Cellular interactions of colorectal cancer (CRC) cells and resident cells within the hepatic sinusoids (namely Kupffer cells (KC)s and sinusoidal endothelial cells (SEC)s) constitute important initial process in CRC liver metastasis. Malignant cell arrest in the sinusoids substantially contributes to the metastatic development and it may be mediated by the carcinoembryonic antigen (CEA), cytokines released by activated KCs and adhesion molecules expressed by SECs. Methodologically, cell cultures were performed to investigate interactions among two CRC cell lines (metastatic HT-29 and non-metastatic Colo741) with rat KCs and SECs, as well as with human umbilical vein- and human dermis-endothelial cells (HUVECs and HuDMECs). Representative cytokines released by KCs, including interleukin 1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α), were measured through enzyme-linked immunosorbent assay (ELISA). Also, adhesion assays explored CRC cell attachment to endothelial cells. Endothelial cells were stimulated either by CEA, activated KC Conditioned Media (CM) or CRC cell CM. Flow cytometry measured E-selectin and vascular cell adhesion molecule 1 (VCAM-1) expressed on endothelial cells. Quantitative data showed that high KC production of TNF-α (p < 0.001) and IL-1β (p < 0.01) was triggered by CEA, 144.6 and 102.7 pg/ml, HT CM, 104.8 and 67.8 pg/ml and Colo CM, 106.3 and 65.9 pg/ml. KC CM collected by stimulated cells via CEA and HT-29 CM caused high HT-29 cell attachment to endothelial cells. Flow cytometry revealed 46.7%-66.8% VCAM-1 expression on HUVECs, 35.8% E-selectin on HuDMECs, and 80.7% VCAM-1 expression and 65% E-selectin on rat SECs, under the influence of CEA-stimulated KC CM. CRC cells do not induce the expression of adhesion molecules on endothelial cells directly, but through the mediation of the KC-produced cytokines. CEA and to a lesser extent HT-29 CM triggered high HT-29 attachment to endothelial cells through KC stimulation. This attachment was mediated by E-selectin and VCAM-1 expressed by endothelial cells. These experimental findings may contribute to the inhibition of the initial steps of CRC liver metastasis in the sinusoids and thus the treatment of the disease.
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