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Molecular pathways linked with CD44 variant 9 (CD44v9), a cell surface glycoprotein tied to aggressive gastric cancer after Helicobacter pylori infection, may open doors to stop cancer before it starts, according to two recent studies.
Findings from the first study suggest that persistent inflammation after eradication therapy may continue to drive cancer risk after infection, while the second study revealed a potential therapeutic target related to preneoplastic changes.
The first study, conducted by lead author Hitoshi Tsugawa, PhD, of Keio University, Tokyo, and colleagues, aimed to determine the origin of CD44v9-positive cancer stem-like cells.
“These cells strongly contribute to the development and recurrence of gastric cancer,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology. “However, the origin of CD44v9-positive cells is uncertain.”
The association between H. pylori infection and gastric cancer has been documented, along with a high risk of cancer when gastric epithelial cells overexpress capping actin protein of muscle Z-line alpha subunit 1 (CAPZA1), the researchers noted. Although it has also been shown that CAPZA1 overexpression leads to intracellular accumulations of the H. pylori–derived oncoprotein cytotoxin-associated gene A (CagA), just how these phenomena were connected remained unknown.
Through in vitro analyses of human cells, and in vitro and in vivo experiments involving Mongolian gerbils, the investigators uncovered a chain of events between H. pylori infection and CD44v9 expression. First, the investigators showed that expression levels of CD44v9 and CAPZA1 were directly correlated in five human cases of gastric cancer. Next, several experiments revealed that H. pylori–related oxidative stress drives overexpression of CAPZA1, which, in combination with high levels of beta-catenin, ESRP1, and CagA, promotes expression of CD44v9.
Most directly relevant to future therapies, the investigators compared levels of CAPZA1 between five active cases of H. pylori infection versus five cases successfully treated with eradication therapy. After eradication therapy, CAPZA1 overexpression decreased, but not to a significant degree.
“Our findings suggest that CAPZA1-overexpressing cells remaining in the gastric mucosa after eradication therapy increase the risk of metachronous gastric cancer and that reduction of CAPZA1 expression by amelioration of chronic inflammation after eradication therapy is important to prevent the development of gastric cancer,” the investigators concluded.
The second study, by lead author Anne R. Meyer, a graduate student at Vanderbilt University, Nashville, Tenn., and colleagues, evaluated how zymogenic chief cells are reprogrammed into spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor to dysplasia and gastric cancer.
It had been previously shown that reprogramming to SPEM is promoted and maintained by epithelial cell damage, such as that caused by H. pylori infection, but underlying processes remained unclear, until recent studies suggested a link between SPEM transition and upregulation of CD44v9. Knowing that CD44v9 stabilizes the cystine/glutamate antiporter xCT, the investigators homed in on xCT for a closer look, questioning what role it had in chief cell reprogramming. Again, oxidative stress was identified as the inciting pathophysiologic driver.
“The oxidative stress response, including upregulation of nutrient transporters, plays an important role in many biological processes and the pathogenesis of a variety of diseases,” the investigators wrote in their report, published in Cellular and Molecular Gastroenterology and Hepatology. “Perturbations to the CD44v9-xCT system often result in redox imbalance.”
Using a combination of mouse and human cell lines, and a mouse model, the investigators demonstrated that xCT was upregulated during the initial stages of chief cell programming. Blocking xCT with sulfasalazine after acute gastric injury limited SPEM transition by more than 80%, an effect that was further supported by xCT siRNA knockdown and observations in xCT knockout mice. Reduction in chief cell reprogramming was not observed in the presence of sulfasalazine metabolites, suggesting that the anti-inflammatory properties of sulfasalazine were not responsible for downregulation of reprogramming.
“Targeting xCT may prove an effective tool for arresting metaplasia development in the stomach as well as mucous metaplasia in other epithelial tissues for the analysis of cellular plasticity and oxidative stress response,” the investigators concluded.
The study by Tsugawa and colleagues was funded by Grants-in-Aid for Scientific Research; the Yakult Bio-Science Foundation; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-supported program for the Strategic Research Foundation at Private Universities; and Keio Gijuku Academic Development Funds. Dr. Suzuki disclosed relationships with Daiichi-Sankyo Co, EA Pharma Co, Otsuka Pharmaceutical Co Ltd, and others. The study by Meyer and colleagues was funded by the National Institutes of Health, the American Association of Cancer Research, the Department of Defense, and others, with no relevant conflicts of interest.
SOURCES: Meyer et al. CMGH. 2019 May 6. doi: 10.1016/j.jcmgh.2019.04.015; Tsugawa et al. CMGH. 2019 May 27. doi: 10.1016/j.jcmgh.2019.05.008.
The mechanisms by which injured cells respond to stress rely in part on their ability to reprogram themselves in the setting of injury. This cellular reprogramming involves sensing and regulating intracellular metabolic cues that dictate survival, organization of secretory and degradative machinery, and proliferation. Meyer et al. and Tsugawa et al. illustrate two distinct mechanisms by which gastric epithelial cells handle oxidative stress during injury.
Meyer et al. focus on the xCT subunit of the cystine/glutamate antiporter as a rheostat for intracellular glutathione stores. Pharmacologic inhibition of xCT activity using sulfasalazine hampers the ability of injured gastric epithelial cells to adequately deal with reactive oxygen species. Importantly, these cells do not appropriately reprogram during injury and instead undergo apoptosis. Tsugawa et al. provide mechanistic insight into how oxidative stress may promote precancerous changes in gastric epithelium. Following H. pylori infection, an intracellular oxidative environment that is characterized by an overexpression of the actin filament capping protein CAPZA1, beta-catenin, and the alternative splicing factor ESRP1, promotes expression of CD44 variant 9 (CD44v9), a cell surface glycoprotein that correlates with gastric cancer. Interestingly, this oxidative milieu promotes accumulation of a critical H. pylori virulence factor, CagA, within infected cells.
Taken together, the ability to manage oxidative stress during cellular injury has significant implications for cell fate. It seems likely that the mechanisms for regulating intracellular oxidative stress are not unique to gastric epithelium and instead underlie a conserved injury response that has correlates in other gastrointestinal organs.
José B. Sáenz, MD, PhD, is an investigator and instructor of medicine in the gastroenterology division, John T. Milliken Department of Internal Medicine at the Washington University in St. Louis School of Medicine. He has no conflicts of interest.
The mechanisms by which injured cells respond to stress rely in part on their ability to reprogram themselves in the setting of injury. This cellular reprogramming involves sensing and regulating intracellular metabolic cues that dictate survival, organization of secretory and degradative machinery, and proliferation. Meyer et al. and Tsugawa et al. illustrate two distinct mechanisms by which gastric epithelial cells handle oxidative stress during injury.
Meyer et al. focus on the xCT subunit of the cystine/glutamate antiporter as a rheostat for intracellular glutathione stores. Pharmacologic inhibition of xCT activity using sulfasalazine hampers the ability of injured gastric epithelial cells to adequately deal with reactive oxygen species. Importantly, these cells do not appropriately reprogram during injury and instead undergo apoptosis. Tsugawa et al. provide mechanistic insight into how oxidative stress may promote precancerous changes in gastric epithelium. Following H. pylori infection, an intracellular oxidative environment that is characterized by an overexpression of the actin filament capping protein CAPZA1, beta-catenin, and the alternative splicing factor ESRP1, promotes expression of CD44 variant 9 (CD44v9), a cell surface glycoprotein that correlates with gastric cancer. Interestingly, this oxidative milieu promotes accumulation of a critical H. pylori virulence factor, CagA, within infected cells.
Taken together, the ability to manage oxidative stress during cellular injury has significant implications for cell fate. It seems likely that the mechanisms for regulating intracellular oxidative stress are not unique to gastric epithelium and instead underlie a conserved injury response that has correlates in other gastrointestinal organs.
José B. Sáenz, MD, PhD, is an investigator and instructor of medicine in the gastroenterology division, John T. Milliken Department of Internal Medicine at the Washington University in St. Louis School of Medicine. He has no conflicts of interest.
The mechanisms by which injured cells respond to stress rely in part on their ability to reprogram themselves in the setting of injury. This cellular reprogramming involves sensing and regulating intracellular metabolic cues that dictate survival, organization of secretory and degradative machinery, and proliferation. Meyer et al. and Tsugawa et al. illustrate two distinct mechanisms by which gastric epithelial cells handle oxidative stress during injury.
Meyer et al. focus on the xCT subunit of the cystine/glutamate antiporter as a rheostat for intracellular glutathione stores. Pharmacologic inhibition of xCT activity using sulfasalazine hampers the ability of injured gastric epithelial cells to adequately deal with reactive oxygen species. Importantly, these cells do not appropriately reprogram during injury and instead undergo apoptosis. Tsugawa et al. provide mechanistic insight into how oxidative stress may promote precancerous changes in gastric epithelium. Following H. pylori infection, an intracellular oxidative environment that is characterized by an overexpression of the actin filament capping protein CAPZA1, beta-catenin, and the alternative splicing factor ESRP1, promotes expression of CD44 variant 9 (CD44v9), a cell surface glycoprotein that correlates with gastric cancer. Interestingly, this oxidative milieu promotes accumulation of a critical H. pylori virulence factor, CagA, within infected cells.
Taken together, the ability to manage oxidative stress during cellular injury has significant implications for cell fate. It seems likely that the mechanisms for regulating intracellular oxidative stress are not unique to gastric epithelium and instead underlie a conserved injury response that has correlates in other gastrointestinal organs.
José B. Sáenz, MD, PhD, is an investigator and instructor of medicine in the gastroenterology division, John T. Milliken Department of Internal Medicine at the Washington University in St. Louis School of Medicine. He has no conflicts of interest.
Molecular pathways linked with CD44 variant 9 (CD44v9), a cell surface glycoprotein tied to aggressive gastric cancer after Helicobacter pylori infection, may open doors to stop cancer before it starts, according to two recent studies.
Findings from the first study suggest that persistent inflammation after eradication therapy may continue to drive cancer risk after infection, while the second study revealed a potential therapeutic target related to preneoplastic changes.
The first study, conducted by lead author Hitoshi Tsugawa, PhD, of Keio University, Tokyo, and colleagues, aimed to determine the origin of CD44v9-positive cancer stem-like cells.
“These cells strongly contribute to the development and recurrence of gastric cancer,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology. “However, the origin of CD44v9-positive cells is uncertain.”
The association between H. pylori infection and gastric cancer has been documented, along with a high risk of cancer when gastric epithelial cells overexpress capping actin protein of muscle Z-line alpha subunit 1 (CAPZA1), the researchers noted. Although it has also been shown that CAPZA1 overexpression leads to intracellular accumulations of the H. pylori–derived oncoprotein cytotoxin-associated gene A (CagA), just how these phenomena were connected remained unknown.
Through in vitro analyses of human cells, and in vitro and in vivo experiments involving Mongolian gerbils, the investigators uncovered a chain of events between H. pylori infection and CD44v9 expression. First, the investigators showed that expression levels of CD44v9 and CAPZA1 were directly correlated in five human cases of gastric cancer. Next, several experiments revealed that H. pylori–related oxidative stress drives overexpression of CAPZA1, which, in combination with high levels of beta-catenin, ESRP1, and CagA, promotes expression of CD44v9.
Most directly relevant to future therapies, the investigators compared levels of CAPZA1 between five active cases of H. pylori infection versus five cases successfully treated with eradication therapy. After eradication therapy, CAPZA1 overexpression decreased, but not to a significant degree.
“Our findings suggest that CAPZA1-overexpressing cells remaining in the gastric mucosa after eradication therapy increase the risk of metachronous gastric cancer and that reduction of CAPZA1 expression by amelioration of chronic inflammation after eradication therapy is important to prevent the development of gastric cancer,” the investigators concluded.
The second study, by lead author Anne R. Meyer, a graduate student at Vanderbilt University, Nashville, Tenn., and colleagues, evaluated how zymogenic chief cells are reprogrammed into spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor to dysplasia and gastric cancer.
It had been previously shown that reprogramming to SPEM is promoted and maintained by epithelial cell damage, such as that caused by H. pylori infection, but underlying processes remained unclear, until recent studies suggested a link between SPEM transition and upregulation of CD44v9. Knowing that CD44v9 stabilizes the cystine/glutamate antiporter xCT, the investigators homed in on xCT for a closer look, questioning what role it had in chief cell reprogramming. Again, oxidative stress was identified as the inciting pathophysiologic driver.
“The oxidative stress response, including upregulation of nutrient transporters, plays an important role in many biological processes and the pathogenesis of a variety of diseases,” the investigators wrote in their report, published in Cellular and Molecular Gastroenterology and Hepatology. “Perturbations to the CD44v9-xCT system often result in redox imbalance.”
Using a combination of mouse and human cell lines, and a mouse model, the investigators demonstrated that xCT was upregulated during the initial stages of chief cell programming. Blocking xCT with sulfasalazine after acute gastric injury limited SPEM transition by more than 80%, an effect that was further supported by xCT siRNA knockdown and observations in xCT knockout mice. Reduction in chief cell reprogramming was not observed in the presence of sulfasalazine metabolites, suggesting that the anti-inflammatory properties of sulfasalazine were not responsible for downregulation of reprogramming.
“Targeting xCT may prove an effective tool for arresting metaplasia development in the stomach as well as mucous metaplasia in other epithelial tissues for the analysis of cellular plasticity and oxidative stress response,” the investigators concluded.
The study by Tsugawa and colleagues was funded by Grants-in-Aid for Scientific Research; the Yakult Bio-Science Foundation; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-supported program for the Strategic Research Foundation at Private Universities; and Keio Gijuku Academic Development Funds. Dr. Suzuki disclosed relationships with Daiichi-Sankyo Co, EA Pharma Co, Otsuka Pharmaceutical Co Ltd, and others. The study by Meyer and colleagues was funded by the National Institutes of Health, the American Association of Cancer Research, the Department of Defense, and others, with no relevant conflicts of interest.
SOURCES: Meyer et al. CMGH. 2019 May 6. doi: 10.1016/j.jcmgh.2019.04.015; Tsugawa et al. CMGH. 2019 May 27. doi: 10.1016/j.jcmgh.2019.05.008.
Molecular pathways linked with CD44 variant 9 (CD44v9), a cell surface glycoprotein tied to aggressive gastric cancer after Helicobacter pylori infection, may open doors to stop cancer before it starts, according to two recent studies.
Findings from the first study suggest that persistent inflammation after eradication therapy may continue to drive cancer risk after infection, while the second study revealed a potential therapeutic target related to preneoplastic changes.
The first study, conducted by lead author Hitoshi Tsugawa, PhD, of Keio University, Tokyo, and colleagues, aimed to determine the origin of CD44v9-positive cancer stem-like cells.
“These cells strongly contribute to the development and recurrence of gastric cancer,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology. “However, the origin of CD44v9-positive cells is uncertain.”
The association between H. pylori infection and gastric cancer has been documented, along with a high risk of cancer when gastric epithelial cells overexpress capping actin protein of muscle Z-line alpha subunit 1 (CAPZA1), the researchers noted. Although it has also been shown that CAPZA1 overexpression leads to intracellular accumulations of the H. pylori–derived oncoprotein cytotoxin-associated gene A (CagA), just how these phenomena were connected remained unknown.
Through in vitro analyses of human cells, and in vitro and in vivo experiments involving Mongolian gerbils, the investigators uncovered a chain of events between H. pylori infection and CD44v9 expression. First, the investigators showed that expression levels of CD44v9 and CAPZA1 were directly correlated in five human cases of gastric cancer. Next, several experiments revealed that H. pylori–related oxidative stress drives overexpression of CAPZA1, which, in combination with high levels of beta-catenin, ESRP1, and CagA, promotes expression of CD44v9.
Most directly relevant to future therapies, the investigators compared levels of CAPZA1 between five active cases of H. pylori infection versus five cases successfully treated with eradication therapy. After eradication therapy, CAPZA1 overexpression decreased, but not to a significant degree.
“Our findings suggest that CAPZA1-overexpressing cells remaining in the gastric mucosa after eradication therapy increase the risk of metachronous gastric cancer and that reduction of CAPZA1 expression by amelioration of chronic inflammation after eradication therapy is important to prevent the development of gastric cancer,” the investigators concluded.
The second study, by lead author Anne R. Meyer, a graduate student at Vanderbilt University, Nashville, Tenn., and colleagues, evaluated how zymogenic chief cells are reprogrammed into spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor to dysplasia and gastric cancer.
It had been previously shown that reprogramming to SPEM is promoted and maintained by epithelial cell damage, such as that caused by H. pylori infection, but underlying processes remained unclear, until recent studies suggested a link between SPEM transition and upregulation of CD44v9. Knowing that CD44v9 stabilizes the cystine/glutamate antiporter xCT, the investigators homed in on xCT for a closer look, questioning what role it had in chief cell reprogramming. Again, oxidative stress was identified as the inciting pathophysiologic driver.
“The oxidative stress response, including upregulation of nutrient transporters, plays an important role in many biological processes and the pathogenesis of a variety of diseases,” the investigators wrote in their report, published in Cellular and Molecular Gastroenterology and Hepatology. “Perturbations to the CD44v9-xCT system often result in redox imbalance.”
Using a combination of mouse and human cell lines, and a mouse model, the investigators demonstrated that xCT was upregulated during the initial stages of chief cell programming. Blocking xCT with sulfasalazine after acute gastric injury limited SPEM transition by more than 80%, an effect that was further supported by xCT siRNA knockdown and observations in xCT knockout mice. Reduction in chief cell reprogramming was not observed in the presence of sulfasalazine metabolites, suggesting that the anti-inflammatory properties of sulfasalazine were not responsible for downregulation of reprogramming.
“Targeting xCT may prove an effective tool for arresting metaplasia development in the stomach as well as mucous metaplasia in other epithelial tissues for the analysis of cellular plasticity and oxidative stress response,” the investigators concluded.
The study by Tsugawa and colleagues was funded by Grants-in-Aid for Scientific Research; the Yakult Bio-Science Foundation; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-supported program for the Strategic Research Foundation at Private Universities; and Keio Gijuku Academic Development Funds. Dr. Suzuki disclosed relationships with Daiichi-Sankyo Co, EA Pharma Co, Otsuka Pharmaceutical Co Ltd, and others. The study by Meyer and colleagues was funded by the National Institutes of Health, the American Association of Cancer Research, the Department of Defense, and others, with no relevant conflicts of interest.
SOURCES: Meyer et al. CMGH. 2019 May 6. doi: 10.1016/j.jcmgh.2019.04.015; Tsugawa et al. CMGH. 2019 May 27. doi: 10.1016/j.jcmgh.2019.05.008.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY