CXCR4 receptor blockage reduces the contribution of tumor and stromal cells to the metastatic growth in the liver

Abstract

The liver is a common site for the metastatic spread of primary malignancies including colorectal cancer, and liver metastasis is a main cause of death in cancer patients. This is due to the complexity of the interactions taking place in the liver between tumor and stromal cells. In fact, cancer‑associated fibroblasts (CAFs) have been shown to support tumor growth through the CXCL12/CXCR4 axis. However, along with cancer cells, myeloid‑derived suppressor cells (MDSCs), immature dendritic cells with immunosuppressive potential, also express CXCR4. It has recently been demonstrated that reducing CXCL12 availability in the tumor microenvironment decreases liver metastasis. Therefore, blocking CXCL12 chemokine receptor CXCR4 may be a successful approach to diminish the metastatic spread of colorectal cancer to the liver. However, the subjacent mechanisms by which this chemokine influences the tumor are not fully understood. Thus, in order to uncover the role of CXCR4 during tumor cell/liver fibroblast crosstalk driving liver metastasis, the CXCR4 antagonist AMD3100 was used for in vitro studies and in an in vivo approach using an orthotopic model of liver metastasis in immune competent mice through intrasplenic injection of grafted C26 cells. In vitro blockage of CXCR4 led to an impaired migratory potential of tumor and hepatic stellate cells (HSCs) and a reduced tumor response to CXCL12. In vivo administration of AMD3100 to tumor‑bearing mice resulted in attenuated metastatic development in the liver, which was accompanied by an impaired infiltration of αSMA‑expressing cells within the tumors. In addition, a reduced CD11+Ly6G+ cell count in the liver was directly correlated with a reduction in MDSC numbers in the blood of AMD3100‑treated mice compared to the vehicle‑treated mice. Therefore, disruption of the CXCR4/CXCL12 axis by CXCR4 antagonist AMD3100 blocked the contribution of both cancer and stromal cells to the metastatic cascade in the liver.