Inhibition of COX-2 Impairs Colon Cancer Liver Metastasis through Reduced Stromal Cell Reaction

Abstract

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 PGE 2 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 PGE 2 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.

Macrophages, as a Promising Strategy to Targeted Treatment for Colorectal Cancer Metastasis in Tumor Immune Microenvironment

“…COX-2 has been found in high levels in CRC (125). Studies have confirmed that COX-2 is a promoting factor for liver metastasis of CRC, and it can convert arachidonic acid into prostaglandin E2 (PGE2) (138,139). TAMs are the main source of COX-2 in intestinal tumors; PGE2-bound EP4 promotes the differentiation of immunosuppressive M2 macrophages and reduces the expansion of immunostimulatory M1 macrophages (128).…”

Neuropilin-1: A feasible link between liver pathologies and COVID-19

“…Blocking NRP-1 protein led to impaired tumor growth and vascular remodeling[ 39 ]. Interestingly, NRP-1 expression stimulated the activation of HSCs[ 101 ], liver-resident myofibroblast-like cells that contribute to the malignant growth of liver metastasis[ 23 , 24 , 102 ]. The NRP-1-dependent activation boosted tumor proliferation, cell migration, and invasiveness[ 101 ].…”

“…Some NRP-1 ligands are involved in liver pathologies. For example, VEGF mediates the angiogenic response of LSECs[ 23 ] and is associated with metastatic growth[ 24 ]. Another NRP-1 ligand, TGF-β, mediates the activation of HSCs during fibrogenesis[ 25 , 26 ], leading to liver fibrosis and extracellular matrix (ECM) remodeling during liver metastasis and the creation of a premetastatic niche[ 27 ].…”

Review: Challenges of In Vitro CAF Modelling in Liver Cancers

“…Mueller et al showed that CAF migration is promoted by the presence of tumour cells, although the factors that mediate this migration remain elusive [ 83 ]. Finally, the Arteta group showed that CT-26 CM promoted LSEC and HSC migration and that soluble ICAM-1 pre-treatment of tumour cells enhanced this effect [ 79 , 80 ]. They later showed that tumoural COX-2 was involved in the pro-migratory effects of soluble ICAM-1 [ 80 ].…”

“…Finally, the Arteta group showed that CT-26 CM promoted LSEC and HSC migration and that soluble ICAM-1 pre-treatment of tumour cells enhanced this effect [ 79 , 80 ]. They later showed that tumoural COX-2 was involved in the pro-migratory effects of soluble ICAM-1 [ 80 ].…”