Cancer cell interactions with injured or activated endothelium

Abstract

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.

Tumoricidal Activity of Endothelial Cells

“…Despite lethal effects on metastatic cells, oxidative stress may additionally create a pro-metastatic microenvironment at target organs by increasing cell adhesion molecule expression in both endothelial (53) and cancer (6) cells, activation of the early growth response-1 transcription factor gene (54), and activation of cancer and endothelial cell metalloproteinases (55). In consequence, although the antioxidant capacity of cancer cells may determine their intravascular survival, surviving cells may benefit from oxidative stress-promoting metastatic mechanisms.…”

Regulatory role of tetraspanin CD9 in tumor–endothelial cell interaction during transendothelial invasion of melanoma cells

“…Most works on the transendothelial migration of cancer cells show the formation of gaps in the EC monolayer that allow direct access of TCs to the exposed subendothelial matrix. 21,22,[37][38][39] In this regard, it has been reported that TC-EC interactions induce a rapid EC-EC dissociation, which correlates with a dramatic loss of VE-cadherin staining around the TCs. 34 In contrast, only local changes in VE-cadherin staining at sites of TC-EC contact were reported using a 3-dimensional EC culture system on matrigel, 40 in accordance with our results with collagen gels.…”

Studies on Breast Cancer Cell Interactions with Aged Endothelial Cells in Culture and Rat Models

“…Indeed research findings support a role for endothelial injury in cancer metastasis (reviewed in [24]). For example, bleomycin-treated mice develop more metastases after the injection of fibrosarcoma cells if the tumor cells are injected soon after bleomycin-induced endothelial injury in comparison to after endothelial repair [25,26].…”

“…After the BPAECs attained a ''cobblestone'' appearance, MCF-7 cells, which were labeled with carboxyfluorescein diacetate, succinimidyl ester (CFDASE; Vybrant TM CFDA SE Cell Tracer Kit, Molecular Probes, Eugene, OR), were added (2500 cells per well) to experimental cultures and fresh culture medium was added to controls. Samples were fixed with 5% formaldehyde at 4,6,12,24 and 48 h after MCF-7 cell addition and mounted for microscopy. In an experiment designed to control for the breast cancer cell addition, CFDASE-labeled 184A1 cells (2500 cells per well) were added to some wells and samples were fixed 24 h after cell addition.…”