Research into the Relationship Between Interleukin-8 and Tumors

IL-8 and the Occurrence and Development of Tumors

IL-8 and tumor occurrence Inflammation is one of the causes of tumor occurrence. Uncontrollable inflammatory response is often closely related to tumor occurrence, and IL-8 is one of the most common pro-inflammatory factors, which may indicate IL -8 is closely related to the occurrence of tumors. The microenvironment in which cells survive will be affected by inflammatory factors and change. Changes in the microenvironment may lead to abnormal cell proliferation or mutations in oncogenic and tumor suppressor genes, thereby causing tumors.

Figure 1. Effects of IL-8 on the tumor and microenvironment. (Sources: David JM, et al. 2016)

• IL-8 and Tumor Development

Studies have shown that IL-8 is closely associated with the proliferation and metastasis of tumor cells. In tumor patients, the proliferation and metastasis of tumor cells are important factors that affect the survival of tumor patients and are also an important factor in the recurrence of tumors after surgery. In studying the relationship between IL-8 and lung adenocarcinoma, it was found that IL-8 was positively correlated with tumor size and the degree of lymph node metastasis, confirming that IL-8 can promote the development of lung adenocarcinoma. Studies have shown that treatment with exogenous IL-8 increased the migration and proliferation efficiency of cancer cells compared with untreated HeLa cells. IL-8 is also involved in tumor angiogenesis. Because the new blood vessels in tumor tissue provide nutrition and metastasis channels for tumors, IL-8 can promote cancer migration and proliferation. In addition, some researchers have found that IL-8 secreted by colorectal cancer cells can promote tumor angiogenesis by activating the Janus signal transduction and transcription activator 3 signal transduction pathways, thereby promoting tumor metastasis in patients.

IL-8 is closely related to the epithelial-mesenchymal transition (EMT) process. The EMT process is related to the metastasis and invasion ability of cells. In the study of the relationship between IL-8 and EMT, it was found that IL-8 can promote the occurrence of EMT in breast cancer cells by activating the phosphatidylinositol 3-kinase/protein kinase B pathway, thereby improving the metastasis and invasion ability of breast cancer cells. In the study of renal cell carcinoma, evidence was also found that IL-8 promotes EMT by activating the protein kinase B cell signaling pathway. These evidences reveal that IL-8 can affect the development of tumors by promoting EMT in some tumors.

IL-8 is closely related to matrix metalloproteinases (MMPs) in the initiation and development of tumors. Because MMPs can degrade protein components in the extracellular matrix, they play an important role in tumor metastasis. MMP-9 can promote neovascularisation, tumor infiltration and metastasis by activating the vascular endothelial growth factor/vascular endothelial growth factor receptor 2 signalling pathway and degrading basement membrane or extrastromal components such as laminin. IL-8 may be involved in the metastatic process of gastric cancer by upregulating the expression of MMP-9. Knocking down the expression of the IL-8 receptor can down-regulate the expression of MMP-9, thereby reducing the invasion of gastric cancer cells. The study found that the expression of MMP-2 and MMP-9 in breast cancer cells was significantly reduced after IL-8 silencing, and the migration and invasion abilities of breast cancer cells were also significantly reduced. IL-8 plays an important role in the development and metastasis of certain tumors. Targeting IL-8 and its signalling pathway to treat related tumors has become one of the current research hotspots.

• IL-8 and Tumor Cell Immune Escape

There are two main mechanisms by which tumor cells escape immunity, namely the accumulation of myeloid-derived suppressor cells (MDSCs) and the signalling of programmed death 1 (PD-1) in T cells. MDSC are considered to be an important immunosuppressive component of T cells in tumor patients. Studies have shown that tumor-derived IL-8 contributes to the chemotactic recruitment and functional regulation of MDSC. Inhibiting the expression of IL-8 or blocking the IL-8 signalling pathway is beneficial in reducing the accumulation of MDSC in the tumor microenvironment, which may inhibit the immune escape of tumor cells to some extent and assist chemotherapeutic drugs or immune cells in exerting their immune effects.

• IL-8 and Chemotherapy

With the widespread use of chemotherapeutic drugs in recent years, the problem of drug resistance in breast cancer, stomach cancer, lung cancer and other tumors has become more prominent. A high level of IL-8 expression has been found in a variety of drug-resistant tumors, after neutralises IL-8, the sensitivity of tumor cells to chemotherapy drugs was found to increase. Researchers have found that co-culturing bone marrow mesenchymal stem cells with acute myeloid leukaemia cells can protect the leukaemia cells from cell death caused by the chemotherapy drug etoposide. They also found that after using IL-8 antibodies to inhibit IL-8 activity, it increased the sensitivity of leukaemia cells to the chemotherapy drug etoposide and increased cell death, showing that IL-8 may be involved in the process of tumor resistance. Other studies have shown that after knocking out the IL-8 gene, both platinum drug-sensitive and drug-resistant strains showed increased sensitivity to platinum drugs. IL-8 can also regulate resistance-related genes and the expression of various anti-apoptosis genes mediates tumor drug resistance. These related studies have confirmed that IL-8 plays an important role in the drug resistance process of tumor cells.

• IL-8 Monoclonal Antibodies and Anti- Tumor Therapy

In order to target IL-8 signalling and thereby inhibit its role in tumor initiation and development, the study of IL-8 monoclonal antibodies has become a research hotspot in recent years, of which Humax-IL8 and ABX-IL8 have been extensively studied. The study found that the combination of Humax-IL8 and docetaxel was more effective in treating tumors than either drug alone. The combined treatment regimen significantly reduced the accumulation of suppressor cells in the tumor microenvironment of triple-negative breast cancer, suggesting that Humax-IL8 may play a tumor suppressor role in tumor treatment. In addition, some investigators have studied the safety and immune recognition of Humax-IL8 in Phase I clinical trials in patients with locally advanced solid tumors. Studies have shown that ABX-IL8 can inhibit tumor growth, angiogenesis and metastasis of human melanoma in in vivo experiments.

• IL-8 Gene Silencing and Anti-Tumor Therapy

In addition to the common immunotherapy, gene silencing therapy is widely used in a variety of tumors. In a study to investigate the effect of silencing the IL-8 gene on the biological properties and drug resistance of cancer stem cells, researchers found that silencing the IL-8 gene can significantly inhibit the self-renewal and in vitro tumorigenicity of hormone-independent prostate cancer stem cells and increase the chemosensitivity of the cells to docetaxel.