; D006801:Humans; D008833:Microcirculation / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009360:Neoplastic Cells, Circulating; D010100:Oxygen
D005609:Free Radicals; D010100:Oxygen