Department of Cellular Biology and Histology, University of The Basque Country, School of Medicine and Nursing, UPV/EHU, Leioa, E‑48940 Biscay, Spain.
Oncol Rep. 2018 Apr;39(4):2022-2030. doi: 10.3892/or.2018.6254. Epub 2018 Feb 8.
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.
肝脏是原发性恶性肿瘤转移的常见部位，包括结直肠癌，肝转移是癌症患者死亡的主要原因。这是由于肿瘤细胞和基质细胞在肝脏中相互作用的复杂性所致。事实上，已经表明癌症相关成纤维细胞（CAFs）通过 CXCL12/CXCR4 轴支持肿瘤生长。然而，与癌细胞一样，具有免疫抑制潜力的髓源性抑制细胞（MDSC）也表达 CXCR4。最近已经证明，减少肿瘤微环境中 CXCL12 的可用性可降低肝转移。因此，阻断 CXCL12 趋化因子受体 CXCR4 可能是减少结直肠癌向肝脏转移的成功方法。然而，这种趋化因子影响肿瘤的潜在机制尚未完全了解。因此，为了揭示 CXCR4 在肿瘤细胞/肝成纤维细胞相互作用驱动肝转移过程中的作用，使用 CXCR4 拮抗剂 AMD3100 进行了体外研究，并在免疫功能正常的小鼠中使用原位肝转移模型进行了体内研究，通过脾内注射移植的 C26 细胞。体外阻断 CXCR4 导致肿瘤和肝星状细胞（HSCs）的迁移能力受损，并且肿瘤对 CXCL12 的反应降低。AMD3100 对荷瘤小鼠的体内给药导致肝转移的发展减弱，这伴随着肿瘤内表达 αSMA 的细胞浸润受损。此外，AMD3100 治疗小鼠的肝脏中 CD11+Ly6G+细胞计数减少与 MDSC 数量在血液中的减少直接相关，与载体处理的小鼠相比。因此，CXCR4 拮抗剂 AMD3100 破坏 CXCR4/CXCL12 轴阻断了癌症和基质细胞对肝脏转移级联反应的贡献。
