Abstract
The liver is the predominant metastatic site for several types of malignancies. Tumor-associated macrophages (TAMs) in the liver play crucial roles in the metastasis process. Shifting tumor-promoting M2-like TAMs toward the M1-like phenotype, which exerts tumor suppressor functions via phagocytosis and the secretion of inhibitory factors, may be a potential therapeutic strategy for liver cancer metastasis treatment.We first cloned NDRG2 (N-myc downstream-regulated gene 2) and verified its tumor suppressor role in multiple solid tumors, including colorectal cancer and hepatocellular carcinoma. However, its role in the tumor-associated liver microenvironment, especially in TAMs, has not been illustrated. By establishing a liver cancer metastasis model in wild-type (WT) and Ndrg2 knockout (Ndrg2−/−) mice, we found that the loss of the tumor suppressor Ndrg2 in liver microenvironment significantly suppressed the growth of liver colonies. In addition, this process was accompanied by a higher proportion of M1-like TAM infiltration in Ndrg2−/− mice. Interestingly, bone marrow (BM) transplantation revealed that BM-derived macrophages (BMDMs) rather than liver resident Kupffer cells were responsible for the inhibitory effect. We further demonstrated that loss of Ndrg2 influenced TAM polarization via the NF-κB pathway. Inhibition of IκBα phosphorylation in cancer cell-conditioned medium-stimulated BMDMs decreased M1 marker expression in Ndrg2−/− macrophages. Finally, in vitro, invasion, migration, and proliferation assays confirmed that NF-κB participated in the tumor suppressor function of Ndrg2−/− macrophages. Collectively, our findings highlight the role of NDRG2 in the regulation of TAM polarization and its function in promoting cancer liver metastasis.
Highlights
Malignancy in the liver threatens the lives of patients
Luciferase-expressing CMT93 murine colorectal cells or Lewis lung carcinoma (LLC) murine lung carcinoma cells were injected into the spleen of WT and Ndrg2−/− mice, which enabled efficient cancer cell dissemination to the liver
After nearly 17 years of work, our laboratory and other groups have clearly shown that N-myc downstreamregulated gene 2 (NDRG2) expression is decreased in multiple tumor tissues, including colorectal cancer (CRC), glioma, and hepatoma[15,16,17,18,19,20,21]
Summary
The liver is the site of primary liver cancer as well as the predominant metastatic site for several kinds of cancer, such as colorectal cancer (CRC), lung cancer, melanoma, and gastric carcinoma[1,2]. Cancer liver metastasis is a complex process that includes several major steps: invasion and penetration of microvessels; cell survival in the circulation and establishment in the liver; formation of a metastatic niche; and tumor cell expansion[3]. Primary tumors can release a large number of cancer cells into the circulation, while only a small proportion of these cells can survive in the liver. During this process, in addition to genetic changes
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call