Liver colonization is initiated through the interplay between
tumor cells and adhesion molecules present in liver sinusoidal endothelial cells (LSECs). This crosstalk stimulates
tumor COX-2 upregulation and
PGE2 secretion. To elucidate the role of the LSEC
intercellular adhesion molecule-1 (ICAM-1) in the prometastatic response exerted by
tumor and stromal COX-2, we utilized
celecoxib (CLX) as a COX-2 inhibitory agent. We analyzed the in vitro proliferative and secretory responses of murine C26
colorectal cancer (CRC) cells to soluble
ICAM-1 (sICAM-1), cultured alone or with LSECs, and their effect on LSEC and hepatic stellate cell (HSC) migration and in vivo liver
metastasis. CLX reduced sICAM-1-stimulated COX-2 activation and
PGE2 secretion in C26 cells cultured alone or cocultured with LSECs. Moreover, CLX abrogated sICAM-1-induced C26 cell proliferation and C26 secretion of promigratory factors for LSECs and HSCs. Interestingly, CLX reduced the protumoral response of HSC, reducing their migratory potential when stimulated with C26 secretomes and impairing their secretion of
chemotactic factors for LSECs and C26 cells and proliferative factors for C26 cells. In vivo, CLX abrogated the prometastatic ability of sICAM-1-activated C26 cells while reducing liver
metastasis. COX-2 inhibition blocked the creation of a favorable tumor microenvironment (TME) by hindering the intratumoral recruitment of activated HSCs and macrophages in addition to the accumulation of
fibrillar collagen. These results point to COX-2 being a key modulator of processes initiated by host
ICAM-1 during
tumor cell/LSEC/HSC crosstalk, leading to the creation of a prometastatic TME in the liver.