IL‐6 and IL‐8, secreted by myofibroblasts in the tumor microenvironment, activate HES1 to expand the cancer stem cell population in early colorectal tumor

Abstract

Interaction between a tumor and its microenvironment is important for tumor initiation and progression. Cancer stem cells (CSCs) within the tumor interact with a microenvironmental niche that controls their maintenance and differentiation. We investigated the CSC‐promoting effect of factors released from myofibroblasts into the microenvironment of early colorectal cancer tumors and its molecular mechanism. By messenger RNA microarray analysis, expression of HES1, a Notch signaling target, significantly increased in Caco‐2 cells cocultured with 18Co cells (pericryptal myofibroblasts), compared to its expression in Caco‐2 cells cultured alone. Caco‐2 cells cultured in 18Co‐conditioned media (CM) showed a significant increase in CD133+CD44+ cells and HES1 expression compared to that in Caco‐2 cells cultured in regular media. Significant amounts of interleukin‐6 (IL‐6) and IL‐8 were detected in 18Co‐CM compared to levels in regular media. The 18Co‐CM‐induced increase in CD133+CD44+ cells was attenuated by IL‐6‐ and IL‐8‐neutralizing antibodies. Furthermore, these neutralizing antibodies and inhibitors of STAT3 and gamma‐secretase reduced the expression of HES1 induced in Caco‐2 cells cultured in 18Co‐CM. Immunohistochemical analysis of human tissues revealed that IL‐6, IL‐8, and HES1 expression increased from normal to adenoma, and from adenoma to cancer tissues. In addition, IL‐6 and HES1 expression was positively correlated in early colorectal cancer tissues. In conclusion, the increase of CSCs by myofibroblasts could be mediated by IL‐6/IL‐8‐induced HES1 activation in the tumor microenvironment. Based on these data, the IL‐6/IL‐8‐mediated Notch/HES1 and STAT3 pathway, through which CSCs interact with their microenvironment, might be a potential target for the prevention and treatment of colorectal tumors.

Correlation and prognostic implications of intratumor and tumor draining lymph node Foxp3+ T regulatory cells in colorectal cancer

“…As a previous study indicated that hypoxic tumor microenvironment (TME) could result in a significant metabolic reprogramming for Tregs (which are especially susceptible to hypoxic metabolic signaling) and subsequently lead to an abnormal survival and proliferation of these cells [ 64 ]. Except this, it was found that certain inflammatory cytokines like IL-6, which was significantly higher in TME and peripheral blood of CRC patients [ 65 , 66 ], could impact the migration capacity of Tregs to the lesion [ 67 ]. Take into account these studies, we speculate that the cases with blank Tregs would have a special TME or significant high IL-6 that could prevent the infiltrating or kill Tregs; however, more studies are still needed to validate this speculation.…”

Combined detection of preoperative neutrophil to lymphocyte ratio and interleukin-6 as an independent prognostic factor for patients with non-metastatic colorectal cancer

“…Gastrointestinal cancer appears to be particularly sensitive to inflammation (20,21). Inflammation can trigger and accelerate the development of cancer, leading to the formation of malignant tumors (22). IL-6 is a key regulator of CRC tumorigenesis, tumor growth, metastasis, and chemotherapy resistance, and it mainly activates the ERK, AKT, JAK2/STAT3 pathway and Twist initiating a vicious loop securing the EMT phenotype (23,24).…”

Combined Detection of Preoperative Neutrophil to Lymphocyte Ratio and Interleukin-6 as an Independent Prognostic Factor for Patients with Non-Metastatic Colorectal Cancer

“…Gastrointestinal cancer seems to be particularly sensitive to inflammation [19,20]. Inflammation can trigger and accelerate the development of cancer, leading to the formation of malignant tumors [21]. IL-6 is a key regulator of prostate tumorigenesis, tumor growth, metastasis and chemotherapy resistance [22].…”