Stage-dependent alterations of the serum cytokine pattern in colorectal carcinoma

Inflammation has a significant influence in the development of colorectal cancer (CRC) (Pages et al, 2010; Terzic et al, 2010). Patients with chronic inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, have an increased risk of developing CRC (Eaden et al, 2001; von Roon et al, 2007). Preventive effect of NSAIDs on the development of CRC has been shown in epidemiological studies (Rothwell et al, 2010) and also in a randomised placebo-controlled trial in HNPCC (Burn et al, 2011). Immune cells also contribute to the immunosurveillance, and high-grade peri- and intratumoral inflammatory cell infiltration is an independent indicator of an improved survival in CRC (Klintrup et al, 2005; Galon et al, 2006; Roxburgh et al, 2009). Moreover, systemic inflammatory markers like modified Glasgow prognostic score (mGPS) and blood neutrophil/lymphocyte ratio have established prognostic value in CRC (Roxburgh and McMillan, 2010). Cytokines are key regulators of immune responses in cancer. They can modulate tumour growth and microenvironment by mediating interactions between cancer cells and infiltrating inflammatory cells. On the basis of their function, cytokines can be grouped into anti- or proinflammatory cytokines, chemokines, and growth factors. Moreover, the classification into Th1 and Th2 cytokines is of importance. In general, Th1-type cytokines, e.g., interleukin (IL)-12, IL-15, and interferon gamma (IFN-γ), contribute to cellular immune reactions considered essential for an effective response against tumour cells, whereas Th2-type cytokines, e.g., IL-4, IL-5, IL-10, and IL-13, may suppress the tumour-specific immune response (Ellyard et al, 2007; Cui and Florholmen, 2008). The development of CRC is accompanied by alterations in cytokine production, which is thought to polarise from Th1 into Th2 along the colorectal adenoma–carcinoma sequence (Cui and Florholmen, 2008). Increased serum cytokine concentrations, e.g., elevated levels of IL-8 (Ueda et al, 1994), IL-6 (Knupfer and Preiss, 2010), and platelet-derived growth factor (PDGF) (Belizon et al, 2009) have been reported in CRC patients compared with healthy individuals, and certain cytokines and chemokines, such as IL-6 and VEGF, are considered to have prognostic value (Chung and Chang, 2003; De Vita et al, 2004; Knupfer and Preiss, 2010). One of the limitations of the previous studies examining serum inflammatory markers has been that they have focused on the levels of one or few cytokines at a time. However, relative alterations in cytokine levels can have substantial effects in the immune functions (Commins et al, 2010). Therefore, it is likely that an analysis of extensive set of cytokines would provide more accurate information on the tumour-related immunological responses, thus also bringing out the importance of individual cytokines on the immune response against CRC. Tumour stage (TNM classification) is the most important prognostic factor in CRC (Puppa et al, 2010), and 5-year survival rate varies from 90% in stage I tumours to <10% in advanced stage IV tumours (O'Connell et al, 2004). To reduce mortality, it is essential to develop diagnostic tools for the early detection of cancer, which could be easily adapted to clinical use. At the moment, stool tests are neither very sensitive nor specific, and colonoscopy is a time-consuming and costly screening method (Sturgeon et al, 2008). Several serum markers have been assessed in the diagnostics of the disease, but none have been adapted to routine use so far (Sturgeon et al, 2008). The aim of this study was to evaluate the pattern of alterations in the serum cytokine levels in CRC patients compared with controls. Accordingly, we analysed serum levels of 27 cytokines and chemokines from a series of 148 newly diagnosed CRC patients, and healthy controls matched for age and gender. An additional goal was to see whether the patterns of the serum cytokines in CRC could provide information of tumour stage.