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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

 Bun Kim  ;  Yoojeong Seo  ;  Ji-Hee Kwon  ;  Youmi Shin  ;  Suhyun Kim  ;  Soo Jung Park  ;  Jae Jun Park  ;  Jae Hee Cheon  ;  Won Ho Kim  ;  Tae Il Kim 
 MOLECULAR CARCINOGENESIS, Vol.60(3) : 188-200, 2021-03 
Journal Title
Issue Date
Caco-2 Cells ; Colorectal Neoplasms / genetics ; Colorectal Neoplasms / metabolism ; Colorectal Neoplasms / pathology* ; Culture Media, Conditioned / pharmacology ; Gene Expression Regulation, Neoplastic ; Humans ; Interleukin-6 / metabolism* ; Interleukin-8 / metabolism* ; Myofibroblasts / metabolism ; Myofibroblasts / pathology ; Neoplastic Stem Cells / drug effects ; Neoplastic Stem Cells / metabolism ; Neoplastic Stem Cells / pathology* ; Organoids / pathology ; STAT3 Transcription Factor / antagonists & inhibitors ; STAT3 Transcription Factor / metabolism ; Transcription Factor HES-1 / genetics ; Transcription Factor HES-1 / metabolism* ; Tumor Microenvironment / drug effects
HES1 ; IL-6 ; IL-8 ; cancer stem cell ; colorectal cancer ; myofibroblast
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Won Ho(김원호) ORCID logo https://orcid.org/0000-0002-5682-9972
Kim, Tae Il(김태일) ORCID logo https://orcid.org/0000-0003-4807-890X
Park, Soo Jung(박수정)
Park, Jae Jun(박재준)
Cheon, Jae Hee(천재희) ORCID logo https://orcid.org/0000-0002-2282-8904
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