CXCL5 as a prognostic biomarker for hepatocellular carcinoma and potential therapeutic target?

• Zhou SL, Dai Z, Zhou ZJ, et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 2012;56:2242–54.

Chronic inflammation has been linked to many aspects of tumour development including initiation, proliferation, survival and metastasis. Uncovering the complicated signalling mechanisms involved in inflammation mediated tumour pathogenenicity remains challenging. Recently, CXCL5 (epithelial neutrophil activating peptide-78) was shown to be highly expressed in various malignancies and was positively associated with disease progression. Functionally, CXCL5 is a chemotactic protein capable of potent neutrophil recruitment. Neutrophil infiltration to the tumour site enhances metastasis in part through the secretion of hepatocyte growth factor and other immunoreactive molecules. However, whether CXCL5 plays a functional role in hepatocellular carcinoma (HCC) is largely unknown. In this study, Zhou et al analysed multiple in vitro HCC cell lines and observed significant expression of CXCL5 with highest abundance evident in the most invasive lines. Stable knockdown of CXCL5 revealed decreased cell proliferation, migration and invasion of the HCC cells, which functioned through a mechanism of PI3K-Akt and ERK1/2 signalling. Orthotropic transplantation of CXCL5 positive HCC cells into nude mice led to larger tumour formation, secondary pulmonary metastases, and increased Gr1⁺ neutrophil infiltration compared to CXCL5 negative transplanted cells. Clinically, human HCC tumours contained higher mRNA levels of CXCL5 compared to peri-tumoural liver tissue. Higher CXCL5 content was associated with increased CD66b⁺ intra-tumoural neutrophil infiltration. Tissue microarray analyses generated from HCC patients revealed high expression of CXCL5 correlated with enhanced tumour size, tumour encapsulation, vascular invasion, and tumour-node-metastasis staging. Strikingly, patients with high CXCL5 and CD66b⁺ phenotypes exhibited lower overall survival rates and increased cumulative recurrence rate. Overall, CXCL5 was found to be a critical component in cancer related inflammation as well as an independent prognostic indicator for overall survival …