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Aspirin “rescued” a cystic intestinal phenotype driven by the Wnt pathway, reduced stem cell expression and function, and increased the expression of Dickkopf (DKK)–1, a Wnt antagonist that is frequently lost as colorectal cancer (CRC) progresses, according to recent study findings.
“Dysregulated Wnt signaling, [which is] primarily driven by adenomatous polyposis coli (APC) gene mutations, is fundamental to cancer initiation in both sporadic CRC and familial adenomatous polyposis (FAP). ... Our observations reveal a novel mechanism of aspirin-mediated Wnt inhibition through DKK-1 increase and potential ‘pheno-markers’ for chemoprevention and adjuvant aspirin human trials,” wrote Karen Dunbar, PhD, and her associates in Cellular and Molecular Gastroenterology and Hepatology.
Aspirin shows benefits in sporadic and familial adenoma, significantly reduces CRC incidence, and may delay disease progression while improving survival. “Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use,” wrote Dr. Dunbar, now with the University of Dundee (Scotland) and colleagues.
She and her coinvestigators found that aspirin promoted the wild-type (budding, noncystic) phenotype in intestinal organoids derived from APC-deficient mice and humans with FAP. They saw the same effect in live APC-deficient mice. With the help of an RNAscope, they confirmed that aspirin significantly reduced RNA transcripts for Lgr5 and TROY, which are stem cell markers in CRC. Aspirin also reduced Lgr5 expression in APC-deficient mice and in human organoids derived from normal colonic mucosa, sporadic colorectal tumors, and colorectal tumors from patients with FAP.
In wound-closure models, aspirin inhibited Wnt and epithelial-mesenchymal transition (EMT) while decreasing migration and invasion by colorectal cancer cells. Aspirin accomplished this by increasing the phosphorylation of GSK-3beta and beta-catenin. Notably, aspirin increased the production of E-cadherin, which buffers excess beta-catenin and thereby limits overactivated Wnt to promote an epithelial, rather than mesenchymal, phenotype. “The novel observation that the aspirin-mediated E-cadherin increase is paralleled by greater E-cadherin–beta-catenin binding further supports the hypothesis that aspirin promotes an epithelial phenotype through Wnt inhibition,” the researchers wrote.
In colorectal cells and FAP organoids, aspirin also increased the expression of the Wnt antagonist DKK-1, which in turn correlated with lower stem cell function. “In humans, high serum DKK-1 correlates with increasing colorectal cancer stage, whereas tissue DKK-1 expression is lost with cancer progression,” the researchers explained. “Here, we demonstrate that aspirin robustly increases DKK-1 expression in CRC models, which contributes to EMT and [cancer stem cell] inhibition observed with aspirin.”
Taken together, the findings “highlight two novel phenotypic indicators of aspirin response, the cystic-phenotype rescue and reduced stem cell marker expression, which may serve as enhanced biomarkers, compared with individual Wnt components,” they concluded. “Through targeting Wnt signaling at multiple levels, aspirin enhances commitment to differentiation, and hence, phenotypic markers of Wnt inhibition represent better targets [for] therapeutic exploitation.”
Dr. Dunbar and her associates reported having no relevant conflicts of interest. The work was supported by Cancer Research UK and the Chief Scientist Office of Scotland, the MRC Centre, and the CRUK.
SOURCE: Dunbar K et al. Cell Mol Gastroenterol Hepatol. 2020 Sep 21. doi: 10.1016/j.jcmgh.2020.09.010.
It is well known that aspirin protects against colorectal polyps and cancers, but the molecular mechanisms by which aspirin confers this protection remain obscure. By developing new models and identifying the molecular targets of aspirin, therapies may be developed that prevent colorectal polyps and cancers but avoid the negative effects of aspirin. Most colorectal cancers (CRC), both spontaneous and familiar, arise from abnormal activation of an important molecular pathway known as the Wnt signaling pathway. Specific mutations in a key member of this pathway, the tumor suppressor APC, are an early event in spontaneous cancers and are the cause of a condition known as familial adenomatous polyposis (FAP). Wnt signaling also drives CRC by regulating cancer stem cells and a process known as epithelial-mesenchymal transition (EMT).
With use of established CRC cell lines, mouse models of FAP, and organoids – three-dimensional models of colonic epithelium – from mice and from human FAP patients, Dunbar and colleagues performed a comprehensive study to define the mechanisms by which aspirin acts to prevent the development and progression of CRC. Here, Dunbar and colleagues found that aspirin limits cancer stem cell populations and the development of EMT, which together are important for tumor cell propagation, invasion, and dissemination. Importantly, they also showed that aspirin increases the expression of a natural Wnt pathway antagonist known as DKK-1, providing a mechanism by which aspirin inhibits Wnt signaling in the context of CRC. Future studies can build on this work by exploring these findings to develop targeted approaches to Wnt inhibition and to prevent colorectal polyps and cancers.
Jonathan P. Katz, MD, is an associate professor of medicine in the division of gastroenterology, department of medicine at the University of Pennsylvania, Philadelphia. He has no conflicts of interest.
It is well known that aspirin protects against colorectal polyps and cancers, but the molecular mechanisms by which aspirin confers this protection remain obscure. By developing new models and identifying the molecular targets of aspirin, therapies may be developed that prevent colorectal polyps and cancers but avoid the negative effects of aspirin. Most colorectal cancers (CRC), both spontaneous and familiar, arise from abnormal activation of an important molecular pathway known as the Wnt signaling pathway. Specific mutations in a key member of this pathway, the tumor suppressor APC, are an early event in spontaneous cancers and are the cause of a condition known as familial adenomatous polyposis (FAP). Wnt signaling also drives CRC by regulating cancer stem cells and a process known as epithelial-mesenchymal transition (EMT).
With use of established CRC cell lines, mouse models of FAP, and organoids – three-dimensional models of colonic epithelium – from mice and from human FAP patients, Dunbar and colleagues performed a comprehensive study to define the mechanisms by which aspirin acts to prevent the development and progression of CRC. Here, Dunbar and colleagues found that aspirin limits cancer stem cell populations and the development of EMT, which together are important for tumor cell propagation, invasion, and dissemination. Importantly, they also showed that aspirin increases the expression of a natural Wnt pathway antagonist known as DKK-1, providing a mechanism by which aspirin inhibits Wnt signaling in the context of CRC. Future studies can build on this work by exploring these findings to develop targeted approaches to Wnt inhibition and to prevent colorectal polyps and cancers.
Jonathan P. Katz, MD, is an associate professor of medicine in the division of gastroenterology, department of medicine at the University of Pennsylvania, Philadelphia. He has no conflicts of interest.
It is well known that aspirin protects against colorectal polyps and cancers, but the molecular mechanisms by which aspirin confers this protection remain obscure. By developing new models and identifying the molecular targets of aspirin, therapies may be developed that prevent colorectal polyps and cancers but avoid the negative effects of aspirin. Most colorectal cancers (CRC), both spontaneous and familiar, arise from abnormal activation of an important molecular pathway known as the Wnt signaling pathway. Specific mutations in a key member of this pathway, the tumor suppressor APC, are an early event in spontaneous cancers and are the cause of a condition known as familial adenomatous polyposis (FAP). Wnt signaling also drives CRC by regulating cancer stem cells and a process known as epithelial-mesenchymal transition (EMT).
With use of established CRC cell lines, mouse models of FAP, and organoids – three-dimensional models of colonic epithelium – from mice and from human FAP patients, Dunbar and colleagues performed a comprehensive study to define the mechanisms by which aspirin acts to prevent the development and progression of CRC. Here, Dunbar and colleagues found that aspirin limits cancer stem cell populations and the development of EMT, which together are important for tumor cell propagation, invasion, and dissemination. Importantly, they also showed that aspirin increases the expression of a natural Wnt pathway antagonist known as DKK-1, providing a mechanism by which aspirin inhibits Wnt signaling in the context of CRC. Future studies can build on this work by exploring these findings to develop targeted approaches to Wnt inhibition and to prevent colorectal polyps and cancers.
Jonathan P. Katz, MD, is an associate professor of medicine in the division of gastroenterology, department of medicine at the University of Pennsylvania, Philadelphia. He has no conflicts of interest.
Aspirin “rescued” a cystic intestinal phenotype driven by the Wnt pathway, reduced stem cell expression and function, and increased the expression of Dickkopf (DKK)–1, a Wnt antagonist that is frequently lost as colorectal cancer (CRC) progresses, according to recent study findings.
“Dysregulated Wnt signaling, [which is] primarily driven by adenomatous polyposis coli (APC) gene mutations, is fundamental to cancer initiation in both sporadic CRC and familial adenomatous polyposis (FAP). ... Our observations reveal a novel mechanism of aspirin-mediated Wnt inhibition through DKK-1 increase and potential ‘pheno-markers’ for chemoprevention and adjuvant aspirin human trials,” wrote Karen Dunbar, PhD, and her associates in Cellular and Molecular Gastroenterology and Hepatology.
Aspirin shows benefits in sporadic and familial adenoma, significantly reduces CRC incidence, and may delay disease progression while improving survival. “Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use,” wrote Dr. Dunbar, now with the University of Dundee (Scotland) and colleagues.
She and her coinvestigators found that aspirin promoted the wild-type (budding, noncystic) phenotype in intestinal organoids derived from APC-deficient mice and humans with FAP. They saw the same effect in live APC-deficient mice. With the help of an RNAscope, they confirmed that aspirin significantly reduced RNA transcripts for Lgr5 and TROY, which are stem cell markers in CRC. Aspirin also reduced Lgr5 expression in APC-deficient mice and in human organoids derived from normal colonic mucosa, sporadic colorectal tumors, and colorectal tumors from patients with FAP.
In wound-closure models, aspirin inhibited Wnt and epithelial-mesenchymal transition (EMT) while decreasing migration and invasion by colorectal cancer cells. Aspirin accomplished this by increasing the phosphorylation of GSK-3beta and beta-catenin. Notably, aspirin increased the production of E-cadherin, which buffers excess beta-catenin and thereby limits overactivated Wnt to promote an epithelial, rather than mesenchymal, phenotype. “The novel observation that the aspirin-mediated E-cadherin increase is paralleled by greater E-cadherin–beta-catenin binding further supports the hypothesis that aspirin promotes an epithelial phenotype through Wnt inhibition,” the researchers wrote.
In colorectal cells and FAP organoids, aspirin also increased the expression of the Wnt antagonist DKK-1, which in turn correlated with lower stem cell function. “In humans, high serum DKK-1 correlates with increasing colorectal cancer stage, whereas tissue DKK-1 expression is lost with cancer progression,” the researchers explained. “Here, we demonstrate that aspirin robustly increases DKK-1 expression in CRC models, which contributes to EMT and [cancer stem cell] inhibition observed with aspirin.”
Taken together, the findings “highlight two novel phenotypic indicators of aspirin response, the cystic-phenotype rescue and reduced stem cell marker expression, which may serve as enhanced biomarkers, compared with individual Wnt components,” they concluded. “Through targeting Wnt signaling at multiple levels, aspirin enhances commitment to differentiation, and hence, phenotypic markers of Wnt inhibition represent better targets [for] therapeutic exploitation.”
Dr. Dunbar and her associates reported having no relevant conflicts of interest. The work was supported by Cancer Research UK and the Chief Scientist Office of Scotland, the MRC Centre, and the CRUK.
SOURCE: Dunbar K et al. Cell Mol Gastroenterol Hepatol. 2020 Sep 21. doi: 10.1016/j.jcmgh.2020.09.010.
Aspirin “rescued” a cystic intestinal phenotype driven by the Wnt pathway, reduced stem cell expression and function, and increased the expression of Dickkopf (DKK)–1, a Wnt antagonist that is frequently lost as colorectal cancer (CRC) progresses, according to recent study findings.
“Dysregulated Wnt signaling, [which is] primarily driven by adenomatous polyposis coli (APC) gene mutations, is fundamental to cancer initiation in both sporadic CRC and familial adenomatous polyposis (FAP). ... Our observations reveal a novel mechanism of aspirin-mediated Wnt inhibition through DKK-1 increase and potential ‘pheno-markers’ for chemoprevention and adjuvant aspirin human trials,” wrote Karen Dunbar, PhD, and her associates in Cellular and Molecular Gastroenterology and Hepatology.
Aspirin shows benefits in sporadic and familial adenoma, significantly reduces CRC incidence, and may delay disease progression while improving survival. “Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use,” wrote Dr. Dunbar, now with the University of Dundee (Scotland) and colleagues.
She and her coinvestigators found that aspirin promoted the wild-type (budding, noncystic) phenotype in intestinal organoids derived from APC-deficient mice and humans with FAP. They saw the same effect in live APC-deficient mice. With the help of an RNAscope, they confirmed that aspirin significantly reduced RNA transcripts for Lgr5 and TROY, which are stem cell markers in CRC. Aspirin also reduced Lgr5 expression in APC-deficient mice and in human organoids derived from normal colonic mucosa, sporadic colorectal tumors, and colorectal tumors from patients with FAP.
In wound-closure models, aspirin inhibited Wnt and epithelial-mesenchymal transition (EMT) while decreasing migration and invasion by colorectal cancer cells. Aspirin accomplished this by increasing the phosphorylation of GSK-3beta and beta-catenin. Notably, aspirin increased the production of E-cadherin, which buffers excess beta-catenin and thereby limits overactivated Wnt to promote an epithelial, rather than mesenchymal, phenotype. “The novel observation that the aspirin-mediated E-cadherin increase is paralleled by greater E-cadherin–beta-catenin binding further supports the hypothesis that aspirin promotes an epithelial phenotype through Wnt inhibition,” the researchers wrote.
In colorectal cells and FAP organoids, aspirin also increased the expression of the Wnt antagonist DKK-1, which in turn correlated with lower stem cell function. “In humans, high serum DKK-1 correlates with increasing colorectal cancer stage, whereas tissue DKK-1 expression is lost with cancer progression,” the researchers explained. “Here, we demonstrate that aspirin robustly increases DKK-1 expression in CRC models, which contributes to EMT and [cancer stem cell] inhibition observed with aspirin.”
Taken together, the findings “highlight two novel phenotypic indicators of aspirin response, the cystic-phenotype rescue and reduced stem cell marker expression, which may serve as enhanced biomarkers, compared with individual Wnt components,” they concluded. “Through targeting Wnt signaling at multiple levels, aspirin enhances commitment to differentiation, and hence, phenotypic markers of Wnt inhibition represent better targets [for] therapeutic exploitation.”
Dr. Dunbar and her associates reported having no relevant conflicts of interest. The work was supported by Cancer Research UK and the Chief Scientist Office of Scotland, the MRC Centre, and the CRUK.
SOURCE: Dunbar K et al. Cell Mol Gastroenterol Hepatol. 2020 Sep 21. doi: 10.1016/j.jcmgh.2020.09.010.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY