Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer

Nakano, Michitaka; Kikushige, Yoshikane; Miyawaki, Kohta; Kunisaki, Yuya; Mizuno, Shinichi; Takenaka, Katsuto; Tamura, Shingo; Okumura, Yuta; Ito, Mamoru; Ariyama, Hiroshi; Kusaba, Hitoshi; Nakamura, Masafumi; Maeda, Takahiro; Baba, Eishi; Akashi, Koichi

doi:10.1038/s41388-018-0480-0

Cited by 91 publications

(85 citation statements)

References 53 publications

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“…One study also showed that E. faecalis , which can cause colitis after infection, can express TGF‐β in the intestinal epithelial cells of wild‐type mice, thereby activating the Smad signaling pathway . In this process, the dedifferentiation of TGF‐β signal transduction enhances the stem cell characteristics of CRC, thereby promoting its occurrence . This is associated with the deletion of the expression of the TLR2 protein and the inhibition of NF‐κB‐dependent pro‐inflammatory gene expression (Fig.…”

Section: Typical Microbial Families Contributing To Colorectal Cancermentioning

confidence: 93%

“…54 In this process, the dedifferentiation of TGF-β signal transduction enhances the stem cell characteristics of CRC, thereby promoting its occurrence. 55 This is associated with the deletion of the expression of the TLR2 protein and the inhibition of NF-κB-dependent pro-inflammatory gene expression 54 (Fig. 3).…”

Section: Typical Microbial Families Contributing To Colorectal Cancermentioning

confidence: 99%

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The role of microbiota in the development of colorectal cancer

Dai

Zhang

et al. 2019

Intl Journal of Cancer

104

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Colorectal cancer is the third largest cancer in worldwide and has been proven to be closely related to the intestinal microbiota. Many reports and clinical studies have shown that intestinal microbial behavior may lead to pathological changes in the host intestines. The changes can be divided into epigenetic changes and carcinogenic changes at the gene level, which ultimately promote the production and development of colorectal cancer. This article reviews the pathways of microbial signaling in the intestinal epithelial barrier, the role of microbiota in inflammatory colorectal tumors, and typical microbial carcinogenesis. Finally, by gaining a deeper understanding of the intestinal microbiota, we hope to achieve the goal of treating colorectal cancer using current microbiota technologies, such as fecal microbiological transplantation.

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Section: Typical Microbial Families Contributing To Colorectal Cancermentioning

confidence: 93%

Section: Typical Microbial Families Contributing To Colorectal Cancermentioning

confidence: 99%

The role of microbiota in the development of colorectal cancer

Dai

Zhang

et al. 2019

Intl Journal of Cancer

104

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“…TWIST1 and SNAI1 (Snail) are master regulators of EMT and the key genes for inducing dedifferentiation of non-CSCs toward a CSC-like state (Batlle & Clevers, 2017;Nakano et al, 2018). TWIST1 mediates this process in a mechanism dependent or independent on EMT (Nakano et al, 2018). ZEB1 is another key regulator of the EMT that its activation by transforming growth factor-β (TGF-β) in non-CSCs could switch them to the CSC state (Chaffer et al, 2013).…”

Section: Plasticity Of Cscs (Stemness Differentiation and Dediffementioning

confidence: 99%

Cancer stem cells (CSCs) in cancer progression and therapy

Najafi

Farhood

Mortezaee

2018

Journal Cellular Physiology

446

268

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Cancer stem cells (CSCs) are self‐renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor‐type dependent. The transition between CSCs with cancer cells and other non‐CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer‐associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non‐CSCs toward attaining a CSC‐like phenotype. WNT/β‐catenin, transforming growth factor‐β, Hedgehog, and Notch are important signals for maintaining self‐renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non‐CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens.

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“…Therefore, Lgr5 + CD44 + EpCAM + cells from DLD-1, and seven tissue samples (patient #1, 3,4,6,8,11,12) sorted by flow cytometry were used for further study. Our data showed that the level of KLF4 expression was significantly higher in Lgr5 + CD44 + EpCAM + cells than those of Lgr5 − CD44 − EpCAM − cells ( Figure S1A).…”

Section: Expression Of Klf4 In Lgr5 + Cd44 + Epcam + Colorectal Cscsmentioning

confidence: 99%

Krüppel‐like factor 4 regulates stemness and mesenchymal properties of colorectal cancer stem cells through the TGF‐β1/Smad/snail pathway

Leng

Zhou

et al. 2019

J Cellular Molecular Medi

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| INTRODUC TI ONCancer metastasis contributes to approximately 90% of cancer-related deaths. 1 Accumulating evidence indicates that cancer stem cells (CSCs) are responsible for the seeding and colonization of cancer metastasis. 2-4 For the past decades, studies have explored and investigated the mechanisms of human carcinogenesis to help develop novel therapeutic strategies. To date, cancer treatment has not been much improved in advanced and chemo-resistant human cancers. Thus, a better understanding of CSCs behaviour in human cancers, including colorectal cancers (CRC), could provide insight into defining the molecular mechanisms of tumorigenesis and cancer progression. Indeed, identification of CSC markers is a very hot topic and interesting data have been generated. 5 For example, CSC markers for breast, prostate, AbstractKrüppel-like factor 4 (KLF4) was closely associated with epithelial-mesenchymal transition and stemness in colorectal cancer stem cells (CSCs)-enriched spheroid cells.Nonetheless, the underlying molecular mechanism is unclear. This study showed that KLF4 overexpression was accompanied with stemness and mesenchymal features in Lgr5 + CD44 + EpCAM + colorectal CSCs. KLF4 knockdown suppressed stemness, mesenchymal features and activation of the TGF-β1 pathway, whereas enforced KLF4 overexpression activated TGF-β1, phosphorylation of Smad 2/3 and Snail expression, and restored stemness and mesenchymal phenotypes. Furthermore, TGF-β1 pathway inhibition invalidated KLF4-facilitated stemness and mesenchymal features without affecting KLF4 expression. The data from the current study are the first to demonstrate that KLF4 maintains stemness and mesenchymal properties through the TGF-β1/Smad/Snail pathway in Lgr5 + CD44 + EpCAM + colorectal CSCs. K E Y W O R D Scancer stem cell, colorectal cancer, Krüppel-like factor 4, snail, TGF-β1

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Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer

Cited by 91 publications

References 53 publications

The role of microbiota in the development of colorectal cancer

The role of microbiota in the development of colorectal cancer

Cancer stem cells (CSCs) in cancer progression and therapy

Krüppel‐like factor 4 regulates stemness and mesenchymal properties of colorectal cancer stem cells through the TGF‐β1/Smad/snail pathway

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