Colorectal cancer (colorectal carcinoma, CRC) is one of the most common malignant tumors in the world, with the third highest incidence of male cancers and the second highest female cancer rate. Its fatality rate ranks second among cancer-related deaths, with more than 940000 deaths per year. Globally, colorectal cancer has an incidence rate of 24.26/100,000, and the number of new cases each year is about 1.93 million, accounting for 10.2% of all new cases of malignant tumors, ranking third.1 Hematogenous metastasis is one of the most common forms of distant metastasis of colorectal cancer, and the liver is one of their main targets, which is also the main cause of death in patients with colorectal cancer. In addition, more than 1/3 of patients die within five years after the initial diagnosis, the primary cause of which also being liver metastasis.2 Liver metastasis is one of the key points and difficulties in the treatment of colorectal cancer, as well as the key factors affecting the prognosis for patients.
CXCL12, a member of the chemokine family, also known as stromal cell-derived factor-1, is a multipotent chemokine, which is widely expressed in brain, lung, colon, heart and liver. It can stimulate a variety of signal transduction and has chemotactic effect on tumor cells which can express its corresponding receptor CXCR4, making tumors form specific metastatic foci.3 Studies have shown that CXCL12 is expressed in the cytoplasm and cell membrane of colon cancer cells, as well as in fibroblasts in tumor stroma. Its expression in colorectal cancer cells and disease site is one of the important factors affecting prognosis. Its high expression in colon cancer is related to advanced disease and low survival rate of patients.4 Our previous studies have found that CXCL12 can also enhance the invasiveness of colon cancer cells and significantly promote the proliferation and migration of human umbilical vein endothelial cells.5 It has been shown that metastasis occurs through angiogenesis, since newly formed blood vessels are able to carry oxygen and nutrients to the tumor and also stimulate the growth of cancer cells.6 C-X-C chemokine receptor 4 (CXCR4), the main receptor of CXCL12, is a G protein coupled receptor, just like CXCL12, which is also widely expressed in different tissues. It is generally considered to be a membrane receptor protein that retains the signal after localization to the nucleus.7 At present, it has been found that CXCL12-CXCR4 axis can play an important role in the occurrence, development and metastasis of many kinds of human tumors, including breast cancer, gastric cancer, colorectal cancer, prostate cancer, renal cell carcinoma, ovarian cancer and so on,8,9 especially in the biological behaviors such as proliferation, adhesion, migration, invasion and metastasis of tumor cells.10 More and more evidence showed that the activation of CXCL12/CXCR4 axis is related to liver metastasis and poor prognosis of patients with colorectal cancer.11 It has been proved that after colorectal cancer cells activate the CXCL12/CXCR4 axis, the miRNAs secreted by colorectal cancer cells can be absorbed by macrophages and transform macrophages to M2 phenotype by targeting PTEN. Then M2 polarized macrophages can promote angiogenesis and liver metastasis of colorectal cancer by secreting VEGF.12 Some in vitro studies showed that CXCL12/CXCR4 promoted the migration and liver metastasis of CRC by upregulating αvβ6 through ERK1/2/Ets-1. 13 And the overexpression of CXCR4 could increase both AOM/DSS-induced CAC and Apc mutation-driven tumorigenesis and progression.14 Therefore, the expression of CXCR4 gene in colorectal cancer is also significantly correlated with tumor recurrence, liver metastasis and prognosis of patients.15
Interleukin-1α has long been known for its multiple effects on inflammation. The role of inflammation in various stages of cancer development is complex and even opposite, as well as being a major component of the tumor microenvironment. 16 IL-1 can enhance the invasiveness of malignant tumor cells and eventually lead to metastasis by stimulating growth factors, angiogenesis and the movement of tumor cells. However, in some cases, IL-1α can also enhance the immunogenicity of malignant tumor cells, thus reducing the invasiveness of tumors.17 IL-1α is regulated by members of the family of IL-1 receptors (ILR). The regulatory factors that inhibit IL-1α include bait receptor (IL-1R2), receptor antagonist (IL-1Ra), IL-1R8 and anti-inflammatory IL-37. IL-1 plays different roles in the occurrence and development of cancers. It can further induce the secretion of growth factors. These growth factors induces proliferation, promote angiogenesis, macrophage recruitment, invasion and metastasis, so as to accelerate the progression of tumor.18 TNF-α and IL-1 in tumor microenvironment can produce DNA damage molecules such as ROS and nitric oxide, which induce mutations in colonic epithelium and promote the development of cancer.19,20 It has been suggested that IL-1α derived from intestinal epithelial cells plays a leading role in the pathogenesis of superior mesenteric colitis. IL-1α released by damaged endothelial cells may activate monocytes and infiltrating cells in the colon to release inflammatory mediators, which amplifies the initial inflammatory response and promotes the occurrence and metastasis of colorectal cance.21
The effects of IL-1α and its receptor antagonist IL-1Ra on the migration colon cancer cells and promoting angiogenesis and the chemotaxis of CXCL12 all play an important role in tumorigenesis and metastasis. However, the molecular mechanism of the synergistic regulation of CXCR4/CXCL12 axis and IL-1Ra on colon cancer metastasis is still not clear. The purpose of this study is to explore the potential of CXCL12 and IL-1Ra to promote the metastasis of colon cancer and its mechanism, to better understand the interaction between colon cancer cells and stromal cells in tumor microenvironment, and to provide new ideas for the treatment of colorectal cancer and inhibition of liver metastasis of colon cancer.