Abstract
Colorectal cancer (CRC) is a major killer. Dysregulation of IL-37 and IL-38, both anti-inflammatory cytokines, is observed in auto-immune diseases. The precise regulatory mechanisms of IL-37/IL-38 during the development of CRC remains unclear, but chronic intestinal inflammation is involved in the carcinogenesis of CRC. Constitutive production of colonic IL-37 and IL-38 is substantially reduced in CRC, consistent with an inverse correlation with CRC differentiation. Reduced colonic IL-37 and IL-38 is relating to CRC invasion and distant metastasis, suggesting a protective role for IL-38 within the tumor micro-environment. IL-38 is reduced in right-sided CRC compared to left-sided CRC, which is in line with multiple risk factors for right-sided CRC, including the embryonic development of the colon, and genetic differences in CRC between these two sides. Finally, colonic IL-37 and tumor associated neutrophils (TAN) seem to be independent biomarkers of prognostic value, whereas colonic IL-38 seems to be a reliable and independent biomarker in predicting the 5-year survival post-surgery in CRC. However, there is room for improvement in available studies, including the extension of these studies to different regions/countries incorporating different races, evaluation of the role of multi-drug resistance, and different subsets of CRC. It would be useful to determine the kinetics of circulating IL-38 and its relationship with drug resistance/targeted therapy. The measurement of colonic IL-38 at the molecular and cellular level is required to explore the contribution of IL-38 pathways during the development of CRC. These approaches could provide insight for the development of personalized medicine.
Highlights
Edited by: Paola Ulivi, Scientific Institute of Romagna for the Study and Treatment of Tumors (IRCCS), Italy
IL-38 is reduced in right-sided Colorectal cancer (CRC) compared to left-sided CRC, which is in line with multiple risk factors for right-sided CRC, including the embryonic development of the colon, and genetic differences in CRC between these two sides
It would be useful to determine the kinetics of circulating IL-38 and its relationship with drug resistance/targeted therapy
Summary
A significant correlation is observed between the level of IL-37 expression and disease-free survival, as well as overall survival [39], suggesting that colonic IL-37 provides protection during the development of CRC. This observation in CRC is partially supported by the findings in gastric cancer, showing that mucosal IL-34 expression is inversely correlated with gastric cancer, including invasion, differentiation, and TNM [42], suggesting that mucosal IL-34 seems to protect against the development of GC, probably by stimulating the maturation of macrophages via the CSF1 receptor.
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