고지방식이에 의한 대장 줄기세포 조절 연구

Abstract

Dietary signals are known to modulate stemness and tumorigenicity of intestinal progenitors. Previous other studies demonstrated that high-fat-diet (HFD) enhanced numbers of Lgr5+ intestinal stem cells (ISCs) and further promoted primary and metastatic colon cancer. However, little is known how HFD-induced obesity affects ISC niche which might be involved in initiation of colorectal cancer. Understanding their effects will provide the mechanism about the risk factors of HFD-induced colorectal cancer. In this study, we found that histopathological scores were enhanced in the colon of HFD-fed mice in comparison to those of purified diet (PD)-fed one in a steady state. We confirmed that HFD feeding resulted in highly enhanced susceptibility to AOM-DSS-induced colorectal cancer. Although no significant changes of ISC numbers were addressed in the colon of HFD-fed mice, Ki67+ proliferating cells were significantly increased in the proximal and distal regions. Since deep crypt secretory cells, one of the niches supporting ISC maintenance in the colon, were not altered by HFD feeding, we next focused on the function of colon mesenchymal stromal cells (MSCs). Compared to those from PD-fed mice, colonic MSCs isolated from HFD-fed mice enhanced the growth of organoid derived from normal and malignant colon. The fact that Wnt2b secretion by colon PDGFR-α+ MSCs was significantly higher in HFD-fed mice than those in PD-fed mice, indicating that MSCs might play a crucial role on tumorigenesis in the colon of obese mice. Metagenomic analysis showed that decreased diversity of resident gut bacteria were found in the feces of HFD-fed mice when compared with those from PD-fed mice. Levels of free-fatty-acid (FFA) in the cecal contents were increased in HFD-fed mice compared to PD-fed mice while no differences of short chain fatty acid were revealed. Furthermore, FFA was indispensable factor to promote colon organogenesis. Taken together, these results demonstrate that colon PDGFR-α+ MSCs and FFA might be critically involved on modulation of intestinal cancer stem cells in HFD-induced obesity. Keywords: HFD; colon cancer; ISCs; MSCs