In vivo tumor cell adhesion in the pulmonary microvasculature is exclusively mediated by tumor cell - endothelial cell interaction

Abstract

BackgroundMetastasis formation is the leading cause of death among colon cancer patients. We established a new in-situ model of in vivo microscopy of the lung to analyse initiating events of metastatic tumor cell adhesion within this typical metastatic target of colon cancer.MethodsAnaesthetized CD rats were mechanically ventilated and 106 human HT-29LMM and T84 colon cancer cells were injected intracardially as single cell suspensions. Quantitative in vivo microscopy of the lung was performed in 10 minute intervals for a total of 40 minutes beginning with the time of injection.ResultsAfter vehicle treatment of HT-29LMM controls 15.2 ± 5.3; 14.2 ± 7.5; 11.4 ± 5.5; and 15.4 ± 6.5 cells/20 microscopic fields were found adherent within the pulmonary microvasculature in each 10 minute interval. Similar numbers were found after injection of the lung metastasis derived T84 cell line and after treatment of HT-29LMM with unspecific mouse control-IgG. Subsequently, HT-29LMM cells were treated with function blocking antibodies against β1-, β4-, and αv-integrins wich also did not impair tumor cell adhesion in the lung. In contrast, after hydrolization of sialylated glycoproteins on the cells' surface by neuraminidase, we observed impairment of tumor cell adhesion by more than 50% (p < 0.05). The same degree of impairment was achieved by inhibition of P- and L-selectins via animal treatment with fucoidan (p < 0.05) and also by inhibition of the Thomson-Friedenreich (TF)-antigen (p < 0.05).ConclusionsThese results demonstrate that the initial colon cancer cell adhesion in the capillaries of the lung is predominantly mediated by tumor cell - endothelial cell interactions, possibly supported by platelets. In contrast to reports of earlier studies that metastatic tumor cell adhesion occurs through integrin mediated binding of extracellular matrix proteins in liver, in the lung, the continuously lined endothelium appears to be specifically targeted by circulating tumor cells.

Integrins and metastasis

“…This occurs through adhesive interactions between cancer cells and endothelial cells involving some cell adhesion proteins like integrins, selectins and members of the immunoglobulin superfamily. 22 The next important phase is invasion of the tumor cells through the endothelial cell layer, neighboring basement membrane (this process is called extravasation), and target organ tissue. Then there is step of development of secondary tumor foci at the distant organ.…”

Role of liver ICAM-1 in metastasis

“…2). At this time, endothelial ICAM-1 is involved in tumor cell adhesion to the endothelium; this is a particularly important phenomenon considering that tumor adherence to vessel walls is a common feature across numerous types of cancer (51). Ghislin et al reported that ICAM-1 expressed on the surface of endothelial cells is crucial for the adhesion of melanoma cells to the endothelial monolayer in vitro.…”

TRAIL-coated leukocytes that kill cancer cells in the circulation

“…Recent studies have shown that CTCs from many types of primary tumors express sialylated carbohydrate ligands similar to leukocytes, which mediate interactions with selectins on the endothelium (5,6). Selectins possess rapid, force-dependent binding kinetics, which can trigger the rolling adhesion of CTCs along the blood vessel wall (7,8). CTCs can subsequently transition from rolling to firm adhesion, allowing for transendothelial migration into tissues and eventual formation of micrometastases (9).…”