Abstract
Simple SummaryLiver metastasis remains the major contributor in colorectal cancer-related death. It has become clear that the unique immune features of liver microenvironment take part in many steps of metastatic cascade, from pre-metastatic niche formation, tumor cell colonization to metastatic tumor establishment. Therefore, better understanding of mechanisms orchestrating the formation of a hospitable hepatic metastatic niche is necessary for the development of effective therapies. This review summarizes the current understandings of the critical role of liver immune microenvironment in metastasis development and provides therapeutic perspective on targeting the metastasis-prone microenvironment. A drastic difference exists between the 5-year survival rates of colorectal cancer patients with localized cancer and distal organ metastasis. The liver is the most favorable organ for cancer metastases from the colorectum. Beyond the liver-colon anatomic relationship, emerging evidence highlights the impact of liver immune microenvironment on colorectal liver metastasis. Prior to cancer cell dissemination, hepatocytes secrete multiple factors to recruit or activate immune cells and stromal cells in the liver to form a favorable premetastatic niche. The liver-resident cells including Kupffer cells, hepatic stellate cells, and liver-sinusoidal endothelial cells are co-opted by the recruited cells, such as myeloid-derived suppressor cells and tumor-associated macrophages, to establish an immunosuppressive liver microenvironment suitable for tumor cell colonization and outgrowth. Current treatments including radical surgery, systemic therapy, and localized therapy have only achieved good clinical outcomes in a minority of colorectal cancer patients with liver metastasis, which is further hampered by high recurrence rate. Better understanding of the mechanisms governing the metastasis-prone liver immune microenvironment should open new immuno-oncology avenues for liver metastasis intervention.
Highlights
We summarize the underlying mechanisms of Colorectal Cancer (CRC) liver metastasis facilitated by liver immune microenvironment in the process of liver metastatic cascade, especially the pre-metastatic niche formation and CRC colonization and propagation in liver
In addition to hepatocyte-derived factors, increasing evidence suggests that nonparenchymal cells, such as liver resident fibroblast hepatic stellate cells (HSCs), liver resident macrophage Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and liver infiltrating immune cells around the hepatocytes have critical roles in multiple stages during the development of CRC liver metastases either by direct or indirect cell-tocell interaction
A better understanding of the molecular mechanisms orchestrating the formation of a hospitable hepatic metastatic niche and the identification of the drivers supporting this process is critical for the development of better therapies to stop or at least decrease liver metastasis
Summary
Cancer metastasis is the major obstacle to successful management of malignant disease and accounts for approximately 90% of cancer related mortality [1]. Numerous studies addressed that the unique structure and characteristic of liver that it enriches in vessels with high permeability and has unparalleled dual blood connectivity, and the immunosuppressive microenvironment, make it vulnerable to the seeding of disseminated tumor cells [3]: The dual vascular supply of the liver by the systemic arterial and portal venous system enhances the entrapment of circulating tumor cells, explaining increased incidence of liver metastasis in patients with gastrointestinal cancers; In addition, the immune microenvironment in liver has evolved to dampen immunity to neoantigens entering the liver from the gut via portal vein so as to avoid damage to the liver [4]. Accumulating evidence shows that both the parenchymal and the nonparenchymal cells play a role in the process of metastatic cascade, including facilitating acquisition of epithelial–mesenchymal transition (EMT). Phenotype, migration to liver, seeding, and colonization as well as the decision to undergo dormancy versus outgrowth [3]
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