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Review
. 2018 Nov 14;24(42):4738-4749.
doi: 10.3748/wjg.v24.i42.4738.

CXC family of chemokines as prognostic or predictive biomarkers and possible drug targets in colorectal cancer

Sara Cabrero-de Las Heras  1 , Eva Martínez-Balibrea  1
Affiliations
Review

CXC family of chemokines as prognostic or predictive biomarkers and possible drug targets in colorectal cancer

Sara Cabrero-de Las Heras et al. World J Gastroenterol. .

Abstract

Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women, worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates. In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines (CXCL1 to 17) are small (8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors (CXCR) 1 to 8. Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively. In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore, the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer. These pathways have been studied in tumor tissues (using immunohistochemistry or measuring mRNA levels) or serum [using enzyme-linked immuno sorbent assay (ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes the most recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy.

Keywords: Bevacizumab; Biomarkers; CXC chemokines; Chemotherapy; Colorectal cancer; Immune system; Immunotherapy; Irinotecan; Oxaliplatin; Treatment.

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Conflict of interest statement

Conflict-of-interest statement: The authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1
CXCL and CXCR regulatory mechanisms. Figure 1 illustrates CXCL binding to the CXCR located at the cellular membrane, internalizing and transducing the signal into the nucleus. CXCR internalization is usually followed by degradation or recycling to the plasma membrane.
Figure 2
Figure 2
CXCL and CXCR network in physiological and cancer conditions. A: The binding of CXCL to CXCR triggers the activation of signaling pathways, such as PKB/AKT and ERK/MAPK. Both pathways share NF-κB as a downstream factor which, in the nucleus, promotes the transcription of the CXCLs. These pathways maintain the physiologic conditions inside the cell. B: In a cancer cell exposed to chemotherapy, the situation is different. The chemotherapeutic treatment promotes the hyperactivation of these pathways. As a result, the CXCLs are also more abundant, promoting an autocrine response and, further, a positive feedback loop. This response results in pathological processes, such as tumor growth and metastasis, and in resistance to anticancer treatments. PKB: Protein kinase B; ERK: Extracellular signal-regulated kinases; MAPK: Mitogen-activated protein kinase; NF-κB: Nuclear factor κB.
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