Colon carcinoma cell interaction with liver sinusoidal endothelium inhibits organ-specific antitumor immunity through interleukin-1-induced mannose receptor in mice

Abstract

Mannose receptor (ManR)-mediated liver sinusoidal endothelial cell (LSEC) endocytosis plays a role in antigen presentation and innate immunity, but its role in hepatic metastasis is unknown. We studied ManR-mediated endocytosis during C26 colorectal cancer cell interaction with LSECs and its implications in metastasis. Uptake of labeled ManR ligands (mannan and ovalbumin) and immunohistochemistry were used to study ManR endocytosis and expression. Several interleukin (IL)-1 inhibitors and the cyclooxygenase-2 (COX-2) inhibitor celecoxib were used to analyze the role of IL-1 and COX-2 in ManR regulation. Anti-mouse ManR antibodies and ManR knockout (ManR 2/2 ) mice were used to identify ManR-dependent mechanisms during antitumor immune response of liver sinusoidal lymphocytes (LSLs) interacting with tumor-activated LSECs. ManR expression and endocytosis increased in tumor-activated LSECs through a two-step mechanism:(1) Release of COX-2-dependent IL-1-stimulating factors by lymphocyte function-associated antigen-1-expressing C26 cells in response to intercellular adhesion molecule-1 (ICAM-1), which was expressed and secreted by tumor-activated LSECs; and (2) widespread up-regulation of ManR in LSECs through tumor-induced IL-1. In addition, LSLs that had interacted with tumoractivated LSECs in vivo decreased their antitumor cytotoxicity and interferon (IFN)-gamma secretion while they increased IL-10 release ex vivo. IFN-gamma/IL-10 ratio also decreased in the hepatic blood from tumor-injected mice. Immunosuppressant effects of tumor-activated LSECs on LSLs were abrogated in both LSECs from ManR 2/2 mice and tumor-activated LSECs given antimouse ManR antibodies. Conclusion: ICAM-1-induced tumor COX-2 decreased antitumor activity during hepatic metastasis through IL-1-induced ManR. ManR constituted a common mediator for prometastatic effects of IL-1, COX-2, and ICAM-1. A rise in hepatic IFN-gamma/IL-10 ratio and antitumor cytotoxicity by way of ManR blockade is consistent with the antimetastatic effects of IL-1, COX-2, and ICAM-1 inhibitors. These data support ManR and ManR-stimulating factors as targets for hepatic colorectal metastasis therapy. (HEPATOLOGY 2010;51:2172-2182 Abbreviations: ASMA, alpha-smooth muscle actin; CM, cell-conditioned medium; COX-2, cyclooxygenase-2; CSPG, chondroitin sulfate proteoglycan; ELISA, enzyme-linked immunosorbent assay; FITC-OVA, fluorescein isothiocyanate-labeled ovalbumin; FSA, formaldehyde treated serum albumin; ICAM-1, intercellular adhesion molecule-1; ICE, IL-1-converting enzyme; IgG2a, immunoglobulin G2a; IL, interleukin; IL-1RI, IL-1 receptor type I; IL-1Ra, IL-1 receptor antagonist; LFA-1, lymphocyte function-associated antigen 1; LSEC, liver sinusoidal endothelial cell; LSL, liver sinusoidal lymphocyte; ManR, mannose receptor; ManR À/À , ManR knockout; SD, standard deviation; sICAM-1, soluble ICAM-1.From the

Role of liver ICAM-1 in metastasis

“…The increasing evidence of tumor cell expression of ICAM-1 ligands, and of the interaction between tumor cells and host ICAM-1, demonstrate that the significance of host cell ICAM-1 expression during the course of liver metastasis, and knowledge of role of ICAM-1 expression, may increase in the coming years. Consistently with this idea, the adhesion of LFA-1-expressing C26 CRC cells to LSECs was shown to be reduced by blocking ICAM-1 with specific antibodies (27,32). The same result was observed when the expression of β2 integrin in C26 cells was reduced via siRNA (Benedicto et al, submitted).…”

“…Modulation of the target organ pro-metastatic response is initiated by interaction of tumor cells with endothelial cells, leading to the activation of these vascular cells and secretion of pro-inflammatory cytokines and growth factors (89). The role of ICAM-1 in the creation of such an environment was reported by Arteta et al (27). The authors reported that ICAM-1 binding with tumor LFA-1 triggered the production of IL-1β by LSECs, which in turn promoted mannose receptor (ManR)-mediated endocytosis.…”

“…Several adhesion molecules, such as E-selectin, vascular cellular adhesion molecule (VCAM)-1 and ICAM-1, exhibit increased expression in the liver during metastatic invasion (22). Among them, ICAM-1 mediates several stages of the metastatic cascade, including the adhesion of tumor cells to the endothelial wall (23)(24)(25), endothelial cell activation of pro-metastatic signaling pathways (26)(27)(28), tumor cell extravasation (23,29), the recruitment of immune cell populations (28,30,31), the pro-angiogenic response (32) and the transdifferentiation of stellate cells during the desmoplastic response (33,34). This review will focus on the role of ICAM-1 during the different events of the metastatic cascade that drives colonization of the liver by circulating tumor cells, and how it modulates the liver microenvironment to facilitate metastasis.…”

Tumor-associated fibroblasts isolated from colorectal cancer tissues exhibit increased ICAM-1 expression and affinity for monocytes

“…Tumor progression and the development of metastasis appear to be influenced by 2,3,6,7,8,9,12,14). In 3 of the pairs, the differences were statistically significant ( * p<0.05, ** p<0.01).…”

“…This molecule typically participates in cell-cell as well as cell-matrix adhesion and is also involved in cancer cell adhesion and in the immune response of tumors (9)(10)(11)(12).…”