Wnt Signaling, Stem Cells, and Cancer of the Gastrointestinal Tract

Schepers, Arnout; Clevers, Hans

doi:10.1101/cshperspect.a007989

Cited by 126 publications

(117 citation statements)

References 122 publications

(123 reference statements)

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“…To our surprise, we detected neither increased lineage tracing nor the formation of intestinal or colonic adenomas for up to 18 months after induction of APC loss ( Figure 4G). Importantly, APC loss did not cause nuclear translocation of β-catenin (Figure 4, H and I) in DCLK1 + cells, a hallmark of pathological Wnt signaling (48). Thus, DCLK1 + tuft cells appeared to remain quiescent in the face of acute injury and for extended periods of time, even in the setting of loss of a key tumor suppressor gene.…”

Section: Dclk1 + Cells Are Involved In Intestinal Homeostasis and Resmentioning

confidence: 88%

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

et al. 2014

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Section: Dclk1 + Cells Are Involved In Intestinal Homeostasis and Resmentioning

confidence: 88%

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

et al. 2014

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“…strengthened by the understanding that intracellular components of the signaling cascade, APC, axin, and b-catenin, are mutated in approximately 90% of human colon tumors (47). Mutations in Wnt pathway components have also now been observed in a broad range of human tumors (3).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

et al. 2016

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Deregulation of the b-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and b-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate b-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate b-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, geneexpression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited b-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of b-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. Cancer Res; 76(3); 713-23. Ó2015 AACR.

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“…In addition, Wg/Wnt is also known as an important maintenance factor for GSSCs and stem cells at other regions of the digestive tract, including the pMG, the hindgut and the cardia/proventriculus [3,9,[46][47][48][49], and is known as a major self-renewal factor in mammalian intestinal and gastric stem cells [1,24]. With the identification of EGFR and Wg signaling as critical proliferation factors and Notch signaling as a key differentiation factor for GSSCs, the Drosophila GSSC lineage should continue to serve as a powerful genetic model for further understanding of GSSC self-renewal, cell lineage specification and gastric function, which may ultimately contribute to our understanding of gastric homeostatic control and diseases in humans.…”

Section: Notch Is a Key Regulator In The Gssc Lineagementioning

confidence: 99%

“…Like in intestine, gastric epithelium in stomach turns over regularly and its regeneration is driven by local stem cells [1]. Dissecting out the mechanisms controlling gastric stem cell (GSSC) proliferation and differentiation should greatly facilitate our understanding of epithelial homeostasis control and gastric diseases, such as gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

EGFR and Notch signaling respectively regulate proliferative activity and multiple cell lineage differentiation of Drosophila gastric stem cells

Wang

Guo

2014

Cell Res

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Quiescent, multipotent gastric stem cells (GSSCs) in the copper cell region of adult Drosophila midgut can produce all epithelial cell lineages found in the region, including acid-secreting copper cells, interstitial cells and enteroendocrine cells, but mechanisms controlling their quiescence and the ternary lineage differentiation are unknown. By using cell ablation or damage-induced regeneration assays combined with cell lineage tracing and genetic analysis, here we demonstrate that Delta (Dl)-expressing cells in the copper cell region are the authentic GSSCs that can self-renew and continuously regenerate the gastric epithelium after a sustained damage. Lineage tracing analysis reveals that the committed GSSC daughter with activated Notch will invariably differentiate into either a copper cell or an interstitial cell, but not the enteroendocrine cell lineage, and loss-of-function and gainof-function studies revealed that Notch signaling is both necessary and sufficient for copper cell/interstitial cell differentiation. We also demonstrate that elevated epidermal growth factor receptor (EGFR) signaling, which is achieved by the activation of ligand Vein from the surrounding muscle cells and ligand Spitz from progenitor cells, mediates the regenerative proliferation of GSSCs following damage. Taken together, we demonstrate that Dl is a specific marker for Drosophila GSSCs, whose cell cycle status is dependent on the levels of EGFR signaling activity, and the Notch signaling has a central role in controlling cell lineage differentiation from GSSCs by separating copper/interstitial cell lineage from enteroendocrine cell lineage.

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Wnt Signaling, Stem Cells, and Cancer of the Gastrointestinal Tract

Cited by 126 publications

References 122 publications

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

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

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

EGFR and Notch signaling respectively regulate proliferative activity and multiple cell lineage differentiation of Drosophila gastric stem cells

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