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CCRK—a hub for liver metastasis and cancer

Cellular & Molecular Immunology volume 18, pages 1341–1342 (2021)Cite this article

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The liver is one of the most common sites for cancer metastasis, which leads to secondary hepatic malignancies. Almost all solid tumors, such as melanoma, breast cancer, gastric cancer, colorectal cancer, and lung cancer, metastasize to the liver.1,2 Overall, 20–25% of colorectal cancer patients may eventually develop liver metastases (also known as CRC liver metastases).3 In addition to some common occurrence of liver metastasis in colorectal cancer, the liver is also one of the predominant metastatic sites for melanoma, including cutaneous and ocular melanoma.2 Thus, an understanding of the mechanism of liver metastasis is urgently needed for the development of novel strategies to prolong overall survival for patients with liver metastases.

In this issue of cell and molecular immunology, Zeng et al. suggested that hepatic CCRK signaling reprograms the microenvironment to undermine antimetastatic immunosurveillance.4 To date, elegant studies have demonstrated that the formation of the premetastatic niche in the liver is initiated by a proinflammatory signal released from the primary tumor site,5 but how this process is maintained by hepatocyte-intrinsic signaling within liver immune homeostasis remains to be investigated. In this study, the investigators hypothesized that CCRK, which is often upregulated in areas of tumor-adjacent liver fibrosis and cirrhosis, may induce the formation of a cancer microenvironment by disturbing the balance between immunosuppression and immunosurveillance. To test their hypotheses, they demonstrated that overexpression of CCRK could enhance liver metastasis of colorectal cancer as well as melanoma through the accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and a reduction in hepatic natural killer T (NKT) cells in liver-specific CCRK-transgenic (CCRK-TG) mice. Depletion of PMN-MDSCs abrogated liver metastases and restored the level of hepatic NKT cells in CCRK-TG mice. Moreover, hepatic CCRK signaling recruited PMN-MDSCs to the liver microenvironment via NF-κB-dependent CXCL1 expression and impaired the balance between immunosuppression and immunosurveillance in CCRK-TG mice, as well as in human livers with metastases. These data uncovered a role of intrinsic hepatic CCRK signaling in inducing premetastatic niche formation for liver metastasis.

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Acknowledgements

This study was supported by a grant from the Ministry of Science and Technology (MOST 108-2314-B-194-003-MY2).

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Authors and Affiliations

  1. Department of Biomedical Sciences, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, China

    Jie-Ting Low, Guan-Ling Lin & Michael W. Y. Chan

  2. Epigenomics and Human Disease Research Center, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, China

    Jie-Ting Low, Guan-Ling Lin & Michael W. Y. Chan

  3. Center for Innovative Research on Aging Society (CIRAS), National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, China

    Michael W. Y. Chan

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  1. Jie-Ting Low
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Correspondence to Michael W. Y. Chan.

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Low, JT., Lin, GL. & Chan, M.W.Y. CCRK—a hub for liver metastasis and cancer. Cell Mol Immunol 18, 1341–1342 (2021). https://doi.org/10.1038/s41423-020-00569-5

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