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

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.

SUBMITTER: Cabrero-de Las Heras S

PROVIDER: S-EPMC6235799 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Cabrero-de Las Heras Sara S Martínez-Balibrea Eva E

World journal of gastroenterology 20181101 42

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 s ...[more]

PMID: 30479461

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Project description:BackgroundPancreatic cancer is one of the principal causes of tumor-related death worldwide. CXC chemokines, a subfamily of functional chemotactic peptides, affect the initiation of tumor cells and clinical outcomes in several human malignant tumors. However, the specific biological functions and clinical significance of CXC chemokines in pancreatic cancer have not been clarified.MethodsBioinformatics analysis tools and databases, including ONCOMINE, GEPIA2, the Human Protein Atlas, DAVID, GeneMANIA, cBioPortal, STRING, DGidb, MethSurv, TRRUST, SurvExpress, SurvivalMeth, and TIMER, were utilized to clarify the clinical significance and biological functions of CXC chemokine in pancreatic cancer.ResultsExcept for CXCL11/12, the transcriptional levels of other CXC chemokines in PAAD tissues were significantly elevated, and the expression level of CXCL16 was the highest among these CXC chemokines. Our findings also suggested that all of the CXC chemokines were linked to tumor-immune dysfunction involving the abundance of immune cell infiltration, and the Cox proportional hazard model confirmed that dendritic and CXCL3/5/7/8/11/17 were significantly associated with the clinical outcome of PAAD patients. Furthermore, increasing expressions of CXCL5/9/10/11/17 were related to unfavorable overall survival (OS), and only CXCL17 was a prognostic factor for disease-free survival (DFS) in PAAD patients. The expression pattern and prognostic power of CXC chemokines were further validated in the independent GSE62452 dataset. For the prognostic value of single CpG of DNA methylation of CXC chemokines in patients with PAAD, we identified 3 CpGs of CXCL1, 2 CpGs of CXCL2, 2 CpGs of CXCL3, 3 CpGs of CXCL4, 10 CpGs of CXCL5, 1 CpG of CXCL6, 1 CpG of CXCL7, 3 CpGs of CXCL12, 3 CpGs of CXCL14, and 5 CpGs of CXCL17 that were significantly associated with prognosis in PAAD patients. Moreover, the prognostic value of CXC chemokine signature in PAAD was explored and tested in two independent cohort, and results indicated that the patients in the low-risk group had a better OS compared with the high-risk group. Survival analysis of the DNA methylation of CXC chemokine signature demonstrated that PAAD patients in the high-risk group had longer survival times.ConclusionsThese findings reveal the novel insights into CXC chemokine expression and their biological functions in the pancreatic cancers, which might serve as accurate prognostic biomarkers and suitable immunotherapeutic targets for patients with pancreatic cancer.

Project description:Background Several studies have indicated that CXC chemokines influence the prognosis and therapy in patients with hepatocellular carcinoma (HCC). However, there are limited studies on the roles of CXC chemokines in HCC based on data acquired from various databases. This study aimed to conduct an in-depth and comprehensive bioinformatic analysis of the expression and functions of CXC chemokines in HCC. Methods Data was obtained from various databases including ONCOMINE, UALCAN, STRING, GeneMinia, DAVID, Kaplan-Meier plotter, TIMER, GSCALite and NetworkAnalyst for the analysis of the expression and functions of the CXC chemokines in HCC. Results Analysis of the differential expression levels of CXC chemokines between HCC and adjacent normal tissues revealed that the mRNA expression levels of CXCL1/2/5/6/7/12/14 were significantly lower in HCC tissues than those in adjacent normal tissues, whereas the mRNA expression levels of CXCL9/16/17 were significantly higher in HCC tissues. Analysis of the relationship between CXC chemokines and overall survival revealed that high mRNA expression levels of CXCL1/3/5/6/8 were associated with poor overall survival, whereas high mRNA expression levels of CXCL2/4/7/9/10/12 were associated with better overall survival. The functions of CXC chemokines and related genes were associated with cytokine-cytokine receptor interactions and chemokine signaling pathway. Analysis of the association between CXC chemokines and activity of cancer pathways indicated that the DNA damage response and hormone androgen receptor (AR) signaling pathways were inhibited, whereas apoptosis, epithelial-mesenchymal transition (EMT) and Ras/mitogen-activated protein kinase (MAPK) signaling pathways were activated. The expression of CXC chemokines was positively correlated with the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells). Conclusions This study has demonstrated that CXC chemokines can influence survival of patients with HCC by recruiting different types of immune cells into the tumor microenvironment.

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

Publications

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

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