Disrupted Expression of CXCL5 in Colorectal Cancer Is Associated with Rapid Tumor Formation in Rats and Poor Prognosis in Patients

Abstract

Purpose: We isolated a subline (CC531M) from the CC531S rat colon carcinoma cell line, which grows and metastasizes much more rapidly than CC531S. We found, using RNA expression profiling, that one of the major changes in the CC531M cell line was a 5.8-fold reduction of the chemokine CXCL5. The purpose of this study was to determine the effect of CXCL5 expression on colorectal tumor growth and metastasis. Experimental Design: CC531 clones were generated with either knockdown or restored expression of CXCL5. These clones were inoculated in the liver of rats. In addition, in two independent cohorts of colorectal cancer patients, the level of CXCL5 expression was determined and associated to clinical variables. Results: Knockdown of CXCL5 expression in CC531S resulted in rapid tumor growth and increased number of metastasis, whereas restored expression of CXCL5 in CC531M resulted in a return of the ''mild'' tumor growth pattern of the parental cell line CC531S. In vitro, no difference was found in proliferation rate between clones with either high or low expression of CXCL5, suggesting that environmental interactions directed by CXCL5 determine tumor outgrowth. Finally, the importance of our findings was established for patients with colorectal cancer. We found that low expression of CXCL5 was significantly associated with poor prognosis for colorectal cancer patients. CXCL5 showed a trend (P = 0.05) for a positive correlation with intratumoral CD8 + T-cell infiltration, suggesting a possible explanation for the observed poorer prognosis. Conclusions: Our results show that CXCL5 is important in growth and development of colorectal cancer, implicating a future role in both cancer therapy and diagnosis.Colorectal cancer is one of the three leading causes of cancerrelated death among men and women in the western world (1, 2). Despite curative surgical resection of the primary tumor, 40% to 50% of the patients ultimately die of metastases (3). Tumor growth and metastasis result from a complex cascade of biological processes. Therefore, knowing key factors in these processes is crucial to design new treatment modalities.In a previous paper, we reported the in vivo selection of an aggressive rat colorectal cell line (CC531M) from the welldescribed CC531S cell line (4, 5). The present study was initiated to identify factors that contribute to rapid growth and metastatic capacity of CC531M. In this study, we focus on the chemokine CXCL5.CXCL5 is a member of the subfamily of lipopolysacharideinducible ELR + CXC chemokines (6). It functions, mainly through interaction with the CXCR2 receptor, both as a chemoattractant and as an angiogenic factor (7 -10). CXCL5 is expressed in the epithelial cells of the colon and overexpressed in colorectal cancer (11,12). It has been reported that CXCL5 plays a role in development and metastasis of several cancer types (13 -15). CXCL5 contributes to the in vivo growth and angiogenic potential of non -small cell lung cancer. Homogenates of human non -small cell lung cancer specimens...

CXCL5 as an autocrine or paracrine cytokine is associated with proliferation and migration of hepatoblastoma HepG2 cells

“…However, the preponderance of evidence showed that chemokines contribute mainly to carcinogenesis in the progress of cancers (19). Although CXCL5 has been reported to have numerous roles in carcinomas (20,21), to the best of our knowledge, the present study was the first to conduct a paracrine secretion assay to investigate the effects of endogenous CXCL5 secreted by hepatic stellate LX-2 cells on the oncogenic potential of HB HepG2 cells. HepG2 was originally thought to be a hepatocellular carcinoma cell line and was utilized to investigate hepatocellular carcinoma.…”

Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways

“…CXCL5 high patients had lower OS and DFS rates compared with CXCL5 low patients. In contrast, Frank et al demonstrated that the absence of CXCL5 expression in tumor tissues was correlated with poor prognosis in CRC, and they also found that CXCL5 was overexpressed in tumor tissues [22]. They attributed these phenomena to intratumoral infiltration of T cells and neutrophils.…”

CXCL5 as a potential novel prognostic factor in early stage non-small cell lung cancer: results of a study of expression levels of 23 genes

“…The CXCL5 expression has been shown to be elevated at both mRNA and protein levels and affect patients’ survival in a number of human tumors, including in pancreatic [31, 33], colorectal [34], breast [35], ovarian [36], or prostate [30] carcinomas. However, survival data are limited and inconsistent [31, 37–39]. In the study of White et al, risk of the recurrence after lung cancer resection in NSCLC patients’ was found to be associated with enhanced expression of the sum angiogenic CXC chemokines [12].…”