The Experts below are selected from a list of 6681 Experts worldwide ranked by ideXlab platform
James R. Goldenring - One of the best experts on this subject based on the ideXlab platform.
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Decrease in MiR-148a Expression During Initiation of Chief Cell Transdifferentiation.
Cellular and molecular gastroenterology and hepatology, 2019Co-Authors: Takahiro Shimizu, Eun-young Choi, Yoojin Sohn, Christine P. Petersen, Nripesh Prasad, James R. GoldenringAbstract:Gastric Chief Cells differentiate from mucous neck Cells and develop their mature state at the base of oxyntic glands with expression of secretory zymogen granules. After parietal Cell loss, Chief Cells transdifferentiate into mucous Cell metaplasia, designated spasmolytic polypeptide-expressing metaplasia (SPEM), which is considered a candidate precursor of gastric cancer. We examined the range of microRNA (miRNA) expression in Chief Cells and identified miRNAs involved in Chief Cell transdifferentiation into SPEM. Among them, miR-148a was strongly and specifically expressed in Chief Cells and significantly decreased during the process of Chief Cell transdifferentiation. Interestingly, suppression of miR-148a in a conditionally immortalized Chief Cell line induced up-regulation of CD44 variant 9 (CD44v9), one of the transcripts expressed at an early stage of SPEM development, and DNA methyltransferase 1 (Dnmt1), an established target of miR-148a. Immunostaining analyses showed that Dnmt1 was up-regulated in SPEM Cells as well as in Chief Cells before the emergence of SPEM in mouse models of acute oxyntic atrophy using either DMP-777 or L635. In the cascade of events that leads to transdifferentiation, miR-148a was down-regulated after acute oxyntic atrophy either in xCT knockout mice or after sulfasalazine inhibition of xCT. These findings suggest that the alteration of miR-148a expression is an early event in the process of Chief Cell transdifferentiation into SPEM.
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Cystine/Glutamate Antiporter (xCT) Is Required for Chief Cell Plasticity After Gastric Injury.
Cellular and Molecular Gastroenterology and Hepatology, 2019Co-Authors: Anne R. Meyer, Amy C. Engevik, Spencer G. Willet, Janice A. Williams, Yong Zou, Pierre P. Massion, Jason C. Mills, Eun-young Choi, James R. GoldenringAbstract:Background & Aims Many differentiated epithelial Cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of Cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic Chief Cells into a metaplastic Cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in Chief Cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of Chief Cells into SPEM. Methods Sulfasalazine (an xCT inhibitor) and small interfering RNA knockdown were used to target xCT on metaplastic Cells in vitro. Sulfasalazine-treated wild-type mice and xCT knockout mice were analyzed. L635 or DMP-777 treatment was used to chemically induce acute gastric damage. The anti-inflammatory metabolites of sulfasalazine (sulfapyridine and mesalazine) were used as controls. Normal gastric lineages, metaplastic markers, autophagy, proliferation, xCT activity, ROS, and apoptosis were assessed. Results xCT was up-regulated early as Chief Cells transitioned into SPEM. Inhibition of xCT or small interfering RNA knockdown blocked cystine uptake and decreased glutathione production by metaplastic Cells and prevented ROS detoxification and proliferation. Moreover, xCT activity was required for Chief Cell reprogramming into SPEM after gastric injury in vivo. Chief Cells from xCT-deficient mice showed decreased autophagy, mucus granule formation and proliferation, as well as increased levels of ROS and apoptosis compared with wild-type mice. On the other hand, the anti-inflammatory metabolites of sulfasalazine did not affect SPEM development. Conclusions The results presented here suggest that maintaining redox balance is crucial for progression through the reprogramming process and that xCT-mediated cystine uptake is required for Chief Cell plasticity and ROS detoxification.
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cystine glutamate antiporter xct is required for Chief Cell plasticity after gastric injury
Cellular and molecular gastroenterology and hepatology, 2019Co-Authors: Anne R. Meyer, Amy C. Engevik, Spencer G. Willet, Janice A. Williams, Yong Zou, Pierre P. Massion, Jason C. Mills, Eun-young Choi, James R. GoldenringAbstract:Background & Aims Many differentiated epithelial Cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of Cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic Chief Cells into a metaplastic Cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in Chief Cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of Chief Cells into SPEM. Methods Sulfasalazine (an xCT inhibitor) and small interfering RNA knockdown were used to target xCT on metaplastic Cells in vitro. Sulfasalazine-treated wild-type mice and xCT knockout mice were analyzed. L635 or DMP-777 treatment was used to chemically induce acute gastric damage. The anti-inflammatory metabolites of sulfasalazine (sulfapyridine and mesalazine) were used as controls. Normal gastric lineages, metaplastic markers, autophagy, proliferation, xCT activity, ROS, and apoptosis were assessed. Results xCT was up-regulated early as Chief Cells transitioned into SPEM. Inhibition of xCT or small interfering RNA knockdown blocked cystine uptake and decreased glutathione production by metaplastic Cells and prevented ROS detoxification and proliferation. Moreover, xCT activity was required for Chief Cell reprogramming into SPEM after gastric injury in vivo. Chief Cells from xCT-deficient mice showed decreased autophagy, mucus granule formation and proliferation, as well as increased levels of ROS and apoptosis compared with wild-type mice. On the other hand, the anti-inflammatory metabolites of sulfasalazine did not affect SPEM development. Conclusions The results presented here suggest that maintaining redox balance is crucial for progression through the reprogramming process and that xCT-mediated cystine uptake is required for Chief Cell plasticity and ROS detoxification.
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Murine Models of Gastric Corpus PreneoplasiaSummary
Elsevier, 2017Co-Authors: Christine P. Petersen, Jason C. Mills, James R. GoldenringAbstract:Intestinal-type gastric adenocarcinoma evolves in a field of pre-existing metaplasia. Over the past 20 years, a number of murine models have been developed to address aspects of the physiology and pathophysiology of metaplasia induction. Although none of these models has achieved true recapitulation of the induction of adenocarcinoma, they have led to important insights into the factors that influence the induction and progression of metaplasia. Here, we review the pathologic definitions relevant to alterations in gastric corpus lineages and classification of metaplasia by specific lineage markers. In addition, we review present murine models of the induction and progression of spasmolytic polypeptide (TFF2)âexpressing metaplasia, the predominant metaplastic lineage observed in murine models. These models provide a basis for the development of a broader understanding of the physiological and pathophysiological roles of metaplasia in the stomach. Keywords: SPEM, Intestinal Metaplasia, Gastric Cancer, TFF2, Chief Cell, Hyperplasi
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Metaplasia in the Stomach Arises From Gastric Chief Cells
Elsevier, 2017Co-Authors: Jason C. Mills, James R. GoldenringAbstract:The development of intestinal-type gastric cancer is preceded by loss of parietal Cells (oxyntic atrophy) and the induction of metaplastic Cell lineages in the gastric mucosa. For example, mouse models have shown that spasmolytic polypeptide-expressing metaplasia can develop following oxyntic atrophy through transdifferentiation of zymogen-secreting Chief Cells. Evolution of spasmolytic polypeptide-expressing metaplasia from Chief Cells occurs via a coordinated dismantling of their secretory apparatus and reprogramming of their transcriptome. Increasing evidence suggests that the process of Chief Cell reprogramming requires the influence of inflammatory cytokines and requires both zymogen granule autophagy and alterations in gene transcription. It is likely that spasmolytic polypeptide-expressing metaplasia is a physiological repair mechanism that is similar to those that occur in other tissues (eg, pancreas) for recruiting reparative progenitor Cells in response to mucosal wounds. Chronic inflammation can induce a recurring pattern of persistent reprogramming/metaplasia that increases the risk for neoplasia
Sumio Watanabe - One of the best experts on this subject based on the ideXlab platform.
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epigenetic regulation of wnt β catenin signal associated genes in gastric neoplasia of the fundic gland Chief Cell predominant type
Pathology International, 2017Co-Authors: Takashi Murakami, Takashi Yao, Hiroyuki Mitomi, Tsuyoshi Saito, Tomoyoshi Shibuya, Sumio WatanabeAbstract:Gastric neoplasia of the fundic gland (Chief Cell-predominant) type (GNCCP) is a rare variant of gastric tumor. This tumor is associated with activation of the Wnt/β-catenin signaling pathway; however, the mechanisms underlying this activation remain unknown. To elucidate potential roles of Wnt/β-catenin signal-associated gene methylation in GNCCP, we performed β-catenin immunostaining and methylation-specific polymerase chain reaction (PCR) for their associated genes, including SFRPs, APC, AXIN2, and MCC, in 26 GNCCPs [i.e., 11 intramucosal (GNCCP-Ms) and 15 submucosal tumors (GNCCP-SMs)], and compared with 27 fundic gland polyps (FGPs), 12 FGPs with dysplasia (FGP-Ds), 27 conventional gastric adenocarcinomas (CGAs). Nuclear β-catenin labeling indices were higher in GNCCPs and CGAs than in FGPs and FGP-Ds. SFRPs, APC, and AXIN2 were more frequently methylated in GNCCPs and CGAs (SFRP1, 88%/96%; SFRP2, 85%/93%; SFRP4, 73%/81%; APC, 81%/81%; AXIN2, 81%/85%; respectively) than in FGPs and FGP-Ds (37%/50%; 41%/42%; 41%/58%; 37%/33%; 41%/50%; respectively). A significant correlation was seen between nuclear β-catenin expression and methylation of SFRP1 in GNCCPs. Furthermore, nuclear β-catenin expression was significantly frequent in high-methylated GNCCPs than in low-methylated tumors. In conclusion, our results suggest that activation of this pathway, mediated by gene methylation, may be associated with progression of some GNCCP cases, similar to CGAs.
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gastric adenocarcinoma of the fundic gland type Chief Cell predominant type
Endoscopy, 2013Co-Authors: Hiroya Ueyama, Takashi Yao, Kenshi Matsumoto, Akihito Nagahara, Takuo Hayashi, Sumio WatanabeAbstract:Gastric adenocarcinoma of the fundic gland (Chief Cell predominant type, GA-FG-CCP) was recently proposed as a new, rare variant of gastric adenocarcinoma. The aim of the current study was to evaluate the endoscopic features of GA-FG-CCP. A total of 10 GA-FG-CCPs were included and evaluated retrospectively. The endoscopic and clinicopathological features of the lesions were analyzed to provide information of diagnostic value. The GA-FG-CCPs were classified into two categories: submucosal tumor shape (60 %) and flat or depressed type (40 %). Endoscopically, the most common features were submucosal tumor shape (60 %), whitish color (70 %), dilated vessels with branching architecture (50 %), and background mucosa without atrophic change (90 %). GA-FG-CCP has distinct endoscopic characteristics, especially in terms of shape, color, vessels, and background mucosa and may be classified into two categories macroscopically. To diagnose GA-FG-CCP correctly by pathological examination of biopsy specimens, these endoscopic features should be taken into consideration.
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alteration in the wnt β catenin signaling pathway in gastric neoplasias of fundic gland Chief Cell predominant type
Human Pathology, 2013Co-Authors: Yasuhiro Hidaka, Takashi Yao, Kenshi Matsumoto, Hiroyuki Mitomi, Tsuyoshi Saito, Michiko Takahashi, Seyong Lee, Sumio WatanabeAbstract:Gastric neoplasia of Chief Cell-predominant type (GN-CCP) has been reported as a new, rare variant of gastric tumor. GN-CCPs were defined as tumors consisting of irregular anastomosing glands of columnar Cells mimicking Chief Cells of fundic gland with nuclear atypia and prolapse-type submucosal involvement. We comparatively evaluated clinicopathologic features between 31 GN-CCPs and 130 cases of conventional gastric adenocarcinoma invading into submucosa (CGA-SM) in addition to nuclear β-catenin immunolabeling and direct sequencing of members of the Wnt/β-catenin pathway, CTNNB1, APC, and AXIN, in a subset of these tumors. GN-CCP presented as small protruded lesions located in the upper third of the stomach, with minimal involvement into the submucosa and rare lymphovascular invasion. None of the lesions have demonstrated a recurrence of disease or metastasis on follow-up. Nuclear β-catenin immunolabeling was higher in GN-CCP (labeling index [LI]: median, 19.3%; high expresser [LI >30%], 7/27 cases [26%]) than CGA-SM (median LI, 14.7%; high expresser, 1/19 cases [6%]). Missense mutation of APC was observed in 1 GN-CCP but not CGA-SM. Missense or nonsense mutations of CTNNB1 and AXIN1 were higher in GN-CCPs (14.8%, both) than CGA-SMs (5.3%, both). Missense mutations of AXIN2 were higher in GN-CCPs (25.9%) than in CGA-SMs (10.5%). Overall, 14 (51.9%) of 27 GN-CCPs and 5 (26.3%) of 19 CGA-SM cases harbored at least 1 of these gene mutations. In conclusion, GN-CCPs as a unique variant of nonaggressive tumor are characterized by nuclear β-catenin accumulation and mutation of CTNNB1 or AXIN gene, suggesting activation of the Wnt/β-catenin pathway.
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gastric adenocarcinoma of fundic gland type Chief Cell predominant type proposal for a new entity of gastric adenocarcinoma
The American Journal of Surgical Pathology, 2010Co-Authors: Hiroya Ueyama, Takashi Yao, Yutaka Nakashima, Katsuya Hirakawa, Yumi Oshiro, Minako Hirahashi, Akinori Iwashita, Sumio WatanabeAbstract:Only a few cases of gastric adenocarcinoma of fundic gland type have been reported. Gastric adenocarcinoma with Chief Cell differentiation (GA-CCD) has been recently reported as a new variant of gastric adenocarcinoma. However, its clinicopathologic features are uncertain. To elucidate them, GA-CCDs exhibiting pepsinogen-I expression (10 lesions: Group A) and randomly selected gastric adenocarcinomas of differentiated type (111 lesions: Group B) were evaluated in this study. Cell differentiation by MUC2, MUC5AC, MUC6, CD10, pepsinogen-I, H+/K+-ATPase and chromogranin A, Cell proliferation by Ki-67, and overexpression of p53 protein were evaluated immunohistochemically. In Group A, all GA-CCDs were located in the upper third of the stomach. Tumors were small, with the average maximum diameter ranging from 4 to 20 (average, 8.6) mm. Histologically, GA-CCDs were well-differentiated adenocarcinomas composed of pale gray-blue, basophilic columnar Cells with mild nuclear atypia, resembling Chief Cells. Immunohistochemically, scattered positivity for H+/K+-ATPase was observed in addition to expression of pepsinogen-I and MUC6, indicating focal differentiation toward parietal Cells. In Group B, pepsinogen-I was very focally expressed in 2 cases. As these 2 cases exhibited different clinicopathological and histologic features, they cannot be categorized as GA-CCD. Mild atypism, no lymphovascular invasion, low proliferative activity, no overexpression of p53, and no recurrence indicated less aggressiveness of GA-CCD. GA-CCD is rare, but it has distinct clinicopathological characteristics, especially in terms of tumor location, histologic features, phenotypic expression, and low-grade malignancy. We propose gastric adenocarcinoma of fundic gland type (Chief Cell predominant type) as a new entity of gastric adenocarcinoma.
Takashi Yao - One of the best experts on this subject based on the ideXlab platform.
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epigenetic regulation of wnt β catenin signal associated genes in gastric neoplasia of the fundic gland Chief Cell predominant type
Pathology International, 2017Co-Authors: Takashi Murakami, Takashi Yao, Hiroyuki Mitomi, Tsuyoshi Saito, Tomoyoshi Shibuya, Sumio WatanabeAbstract:Gastric neoplasia of the fundic gland (Chief Cell-predominant) type (GNCCP) is a rare variant of gastric tumor. This tumor is associated with activation of the Wnt/β-catenin signaling pathway; however, the mechanisms underlying this activation remain unknown. To elucidate potential roles of Wnt/β-catenin signal-associated gene methylation in GNCCP, we performed β-catenin immunostaining and methylation-specific polymerase chain reaction (PCR) for their associated genes, including SFRPs, APC, AXIN2, and MCC, in 26 GNCCPs [i.e., 11 intramucosal (GNCCP-Ms) and 15 submucosal tumors (GNCCP-SMs)], and compared with 27 fundic gland polyps (FGPs), 12 FGPs with dysplasia (FGP-Ds), 27 conventional gastric adenocarcinomas (CGAs). Nuclear β-catenin labeling indices were higher in GNCCPs and CGAs than in FGPs and FGP-Ds. SFRPs, APC, and AXIN2 were more frequently methylated in GNCCPs and CGAs (SFRP1, 88%/96%; SFRP2, 85%/93%; SFRP4, 73%/81%; APC, 81%/81%; AXIN2, 81%/85%; respectively) than in FGPs and FGP-Ds (37%/50%; 41%/42%; 41%/58%; 37%/33%; 41%/50%; respectively). A significant correlation was seen between nuclear β-catenin expression and methylation of SFRP1 in GNCCPs. Furthermore, nuclear β-catenin expression was significantly frequent in high-methylated GNCCPs than in low-methylated tumors. In conclusion, our results suggest that activation of this pathway, mediated by gene methylation, may be associated with progression of some GNCCP cases, similar to CGAs.
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gastric adenocarcinoma of the fundic gland type Chief Cell predominant type
Endoscopy, 2013Co-Authors: Hiroya Ueyama, Takashi Yao, Kenshi Matsumoto, Akihito Nagahara, Takuo Hayashi, Sumio WatanabeAbstract:Gastric adenocarcinoma of the fundic gland (Chief Cell predominant type, GA-FG-CCP) was recently proposed as a new, rare variant of gastric adenocarcinoma. The aim of the current study was to evaluate the endoscopic features of GA-FG-CCP. A total of 10 GA-FG-CCPs were included and evaluated retrospectively. The endoscopic and clinicopathological features of the lesions were analyzed to provide information of diagnostic value. The GA-FG-CCPs were classified into two categories: submucosal tumor shape (60 %) and flat or depressed type (40 %). Endoscopically, the most common features were submucosal tumor shape (60 %), whitish color (70 %), dilated vessels with branching architecture (50 %), and background mucosa without atrophic change (90 %). GA-FG-CCP has distinct endoscopic characteristics, especially in terms of shape, color, vessels, and background mucosa and may be classified into two categories macroscopically. To diagnose GA-FG-CCP correctly by pathological examination of biopsy specimens, these endoscopic features should be taken into consideration.
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alteration in the wnt β catenin signaling pathway in gastric neoplasias of fundic gland Chief Cell predominant type
Human Pathology, 2013Co-Authors: Yasuhiro Hidaka, Takashi Yao, Kenshi Matsumoto, Hiroyuki Mitomi, Tsuyoshi Saito, Michiko Takahashi, Seyong Lee, Sumio WatanabeAbstract:Gastric neoplasia of Chief Cell-predominant type (GN-CCP) has been reported as a new, rare variant of gastric tumor. GN-CCPs were defined as tumors consisting of irregular anastomosing glands of columnar Cells mimicking Chief Cells of fundic gland with nuclear atypia and prolapse-type submucosal involvement. We comparatively evaluated clinicopathologic features between 31 GN-CCPs and 130 cases of conventional gastric adenocarcinoma invading into submucosa (CGA-SM) in addition to nuclear β-catenin immunolabeling and direct sequencing of members of the Wnt/β-catenin pathway, CTNNB1, APC, and AXIN, in a subset of these tumors. GN-CCP presented as small protruded lesions located in the upper third of the stomach, with minimal involvement into the submucosa and rare lymphovascular invasion. None of the lesions have demonstrated a recurrence of disease or metastasis on follow-up. Nuclear β-catenin immunolabeling was higher in GN-CCP (labeling index [LI]: median, 19.3%; high expresser [LI >30%], 7/27 cases [26%]) than CGA-SM (median LI, 14.7%; high expresser, 1/19 cases [6%]). Missense mutation of APC was observed in 1 GN-CCP but not CGA-SM. Missense or nonsense mutations of CTNNB1 and AXIN1 were higher in GN-CCPs (14.8%, both) than CGA-SMs (5.3%, both). Missense mutations of AXIN2 were higher in GN-CCPs (25.9%) than in CGA-SMs (10.5%). Overall, 14 (51.9%) of 27 GN-CCPs and 5 (26.3%) of 19 CGA-SM cases harbored at least 1 of these gene mutations. In conclusion, GN-CCPs as a unique variant of nonaggressive tumor are characterized by nuclear β-catenin accumulation and mutation of CTNNB1 or AXIN gene, suggesting activation of the Wnt/β-catenin pathway.
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long term follow up of gastric adenocarcinoma with Chief Cell differentiation using upper gastrointestinal tract endoscopy
Internal Medicine, 2013Co-Authors: Takashi Abe, Takayuki Nagai, Junji Fukunaga, Hitoshi Okawara, Hiroshi Nakashima, Mitsutaka Syutou, Nobuaki Kajimoto, Ryojin Wake, Tsuneo Oyama, Takashi YaoAbstract:During upper endoscopic screening, a 71-year-old asymptomatic woman was found to have a small, yellowish, superficial elevated lesion in the upper third of her stomach, without any signs of atrophic mucosa. The patient underwent endoscopic follow-up once a year for approximately five years; however, changes in the tumor were barely detectable. Endoscopic mucosal resection was performed, and a histological examination confirmed the diagnosis of gastric adenocarcinoma with Chief Cell differentiation (GA-CCD). GA-CCD is rare; therefore, its clinicopathological features remain unknown. This case suggests that only barely detectable endoscopic changes may be observed in GA-CCD during long-term follow-up.
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gastric adenocarcinoma of fundic gland type Chief Cell predominant type treated with endoscopic aspiration mucosectomy
Digestive Endoscopy, 2011Co-Authors: Hirotoshi Fukatsu, Haruka Miyoshi, Kuniharu Ishiki, Maiko Tamura, Takashi YaoAbstract:Upper endoscopy screening in an asymptomatic 56-year-old man showed a small, yellowish elevated lesion with a central depression on the posterior wall in the gastric cardia. Biopsy specimens from this lesion were suspicious of carcinoid tumor. We suspected this lesion to be a sporadic gastric carcinoid tumor with a diameter of 5 mm, limited to the mucosal layer. We then performed an endoscopic aspiration mucosectomy with a cap-fitted endoscope. Microscopically, the lesion obtained from the resected specimen was minimally invasive to the submucosa and showed highly differentiated columnar Cells in irregularly anastomosing glands. Immunohistology was positive for pepsinogen-I, and MUC6, partially positive for H(+)/K(+)-ATPase, and negative for MUC5AC. In addition, it was positive for synaptophysin and CD56, and negative for chromogranin A. We finally diagnosed the patient as having gastric adenocarcinoma of fundic gland type (Chief Cell predominant type) with minimal invasion (100 µm) to the submucosa. Surveillance endoscopy with biopsy specimens and abdominal computed tomography at 1 year revealed no evidence of tumor recurrence. We herein report this rare case of gastric adenocarcinoma of fundic gland type (Chief Cell predominant type).
Jason C. Mills - One of the best experts on this subject based on the ideXlab platform.
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Cystine/Glutamate Antiporter (xCT) Is Required for Chief Cell Plasticity After Gastric Injury.
Cellular and Molecular Gastroenterology and Hepatology, 2019Co-Authors: Anne R. Meyer, Amy C. Engevik, Spencer G. Willet, Janice A. Williams, Yong Zou, Pierre P. Massion, Jason C. Mills, Eun-young Choi, James R. GoldenringAbstract:Background & Aims Many differentiated epithelial Cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of Cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic Chief Cells into a metaplastic Cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in Chief Cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of Chief Cells into SPEM. Methods Sulfasalazine (an xCT inhibitor) and small interfering RNA knockdown were used to target xCT on metaplastic Cells in vitro. Sulfasalazine-treated wild-type mice and xCT knockout mice were analyzed. L635 or DMP-777 treatment was used to chemically induce acute gastric damage. The anti-inflammatory metabolites of sulfasalazine (sulfapyridine and mesalazine) were used as controls. Normal gastric lineages, metaplastic markers, autophagy, proliferation, xCT activity, ROS, and apoptosis were assessed. Results xCT was up-regulated early as Chief Cells transitioned into SPEM. Inhibition of xCT or small interfering RNA knockdown blocked cystine uptake and decreased glutathione production by metaplastic Cells and prevented ROS detoxification and proliferation. Moreover, xCT activity was required for Chief Cell reprogramming into SPEM after gastric injury in vivo. Chief Cells from xCT-deficient mice showed decreased autophagy, mucus granule formation and proliferation, as well as increased levels of ROS and apoptosis compared with wild-type mice. On the other hand, the anti-inflammatory metabolites of sulfasalazine did not affect SPEM development. Conclusions The results presented here suggest that maintaining redox balance is crucial for progression through the reprogramming process and that xCT-mediated cystine uptake is required for Chief Cell plasticity and ROS detoxification.
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cystine glutamate antiporter xct is required for Chief Cell plasticity after gastric injury
Cellular and molecular gastroenterology and hepatology, 2019Co-Authors: Anne R. Meyer, Amy C. Engevik, Spencer G. Willet, Janice A. Williams, Yong Zou, Pierre P. Massion, Jason C. Mills, Eun-young Choi, James R. GoldenringAbstract:Background & Aims Many differentiated epithelial Cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of Cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic Chief Cells into a metaplastic Cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in Chief Cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of Chief Cells into SPEM. Methods Sulfasalazine (an xCT inhibitor) and small interfering RNA knockdown were used to target xCT on metaplastic Cells in vitro. Sulfasalazine-treated wild-type mice and xCT knockout mice were analyzed. L635 or DMP-777 treatment was used to chemically induce acute gastric damage. The anti-inflammatory metabolites of sulfasalazine (sulfapyridine and mesalazine) were used as controls. Normal gastric lineages, metaplastic markers, autophagy, proliferation, xCT activity, ROS, and apoptosis were assessed. Results xCT was up-regulated early as Chief Cells transitioned into SPEM. Inhibition of xCT or small interfering RNA knockdown blocked cystine uptake and decreased glutathione production by metaplastic Cells and prevented ROS detoxification and proliferation. Moreover, xCT activity was required for Chief Cell reprogramming into SPEM after gastric injury in vivo. Chief Cells from xCT-deficient mice showed decreased autophagy, mucus granule formation and proliferation, as well as increased levels of ROS and apoptosis compared with wild-type mice. On the other hand, the anti-inflammatory metabolites of sulfasalazine did not affect SPEM development. Conclusions The results presented here suggest that maintaining redox balance is crucial for progression through the reprogramming process and that xCT-mediated cystine uptake is required for Chief Cell plasticity and ROS detoxification.
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maturity and age influence Chief Cell ability to transdifferentiate into metaplasia
American Journal of Physiology-gastrointestinal and Liver Physiology, 2017Co-Authors: Victoria G Weis, Anne R. Meyer, Eun-young Choi, Christine P. Petersen, Jared A Weis, Jason C. MillsAbstract:Previous investigations have indicated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach arises from transdifferentiation of Chief Cells. Nevertheless, the intrinsic properti...
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Murine Models of Gastric Corpus PreneoplasiaSummary
Elsevier, 2017Co-Authors: Christine P. Petersen, Jason C. Mills, James R. GoldenringAbstract:Intestinal-type gastric adenocarcinoma evolves in a field of pre-existing metaplasia. Over the past 20 years, a number of murine models have been developed to address aspects of the physiology and pathophysiology of metaplasia induction. Although none of these models has achieved true recapitulation of the induction of adenocarcinoma, they have led to important insights into the factors that influence the induction and progression of metaplasia. Here, we review the pathologic definitions relevant to alterations in gastric corpus lineages and classification of metaplasia by specific lineage markers. In addition, we review present murine models of the induction and progression of spasmolytic polypeptide (TFF2)âexpressing metaplasia, the predominant metaplastic lineage observed in murine models. These models provide a basis for the development of a broader understanding of the physiological and pathophysiological roles of metaplasia in the stomach. Keywords: SPEM, Intestinal Metaplasia, Gastric Cancer, TFF2, Chief Cell, Hyperplasi
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Metaplasia in the Stomach Arises From Gastric Chief Cells
Elsevier, 2017Co-Authors: Jason C. Mills, James R. GoldenringAbstract:The development of intestinal-type gastric cancer is preceded by loss of parietal Cells (oxyntic atrophy) and the induction of metaplastic Cell lineages in the gastric mucosa. For example, mouse models have shown that spasmolytic polypeptide-expressing metaplasia can develop following oxyntic atrophy through transdifferentiation of zymogen-secreting Chief Cells. Evolution of spasmolytic polypeptide-expressing metaplasia from Chief Cells occurs via a coordinated dismantling of their secretory apparatus and reprogramming of their transcriptome. Increasing evidence suggests that the process of Chief Cell reprogramming requires the influence of inflammatory cytokines and requires both zymogen granule autophagy and alterations in gene transcription. It is likely that spasmolytic polypeptide-expressing metaplasia is a physiological repair mechanism that is similar to those that occur in other tissues (eg, pancreas) for recruiting reparative progenitor Cells in response to mucosal wounds. Chronic inflammation can induce a recurring pattern of persistent reprogramming/metaplasia that increases the risk for neoplasia
Eun-young Choi - One of the best experts on this subject based on the ideXlab platform.
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Chief Cell plasticity is the origin of metaplasia following acute injury in the stomach mucosa
Gut, 2021Co-Authors: Brianna M Caldwell, Anne R. Meyer, Amy C. Engevik, Jared A Weis, Eun-young ChoiAbstract:OBJECTIVE Metaplasia arises from differentiated Cell types in response to injury and is considered a precursor in many cancers. Heterogeneous Cell lineages are present in the reparative metaplastic mucosa with response to injury, including foveolar Cells, proliferating Cells and spasmolytic polypeptide-expressing metaplasia (SPEM) Cells, a key metaplastic Cell population. Zymogen-secreting Chief Cells are long-lived Cells in the stomach mucosa and have been considered the origin of SPEM Cells; however, a conflicting paradigm has proposed isthmal progenitor Cells as an origin for SPEM. DESIGN Gastric intrinsic factor (GIF) is a stomach tissue-specific gene and exhibits protein expression unique to mature mouse Chief Cells. We generated a novel Chief Cell-specific driver mouse allele, GIF-rtTA. GIF-GFP reporter mice were used to validate specificity of GIF-rtTA driver in Chief Cells. GIF-Cre-RnTnG mice were used to perform lineage tracing during homoeostasis and acute metaplasia development. L635 treatment was used to induce acute mucosal injury and coimmunofluorescence staining was performed for various gastric lineage markers. RESULTS We demonstrated that mature Chief Cells, rather than isthmal progenitor Cells, serve as the predominant origin of SPEM Cells during the metaplastic process after acute mucosal injury. Furthermore, we observed long-term label-retaining Chief Cells at 1 year after the GFP labelling in Chief Cells. However, only a very small subset of the long-term label-retaining Chief Cells displayed the reprogramming ability in homoeostasis. In contrast, we identified Chief Cell-originating SPEM Cells as contributing to lineages within foveolar Cell hyperplasia in response to the acute mucosal injury. CONCLUSION Our study provides pivotal evidence for Cell plasticity and lineage contributions from differentiated gastric Chief Cells during acute metaplasia development.
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Decrease in MiR-148a Expression During Initiation of Chief Cell Transdifferentiation.
Cellular and molecular gastroenterology and hepatology, 2019Co-Authors: Takahiro Shimizu, Eun-young Choi, Yoojin Sohn, Christine P. Petersen, Nripesh Prasad, James R. GoldenringAbstract:Gastric Chief Cells differentiate from mucous neck Cells and develop their mature state at the base of oxyntic glands with expression of secretory zymogen granules. After parietal Cell loss, Chief Cells transdifferentiate into mucous Cell metaplasia, designated spasmolytic polypeptide-expressing metaplasia (SPEM), which is considered a candidate precursor of gastric cancer. We examined the range of microRNA (miRNA) expression in Chief Cells and identified miRNAs involved in Chief Cell transdifferentiation into SPEM. Among them, miR-148a was strongly and specifically expressed in Chief Cells and significantly decreased during the process of Chief Cell transdifferentiation. Interestingly, suppression of miR-148a in a conditionally immortalized Chief Cell line induced up-regulation of CD44 variant 9 (CD44v9), one of the transcripts expressed at an early stage of SPEM development, and DNA methyltransferase 1 (Dnmt1), an established target of miR-148a. Immunostaining analyses showed that Dnmt1 was up-regulated in SPEM Cells as well as in Chief Cells before the emergence of SPEM in mouse models of acute oxyntic atrophy using either DMP-777 or L635. In the cascade of events that leads to transdifferentiation, miR-148a was down-regulated after acute oxyntic atrophy either in xCT knockout mice or after sulfasalazine inhibition of xCT. These findings suggest that the alteration of miR-148a expression is an early event in the process of Chief Cell transdifferentiation into SPEM.
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Cystine/Glutamate Antiporter (xCT) Is Required for Chief Cell Plasticity After Gastric Injury.
Cellular and Molecular Gastroenterology and Hepatology, 2019Co-Authors: Anne R. Meyer, Amy C. Engevik, Spencer G. Willet, Janice A. Williams, Yong Zou, Pierre P. Massion, Jason C. Mills, Eun-young Choi, James R. GoldenringAbstract:Background & Aims Many differentiated epithelial Cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of Cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic Chief Cells into a metaplastic Cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in Chief Cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of Chief Cells into SPEM. Methods Sulfasalazine (an xCT inhibitor) and small interfering RNA knockdown were used to target xCT on metaplastic Cells in vitro. Sulfasalazine-treated wild-type mice and xCT knockout mice were analyzed. L635 or DMP-777 treatment was used to chemically induce acute gastric damage. The anti-inflammatory metabolites of sulfasalazine (sulfapyridine and mesalazine) were used as controls. Normal gastric lineages, metaplastic markers, autophagy, proliferation, xCT activity, ROS, and apoptosis were assessed. Results xCT was up-regulated early as Chief Cells transitioned into SPEM. Inhibition of xCT or small interfering RNA knockdown blocked cystine uptake and decreased glutathione production by metaplastic Cells and prevented ROS detoxification and proliferation. Moreover, xCT activity was required for Chief Cell reprogramming into SPEM after gastric injury in vivo. Chief Cells from xCT-deficient mice showed decreased autophagy, mucus granule formation and proliferation, as well as increased levels of ROS and apoptosis compared with wild-type mice. On the other hand, the anti-inflammatory metabolites of sulfasalazine did not affect SPEM development. Conclusions The results presented here suggest that maintaining redox balance is crucial for progression through the reprogramming process and that xCT-mediated cystine uptake is required for Chief Cell plasticity and ROS detoxification.
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cystine glutamate antiporter xct is required for Chief Cell plasticity after gastric injury
Cellular and molecular gastroenterology and hepatology, 2019Co-Authors: Anne R. Meyer, Amy C. Engevik, Spencer G. Willet, Janice A. Williams, Yong Zou, Pierre P. Massion, Jason C. Mills, Eun-young Choi, James R. GoldenringAbstract:Background & Aims Many differentiated epithelial Cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of Cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic Chief Cells into a metaplastic Cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in Chief Cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of Chief Cells into SPEM. Methods Sulfasalazine (an xCT inhibitor) and small interfering RNA knockdown were used to target xCT on metaplastic Cells in vitro. Sulfasalazine-treated wild-type mice and xCT knockout mice were analyzed. L635 or DMP-777 treatment was used to chemically induce acute gastric damage. The anti-inflammatory metabolites of sulfasalazine (sulfapyridine and mesalazine) were used as controls. Normal gastric lineages, metaplastic markers, autophagy, proliferation, xCT activity, ROS, and apoptosis were assessed. Results xCT was up-regulated early as Chief Cells transitioned into SPEM. Inhibition of xCT or small interfering RNA knockdown blocked cystine uptake and decreased glutathione production by metaplastic Cells and prevented ROS detoxification and proliferation. Moreover, xCT activity was required for Chief Cell reprogramming into SPEM after gastric injury in vivo. Chief Cells from xCT-deficient mice showed decreased autophagy, mucus granule formation and proliferation, as well as increased levels of ROS and apoptosis compared with wild-type mice. On the other hand, the anti-inflammatory metabolites of sulfasalazine did not affect SPEM development. Conclusions The results presented here suggest that maintaining redox balance is crucial for progression through the reprogramming process and that xCT-mediated cystine uptake is required for Chief Cell plasticity and ROS detoxification.
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maturity and age influence Chief Cell ability to transdifferentiate into metaplasia
American Journal of Physiology-gastrointestinal and Liver Physiology, 2017Co-Authors: Victoria G Weis, Anne R. Meyer, Eun-young Choi, Christine P. Petersen, Jared A Weis, Jason C. MillsAbstract:Previous investigations have indicated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach arises from transdifferentiation of Chief Cells. Nevertheless, the intrinsic properti...