Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma

Abstract

CXCL5 (epithelial neutrophil-activating peptide-78) is a member of a proangiogenic subgroup of the CXC-type chemokine family of small, secreted proteins. Recently, evidence that CXCL5 is involved in carcinogenesis and cancer progression has emerged. To investigate the role of CXCL5 in tumor growth, invasion, and prognosis of hepatocellular carcinoma (HCC), we examined CXCL5 messenger RNA (mRNA) and protein levels in HCC cell lines with various metastatic potentials and in three independent cohorts of 919 HCC patients. We found that CXCL5 expression was increased in the highly metastatic HCC cell lines and in tumor tissues from patients with recurrent HCC compared to controls. CXCL5 activated the PI3K-Akt and ERK1/2 signaling pathways in HCC cells and promoted proliferation, migration, and invasion. Furthermore, we found that CXCL5 had a direct chemoattractant effect on neutrophils in vitro. In animal studies, the up-regulation of CXCL5 in HCC cells promoted tumor growth, lung metastasis, and intratumoral neutrophil infiltration. Conversely, down-regulation of CXCL5 in HCC cells reduced tumor growth, metastasis, and intratumoral neutrophil infiltration. Immunohistochemical analysis in HCC samples showed that overexpression of CXCL5 was well correlated with intratumoral neutrophil infiltration, shorter overall survival, and tumor recurrence. Multivariate analysis revealed that CXCL5 overexpression alone, or combined with the presence of intratumoral neutrophils, was an independent prognostic indicator for overall survival and cumulative recurrence. Conclusion: CXCL5 promotes HCC cell proliferation, invasion, and intratumoral neutrophil infiltration. CXCL5 overexpression, alone or combined with intratumoral neutrophil presence, is a novel prognostic predictor, and CXCL5 is a potential therapeutic target for HCC. (HEPATOLOGY 2012;56:2242-2254

Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway

“…It should be noted that this study primarily focused on macrophages that infiltrated the stroma of the tumor. However, the tumor immune microenvironment is composed of various kinds of immune-related cells, such as neutrophils (49), natural killer T cells (50), T lymphocytes (51) and T regulatory cells (52), which can influence the biological activity of HCC cells. Although the macrophage is widely recognized as the major type of inflammatory cell that infiltrates tumors, we cannot be certain that the macrophage is the only cell type influencing EMT in HCC.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…[149] Urothelial carcinoma An NLR>2.5 was found to be a predictor of invasiveness. [433] overexpressed in hepatocellular carcinoma from patients with recurrent disease as well as in highly metastatic hepatocellular carcinoma cell lines [381]. The upregulation of CXCL5 in hepatocellular carcinoma cells correlated with the promotion of tumor growth, lung metastasis and intratumoral neutrophil infiltration [381].…”

“…[433] overexpressed in hepatocellular carcinoma from patients with recurrent disease as well as in highly metastatic hepatocellular carcinoma cell lines [381]. The upregulation of CXCL5 in hepatocellular carcinoma cells correlated with the promotion of tumor growth, lung metastasis and intratumoral neutrophil infiltration [381]. Is it possible that the elevated neutrophil counts in cancer patients are actually the consequence of a more advanced stage, and therefore predict an apparent poorer prognosis?…”

The role of neutrophils in the development of liver diseases

“…CXCL5 overexpression, alone or in combination with intratumoral neutrophils, was an important HCC prognostic predictor. 65 The tumor microenvironment polarizes tumor-associated macrophages toward a pro-tumor (M2) versus an anti-tumor (M1) phenotype. 66 Like tumor-associated macrophages, tumor-associated neutrophils also have differential states of activation/differentiation, suggesting a tumor-associated neutrophil classification scheme that is similar to that of the tumor-associated macrophages.…”