Decreased expression of the β2 integrin on tumor cells is associated with a reduction in liver metastasis of colorectal cancer in mice

Abstract

BackgroundLymphocyte Function-Associated Antigen-1 (LFA-1; CD18/CD11a) is one of the main adhesion molecules used by immune cells to infiltrate the liver under inflammatory conditions. Recently, the expression of this integrin has also been reported on several solid tumors, including colorectal cancer. However, its functional role in the metastatic progression to the liver remains unknown. Using in vitro assays and an experimental orthotopic in vivo model of liver metastasis, we aimed to elucidate the role of tumor LFA-1 in the metastatic progression by means of the partial depletion of the β2 subunit of LFA-1, required for integrin activation, firm adhesion and signaling.MethodsTo do so, we evaluated the effects of β2 reduction on the murine colon carcinoma C26 cell line on their pro-metastatic features in vitro and their metastatic potential in vivo in a mouse model of colon carcinoma metastasis to the liver.ResultsThe reduction in β2 integrin expression correlated with a slower proliferation, and a reduced adhesion and migration of C26 cells in an in vitro setting. Additionally, tumor cells with a reduced in β2 integrin expression were unable to activate the liver sinusoidal endothelial cells (LSECs). This resulted in a recovery of the cytotoxic potential of liver lymphocytes which is compromised by LSECs activated by C26 cells. This was related to the abrogation of RNA expression of inflammatory and angiogenic cytokines by C26 cells after their activation with sICAM-1, the main ligand of β2αL. Furthermore, in vivo tumor cell retention and metastasis were profoundly reduced, along with a decrease in the recruitment and infiltration of myeloid derived suppressor cells (MDSCs) and lymphocytes to the liver.ConclusionTaken together, our findings uncovered the modulatory role for the tumor β2 subunit of the LFA-1 integrin in the metastatic progression of colorectal cancer to the liver by impairing activation of liver endothelium and thus, the local immune response in the liver. Besides, this integrin also showed to be critical in vivo for tumor cell retention, cytokine release, leukocyte recruitment and metastasis development. These data support a therapeutical potential of the integrin LFA-1 as a target for the treatment of colorectal liver metastasis.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3823-2) contains supplementary material, which is available to authorized users.

Liver sinusoidal endothelial cell ICAM-1 mediated tumor/endothelial crosstalk drives the development of liver metastasis by initiating inflammatory and angiogenic responses

“…The involvement of ICAM-1 in tumor cell adhesion to the hepatic sinusoidal wall was confirmed by in vivo retention assays. One day after intrasplenic inoculation, tumor cells are already retained in the liver 16 . At this time point, ICAM-1-silenced livers contain 50% fewer tumor cells than livers from mice injected with scramble siRNA (Fig.…”

“…We have previously shown that activated LSECs release inflammatory factors after ICAM-1 ligation with tumor LFA-1, that correlates with a decreased lymphocyte cytotoxic activity 15 . Moreover, decreased expression of LFA-1 on tumor cells is associated with a reduction in liver metastasis of colorectal cancer in mice 16 . Indeed, a role for endothelial ICAM-1 on tumor transmigration could be envisioned as ICAM-1 ligation by LFA-1 receptor on bladder carcinoma cells leads to HUVEC cell retraction and transmigration 17 .…”

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

“…Whereas LFA-1 expression is confined to leukocytes under normal conditions [6], tumor cells may express this β2 integrin as well, shown to elevate their metastatic activity [328]. The surface glykoprotein CD44 is frequently expressed by tumor cells and mediates tumor cell migration by binding collagen as a constituent of the ECM [329].…”

A Recurrence-Specific Gene-Based Prognosis Prediction Model for Lung Adenocarcinoma through Machine Learning Algorithm

“…Instead of extracting genes merely associated with survival outcomes using the Cox regression analysis, we developed our prediction model based on recurrence-specific genes using the machine learning algorithm. Most genes included in our final prediction model were reported to be related to survival in lung cancer or other cancers [ 34 – 42 ], which indicates the rationality of our prediction model. For example, high expression of P4HA1 and S100A10 was reported to be associated with dismal survival outcomes in LUAD [ 36 , 38 ].…”