Long-lived intestinal tuft cells serve as colon cancer–initiating cells

Westphalen, C. Benedikt; Asfaha, Samuel; Hayakawa, Yoku; Takemoto, Yasuhiko; Lukin, Dana J.; Nuber, Andreas H.; Brandtner, Anna; Setlik, Wanda; Remotti, Helen; Muley, Ashlesha; Chen, Xiaowei; May, Randal; Houchen, Courtney W.; Fox, James G.; Gershon, Michael D.; Quante, Michael; Wang, Yichen

doi:10.1172/jci73434

Cited by 336 publications

(464 citation statements)

References 67 publications

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“…47 Moreover, in the setting of APC deficiency, Dclk1C cells remained persistently quiescent, but surprisingly could be converted into potent cancer initiating cells in the setting of an inflammatory stimulus such as DSS colitis. 10 While surprising at first, the exquisite role of NF-kB signaling in inflammatory gastrointestinal carcinogenesis is well established, 48 and in fact the results are in line with observations from Florian Greten's group. 49 In a series of elegant experiments, Schwittala and colleagues were able to demonstrate that intestinal inflammation induced NF-kB signaling, which in turn stimulated Wnt signaling.…”

Section: Dclk1 As a Marker Of Cancer Stem And Initiating Cellssupporting

confidence: 69%

“…11 The profound differences between the 2 studies might be explained through the Dclk1 haploinsufficiency in Dclk1-CreERT knockin mice, pointing to an importance of protein function of Dclk1 itself. Indeed, the specific knock out of one copy of Dclk1 in our Dclk1-CreERT-BAC transgenic mice (Dclk1 ko/wt ) resulted in the loss of the long-lived Dclk1C population 10 ( Fig. 1).…”

Section: Introductionmentioning

confidence: 91%

“…10 Using a knockin construct of Dclk1-CreERT, Chiba and co-workers also investigated the role of Dclk1C cells in homeostasis and malignancy. The suggested that Dclk1 cells were short lived and did not display progenitor abilities and that Dclk1 might also define cancer stem cells in APC min adenomas.…”

Section: Introductionmentioning

confidence: 99%

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Functional implication of Dclk1 and Dclk1-expressing cells in cancer

2016

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Doublecortin like kinase protein 1 (Dclk1) is a microtubule-associated protein with C-terminal serine/threonine kinase domain. Originally designated Doublecortin and CaM kinase-like 1 protein (Dcamkl1) or KIAA0369, Dclk1 was first described as a marker for radial glia cells in the context of microtubule polymerization and neuronal migration, possibly contributing to early neurogenesis. Additionally, Dclk1 was proposed as a marker of quiescent gastrointestinal and pancreatic stem cells, but in recent years has been recognized as a marker for tuft cells in the gastrointestinal tract. While Dclk1C tuft cells are now considered as niche or sensory cells in the normal gut, growing evidence supports a role for Dclk1 function in a variety of malignancies, modulating the activity of multiple key pathways, including Kras signaling. Here, we review the recent advances in understanding of the importance of Dclk1 function in tumorigenesis and cancer.

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Section: Dclk1 As a Marker Of Cancer Stem And Initiating Cellssupporting

confidence: 69%

Section: Introductionmentioning

confidence: 91%

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Functional implication of Dclk1 and Dclk1-expressing cells in cancer

2016

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“…Studies have shown that the most relevant origin of sporadic cancer is the ISC [96]. However, recruitment of a certain population of differentiated cells into the stem cell pool is observed in several disease models, where the intrinsic ISCs are severely impaired or lost due to inflammation-induced tissue damage [97,98]. Accordingly, activation of NF-jB signaling may de-differentiate villus nonstem cells and guide those cells to initiate ''Top-down'' type of tumorigenesis [99].…”

Section: Colitis-associated Cancer Represents Another Aspect Of Iec-dmentioning

confidence: 99%

“…Accordingly, activation of NF-jB signaling may de-differentiate villus nonstem cells and guide those cells to initiate ''Top-down'' type of tumorigenesis [99]. In addition, tuft cells seem to have the potential to initiate tumors exclusively after exposure to the inflammatory environment [98]. Thus, the intestinal inflammation may recruit certain population of IECs that are otherwise insusceptible to tumor initiation, to acquire tumorigenic potency, and subsequently promote formation of CACs arising from a distinct cell origin compared to sporadic cancers.…”

Section: Colitis-associated Cancer Represents Another Aspect Of Iec-dmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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Dynamic tuft cell expansion during gastric metaplasia and dysplasia

Jang,

Kim,

Lee

et al. 2023

The Journal of Pathology CR

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Tuft cells are chemosensory cells associated with luminal homeostasis, immune response, and tumorigenesis in the gastrointestinal tract. We aimed to elucidate alterations in tuft cell populations during gastric atrophy and tumorigenesis in humans with correlative comparison to relevant mouse models. Tuft cell distribution was determined in human stomachs from organ donors and in gastric pathologies including Ménétrier's disease, Helicobacter pylori gastritis, intestinal metaplasia (IM), and gastric tumors. Tuft cell populations were examined in Lrig1‐KrasG12D, Mist1‐KrasG12D, and MT‐TGFα mice. Tuft cells were evenly distributed throughout the entire normal human stomach, primarily concentrated in the isthmal region in the fundus. Ménétrier's disease stomach showed increased tuft cells. Similarly, Lrig1‐Kras mice and mice overexpressing TGFα showed marked foveolar hyperplasia and expanded tuft cell populations. Human stomach with IM or dysplasia also showed increased tuft cell numbers. Similarly, Mist1‐Kras mice had increased numbers of tuft cells during metaplasia and dysplasia development. In human gastric cancers, tuft cells were rarely observed, but showed positive associations with well‐differentiated lesions. In mouse gastric cancer xenografts, tuft cells were restricted to dysplastic well‐differentiated mucinous cysts and were lost in less differentiated cancers. Taken together, tuft cell populations increased in atrophic human gastric pathologies, metaplasia, and dysplasia, but were decreased in gastric cancers. Similar findings were observed in mouse models, suggesting that, while tuft cells are associated with precancerous pathologies, their loss is most associated with the progression to invasive cancer.

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Long-lived intestinal tuft cells serve as colon cancer–initiating cells

Cited by 336 publications

References 67 publications

Functional implication of Dclk1 and Dclk1-expressing cells in cancer

Functional implication of Dclk1 and Dclk1-expressing cells in cancer

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Dynamic tuft cell expansion during gastric metaplasia and dysplasia

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