Interleukin-8 and Interleukin-6 Are Biomarkers of Poor Prognosis in Esophageal Squamous Cell Carcinoma

SIMPLE SUMMARY: Esophageal squamous cell carcinoma (SCC) is an extremely aggressive malignancy with high mortality rates. An important variable in understanding this aggressiveness seems to be in controlling the proliferation of malignant cells directly or indirectly related to systemic levels of inflammatory cytokines. Therefore, we sought to assess the usefulness of determining the most prominent cytokines in this context and their potential role as diagnostic biomarkers. For this purpose, we analyzed the levels of IL-1β, IL-6, IL-8, IL-10, TNF-α and IL-12p70 in a group of 70 patients with ESCC and 70 healthy individuals and detected increased levels of IL-1β, IL-6, IL-8 and IL-10 in patients with ESCC compared to controls. We also observed that patients with low IL-6, IL-8 had a significantly higher overall survival rate. To confirm these findings, we studied Kyse-30 and Kyse-410 cells cultured in mice and confirmed that increased growth of these cells was associated with recruitment/accumulation of intratumoral polymorphonuclear leukocytes. ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is a common type of cancer characterized by fast progression and high mortality rates, which generally implies a poor prognosis at time of diagnosis. Intricate interaction networks of cytokines produced by resident and inflammatory cells in the tumor microenvironment play crucial roles in ESCC development and metastasis, thus influencing therapy efficiency. As such, cytokines are the most prominent targets for specific therapies and prognostic parameters to predict tumor progression and aggressiveness. In this work, we examined the association between ESCC progression and the systemic levels of inflammatory cytokines to determine their usefulness as diagnostic biomarkers. We analyzed the levels of IL-1β, IL-6, IL-8, IL-10, TNF-α e IL-12p70 in a group of 70 ESCC patients and 70 healthy individuals using Cytometric Bead Array (CBA) technology. We detected increased levels of IL-1β, IL-6, IL-8, and IL-10 in ESCC patients compared to controls. However, multivariate analysis revealed that only IL8 was an independent prognostic factor for ESCC, as were the well-known risk factors: alcohol consumption, tobacco usage, and exposure to pesticides/insecticides. Importantly, patients with low IL-6, IL-8, TNM I/II, or those who underwent surgery had a significantly higher overall survival rate. We also studied cultured Kyse-30 and Kyse-410 cells in mice. We determined that the ESCC cell line Kyse-30 grew more aggressively than the Kyse-410 cell line. This enhanced growth was associated with the recruitment/accumulation of intratumoral polymorphonuclear leukocytes. In conclusion, our data suggest IL-8 as a valuable prognostic factor with potential as a biomarker for ESCC.