Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis.

Colorectal cancer (CRC) is the third most common cancer and also the leading cause of death from gastrointestinal malignancy in the United States. Colorectal cancer ranks second after lung cancer in death rates in the United States (Siegel et al, 2011). Studies suggest that chemokines and their receptors serve as important regulators of various metastatic and advanced cancers (Coussens and Werb, 2001; Coussens and Werb, 2002). Among them, interleukin-8 (IL-8) and its receptor CXCR2 are two of the most significantly upregulated chemokines in colon cancer (Chen et al, 2004). The role of IL-8 and CXCR2 in tumour development and progression has been well documented in a wide range cancer cells (Brat et al, 2005; Singh et al, 2006; Araki et al, 2007; Yao et al, 2007; Merritt et al, 2008; Waugh and Wilson, 2008; Singh et al, 2009). Expression and secretion of IL-8 by tumour cells enhance proliferation and survival of the cells through autocrine activation, and promote angiogenesis and neutrophil infiltration into the tumour. The proangiogenic effects of IL-8 have been shown to be independent from its chemotactic activity for neutrophils and other pro-inflammatory effects (Strieter et al, 1992; Hu et al, 1993; Li et al, 2003). The IL-8/CXCR2-mediated autocrine properties have been demonstrated to activate the intrinsic mechanism of tumour cells to evade stress-induced apoptosis (Maxwell et al, 2007). Therefore, tumour cell-derived IL-8 can exert profound effects on tumour growth, survival, invasion, angiogenesis, metastases, resistance and recurrence. Nonetheless, studies on the effects of tumour microenvironment-encoded IL-8 and CXCR2 are rather limited, mostly due to the intuitive speculation for the equivalent roles regardless of their sources. Importantly, a common single-nucleotide polymorphism (SNP) in IL-8 at −251 bp (251-bp upstream of the IL-8 transcription start site) has been associated with increased plasma levels of IL-8 (Hull et al, 2000) and with IL-8 promoter activities (Lee et al, 2005; Ohyauchi et al, 2005). This allele has recently been correlated with an increased risk of developing breast, prostate and gastric cancers (McCarron et al, 2002; Taguchi et al, 2005; Snoussi et al, 2006). We – for the first time – demonstrated that this IL-8T −251A polymorphism was individually associated with risk of tumour recurrence (Gordon et al, 2006). Moreover, our classification and regression tree analyses of CRC produced a classification tree with node status and four marker genes (IL-8, intracellular adhesion molecule-1, transforming growth factor-β and fibroblast growth factor receptor-4) (Gordon et al, 2006). Our genotyping study of 12 biomarker genes in 125 patients with advanced CRC found that patients with vascular endothelial growth factor (VEGF) +936 C/C and IL-8 −251A/A genotype were at the greatest risk to develop tumour recurrence (Lurje et al, 2008), suggesting that polymorphisms in VEGF and IL-8 may serve as a key biomarker to identify stage III CRC patients who are at a great risk for tumour recurrence. In a separate study (Schultheis et al, 2008), we identified statistically significant four polymorphisms in CXCR2 and VEGF and demonstrated that the IL-8A −251T polymorphism may be a molecular predictor of response to anti-VEGF chemotherapy. The CXCR2 C+785T and VEGF C+936T SNPs can be used as molecular markers for progression-free survival (PFS) in cancer patients. Together, the polymorphisms and expression of IL-8 and CXCR2 are strongly associated with not only tumour progression, but also tumour recurrence and oxaliplatin chemoresistance in patients with various cancers, including CRC (Gordon et al, 2006; Lurje et al, 2008; Schultheis et al, 2008; Zhang et al, 2009). We have recently reported that IL-8 regulates proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer models (Ning et al, 2011). In addition, our clinical data showed that patients with stage IV CRC display more than 10 times higher serum level of IL-8 (1089 pg ml−1±311), compared with individuals with no evidence of disease (79 pg ml−1±56) (Ning et al, 2011). In the current study, we tested whether the in-vivo tissue microenvironment with either elevated IL-8 or CXCR2 deletion will promote colon cancer growth, invasion and metastases using a novel IL-8 transgenic mouse model and a CXCR2 knockout (KO) model. Our findings using these mouse models demonstrate the critical roles of IL-8/CXCR2 in the tumour environment, which is highly cohesive with our numerous previous experimental and clinical data, and further indicates that IL-8 and CXCR2 may be an important therapeutic target against colon cancer.