Prophylactical low dose whole-liver irradiation inhibited colorectal liver metastasis by regulating hepatic niche in mice
Lu Wang, Yinan Sun, Xiaoxiao Luo, Hu Han, Han Yin, Ben Zhao, Xinyi Chen, Qianqian Yu, Hong Qiu, Xianglin YuanOncoTargets and Therapy2020
Background: The liver is the most common target for metastatic colorectal cancer. Changes of the local hepatic niche due to hepatic diseases such as cirrhosis decrease the incidence of colorectal cancer liver metastasis. Hepatic niche heterogeneity could influence the risk of hepatic metastasis. Materials and Methods: We simulated changes of the hepatic niche via prophylactical liver irradiation with a safe dose of 6 Gy. GEO dataset and GO analysis revealed a difference in the expression of matrix metalloproteinase 1 (MMP1) in primary colorectal cancer versus liver metastasis, as well as synchronous versus metachronous liver metastasis. Western blotting, Immunofluorescence and qRT-PCR were conducted to measure protein expressions, location and RNA expressions. Colony formation, wound-healing, transwell assays experi-ments were performed to determine the malignant biological properties of colorectal cancer cells. shRNA transfection was used to conduct stable transfected cell lines. Results: Tissue inhibitor of metalloproteinases 1 (TIMP1) expression was significantly higher in metastases lesions than primary tumors. In vivo, TIMP1 expression in the hepatic niche increased after a safe dose of 6 Gy irradiation, along with MMP1 decreased, leading to collagen fiber deposition and impairment of hepatic microcirculation. In vitro, irradiated hepatic stellate cells-conditioned media reduced the migration and clone formation ability of colon cancer cells SW480 and HCT116. Low TIMP1 expression in hepatic stellate cells reduced tumor cell invasion and migration. Conclusion: Prophylactical 6 Gy whole-liver irradiation could inhibit colorectal cancer liver metastasis by regulating TIMP1/MMP1 balance in the hepatic niche before liver metastatic lesion formed.