Role of CXCL7 in Colon Cancer Proliferation

Abstract

Colorectal cancer (CRC) is the third commonly diagnosed cancer worldly and the second cause of cancer-related mortality in the United States. It is a complex disease, and despite the improvements in CRC screening and treatments approximately half of the patients discovered their cancers at late and aggressive stage of the disease. Thus, there is a need to increase public awareness for the importance of early diagnosis that can interrupt CRC progression, especially among populations who are at higher risk for CRC. Furthermore, understanding the predisposition factors and molecular mechanisms can help to improve preventative strategies and develop an effective-targeted therapy for CRC. The tumor microenvironment (TME) is heterogeneous, consisting of blood vessels, lymph vessels, secreted proteins, extracellular matrix (ECM), stromal cells, immune/inflammatory cells, and other components. The continuous and dynamic interaction between cancer cells and the TME can promote cancer progression. One of the important players in the TME is the chemokines family, a class of pro-inflammatory cytokines with small molecular weights (~8–14 kDa) that are capable of chemotactic cell-directed movement. Recently, the role of chemokines in the TME has received great attention, and a vast number of studies indicate their role in cancer progression, especially in CRC. Chemokine (C-X-C motif) ligand 7 (CXCL7)/ NAP2 is an immediate mediator for neutrophils recruitment released from platelets at sites of inflammation, and it has been suggested as a potential biomarker for CRC diagnosis. Literature has reported that CXCL7 drives tumor progression and metastasis by binding to its receptor (CXCR2) in various cancer types such as cholangiocarcinoma, breast cancer, and CRC. Furthermore, several pieces of evidence indicate that the encoding gene for CXCL7 (PPBP) and CXCR2 receptors are highly expressed in patients with CRC. Thus, CXCL7 has been a potential biomarker for diagnosis of many cancers including early lung and CRC. CXCL7 also has been shown to stimulate glucose transporters and glycolysis in non-cancer cells. Additionally, recent evidence reports a correlation between CXCL7 and the key glycolytic enzyme; lactate dehydrogenase (LDH) and it is an independent risk factor for CRC prognosis. However, the role of the CXCL7-CXCR2 axis in CRC progression has not been fully understood. Hereby, we carried out this study to examine the role of the CXCL7-CXCR2 axis in mediating colon cancer proliferation. This study was the first to demonstrate that CXCL7 stimulates proliferation, lactate production, and glycolytic function in human colon cancer cells, suggesting that CXCL7 may stimulate colon cancer proliferation by enhancing aerobic glycolysis.