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Role of C-X-C chemokine ligand 12/C-X-C chemokine receptor 4 in the progression of hepatocellular carcinoma.

ABSTRACT: The efficacy of the current non-surgical treatments for advanced hepatocellular carcinoma (HCC) remains limited and novel treatments are required to improve patient outcomes. The majority of HCCs develop from chronically damaged tissue that contains a high degree of inflammation and fibrosis, which promotes tumor progression and resistance to therapy. Understanding the interaction between stromal components and cancer cells (and the signaling pathways involved in this interaction) could aid the identification of novel therapeutic targets. Numerous studies have demonstrated a marked association between high C-X-C chemokine receptor 4 (CXCR4) expression and the invasiveness, progression and metastasis of HCC. The present review will investigate the different roles of CXCR4 in the progression of HCC and discuss possible future treatments. Through the C-X-C chemokine ligand 12 (CXCL12)/CXCR4 signaling pathway, ephrin A1 activation enhances the migration of endothelial progenitor cells to HCC to enable the neovascularization of tumors. There is an association between nuclear CXCR4 expression and the lymph node metastasis of HCC to distant areas. CXCR4 enhances cell migration in vitro and cell homing in vivo. CXCR4 levels are concentrated at the border of a tumor and in perivascular areas, inducing invasive behavior. The binding of CXCL12 to CXCR4 activates intracellular signaling pathways and induces crosstalk with transforming growth factor-β signaling, which enhances the migration of cancer cells. The CXCL12/CXCR4 axis also activates expression of matrix metalloproteinase 10, which further stimulates migration. CXCR4 is likely to crosstalk with the sonic hedgehog signaling pathway, contributing to tumor invasiveness and supporting the cancer stem-cell population; as a result, CXCR4 can be regarded as a cancer stem-cell marker. CXCR4 influences interstitial fluid flow-induced invasion. CXCR4 expression and HCC cell migration are promoted by α-fetoprotein, which activates AKT/mechanistic target of rapamycin signaling. CXCR4 also has the potential to affect sorafenib treatment for HCC. Targeting the CXCL12/CXCR4 signaling pathway may, therefore, be a promising strategy in HCC treatment.

SUBMITTER: Jeng KS

PROVIDER: S-EPMC5529928 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:Background and aimsHepatocellular carcinoma (HCC) is an aggressive malignancy which is often associated with a complex tumor microenvironment attributable to etiology-induced cellular inflammation. γδ T cells are known to detect and react to chronic inflammation, which is linked to cancer development, progression, and metastasis. Our recent genomic study revealed an increased infiltration of several immune cell types, including γδ T cells, in tumor microenvironments of a Thai HCC subtype associated with a good prognosis.Approach and resultsHere, we quantified the amount of γδ T cells using a γδ T-cell-specific gene signature in 247 Chinese HCC patients. We also validated the γδ T-cell signature in American HCC patients. Additionally, such an association was only found in tumor transcriptomic data, but not in adjacent nontumor transcriptomic data, suggesting a selective enrichment of γδ T cells in the tumor microenvironment. Moreover, the γδ T-cell signature was positively correlated with the expression of natural killer cell receptor genes, such as NKG2D and cytolytic T-cell genes granzymes and perforin, suggesting a stronger T-cell-mediated cytotoxic activity. Furthermore, we found that the γδ T-cell-specific gene expression is positively correlated with the expression of chemokine (C-C motif) ligand 4 (CCL4)/chemokine (C-C motif) ligand 5 (CCL5) and C-C chemokine receptor type 1 (CCR1)/C-C chemokine receptor type 5 (CCR5), the receptors for γδ T cells. We validated these results using immunohistochemical analysis of formalin-fixed, paraffin-embedded tumor biopsies from 182 HCC patients. Moreover, we found evidence of CCL4/CCL5-mediated recruitment of γδ T cells both in vitro and in a murine orthotopic Hepa1-6 HCC model.ConclusionsWe propose that CCL4/CCL5 may interact with their receptor, CCR1/CCR5, which may facilitate the recruitment of γδ T cells from peripheral blood or peritumor regions to the tumor regions. Consequently, an increasing infiltration of γδ T cells in tumors may enhance antitumor immunity and improve patients' prognosis.

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Role of C-X-C chemokine ligand 12/C-X-C chemokine receptor 4 in the progression of hepatocellular carcinoma.

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