Abstract:Background: The WHO defines early gastric carcinoma (EGC) as invasive carcinoma up to the submucosal layer, regardless of nodal metastasis. The recent study results indicate that EGC varies in location, histology, nodal metastasis, and prognosis. Summary: The heterogeneity in EGC may be related to various types of epithelial stem cells. The most important stem cells include Lgr5+ cells at the base of a gastric unit in the antrum-pylorus-cardia, Mist1+ cells at the isthmus/Troy+… Show more
“…To examine the alteration of gastric cancer cell populations upon treatment with anticancer drugs, we conducted single‐cell analysis for the expressions of gastric tissue lineage, stem cell and drug‐tolerant persister‐related genes. Gastric tissue consists of cells in various differentiation stages, including stem, progenitor, surface mucous, mucous gland and chief cells and endocrine cells, and specific markers for each cell type have been established (Figure A) . To induce persister cells, JSC15‐3 cells were treated with 3 µmol/L 5‐FU or 30 nmol/L SN38, an active metabolite of irinotecan, for 7 days and JSC17‐2 cells were treated with 3 µmol/L 5‐FU for 6 days.…”
Section: Resultsmentioning
confidence: 99%
“…Gastric tissue consists of cells in various differentiation stages, including stem, progenitor, surface mucous, mucous gland and chief cells and endocrine cells, and specific markers for each cell type have been established ( Figure 1A). [13][14][15][16][17][18][19] To induce persister cells, JSC15-3 cells were treated with 3 µmol/L 5-FU or 30 nmol/L SN38, an active metabolite of irinotecan, for 7 days and JSC17-2 cells were treated with 3 µmol/L 5-FU for 6 days. We focused on these two drugs because their prodrugs, capecitabine, tegafur and irinotecan, are commonly used for gastric cancer treatment in Japan.…”
Section: Anticancer Drugs Alter the Patterns Of Heterogeneity In Thmentioning
confidence: 99%
“…Normal gastric tissue consists of various cell types that are differentiated from stem cells into progenitor cells and then surface mucous (pit), mucous gland (neck) and endocrine cells through multiple steps . Recent studies have revealed the gastric cell lineage and specific markers for each cell type (summarized in Figure A) . For example, LGR5 and TROY are gastric stem cell markers, whereas SOX9 is a progenitor cell marker.…”
Section: Introductionmentioning
confidence: 99%
“…[13][14][15] Recent studies have revealed the gastric cell lineage and specific markers for each cell type (summarized in Figure 1A). [13][14][15][16][17][18][19] For example, LGR5 and TROY are gastric stem cell markers, whereas SOX9 is a progenitor cell marker. MUC5AC, TFF1 and GKN1 mark pit cells, whereas MUC6 and TFF2 are hallmarks of neck cells.…”
Tumors consist of heterogeneous cell populations that contain cancer cell subpopulations with anticancer drug‐resistant properties called “persister” cells. While this early‐phase drug tolerance is known to be related to the stem cell‐like characteristic of persister cells, how the stem cell‐related pathways contribute to drug resistance has remained elusive. Here, we conducted a single‐cell analysis based on the stem cell lineage‐related and gastric cell lineage‐related gene expression in patient‐derived gastric cancer cell models. The analyses revealed that 5‐fluorouracil (5‐FU) induces a dynamic change in the cell heterogeneity. In particular, cells highly expressing stem cell‐related genes were enriched in the residual cancer cells after 5‐FU treatment. Subsequent functional screening identified aldehyde dehydrogenase 1A3 (ALDH1A3) as a specific marker and potential therapeutic target of persister cells. ALDH1A3 was selectively overexpressed among the ALDH isozymes after treatment with 5‐FU or SN38, a DNA topoisomerase I inhibitor. Attenuation of ALDH1A3 expression by RNA interference significantly suppressed cell proliferation, reduced the number of persister cells after anticancer drug treatment and interfered with tumor growth in a mouse xenograft model. Mechanistically, ALDH1A3 depletion affected gene expression of the mammalian target of rapamycin (mTOR) cell survival pathway, which coincided with a decrease in the activating phosphorylation of S6 kinase. Temsirolimus, an mTOR inhibitor, reduced the number of 5FU‐tolerant persister cells. High ALDH1A3 expression correlated with worse prognosis of gastric cancer patients. These observations indicate that the ALDH1A3‐mTOR axis could be a novel therapeutic target to eradicate drug‐tolerant gastric cancer cells.
“…To examine the alteration of gastric cancer cell populations upon treatment with anticancer drugs, we conducted single‐cell analysis for the expressions of gastric tissue lineage, stem cell and drug‐tolerant persister‐related genes. Gastric tissue consists of cells in various differentiation stages, including stem, progenitor, surface mucous, mucous gland and chief cells and endocrine cells, and specific markers for each cell type have been established (Figure A) . To induce persister cells, JSC15‐3 cells were treated with 3 µmol/L 5‐FU or 30 nmol/L SN38, an active metabolite of irinotecan, for 7 days and JSC17‐2 cells were treated with 3 µmol/L 5‐FU for 6 days.…”
Section: Resultsmentioning
confidence: 99%
“…Gastric tissue consists of cells in various differentiation stages, including stem, progenitor, surface mucous, mucous gland and chief cells and endocrine cells, and specific markers for each cell type have been established ( Figure 1A). [13][14][15][16][17][18][19] To induce persister cells, JSC15-3 cells were treated with 3 µmol/L 5-FU or 30 nmol/L SN38, an active metabolite of irinotecan, for 7 days and JSC17-2 cells were treated with 3 µmol/L 5-FU for 6 days. We focused on these two drugs because their prodrugs, capecitabine, tegafur and irinotecan, are commonly used for gastric cancer treatment in Japan.…”
Section: Anticancer Drugs Alter the Patterns Of Heterogeneity In Thmentioning
confidence: 99%
“…Normal gastric tissue consists of various cell types that are differentiated from stem cells into progenitor cells and then surface mucous (pit), mucous gland (neck) and endocrine cells through multiple steps . Recent studies have revealed the gastric cell lineage and specific markers for each cell type (summarized in Figure A) . For example, LGR5 and TROY are gastric stem cell markers, whereas SOX9 is a progenitor cell marker.…”
Section: Introductionmentioning
confidence: 99%
“…[13][14][15] Recent studies have revealed the gastric cell lineage and specific markers for each cell type (summarized in Figure 1A). [13][14][15][16][17][18][19] For example, LGR5 and TROY are gastric stem cell markers, whereas SOX9 is a progenitor cell marker. MUC5AC, TFF1 and GKN1 mark pit cells, whereas MUC6 and TFF2 are hallmarks of neck cells.…”
Tumors consist of heterogeneous cell populations that contain cancer cell subpopulations with anticancer drug‐resistant properties called “persister” cells. While this early‐phase drug tolerance is known to be related to the stem cell‐like characteristic of persister cells, how the stem cell‐related pathways contribute to drug resistance has remained elusive. Here, we conducted a single‐cell analysis based on the stem cell lineage‐related and gastric cell lineage‐related gene expression in patient‐derived gastric cancer cell models. The analyses revealed that 5‐fluorouracil (5‐FU) induces a dynamic change in the cell heterogeneity. In particular, cells highly expressing stem cell‐related genes were enriched in the residual cancer cells after 5‐FU treatment. Subsequent functional screening identified aldehyde dehydrogenase 1A3 (ALDH1A3) as a specific marker and potential therapeutic target of persister cells. ALDH1A3 was selectively overexpressed among the ALDH isozymes after treatment with 5‐FU or SN38, a DNA topoisomerase I inhibitor. Attenuation of ALDH1A3 expression by RNA interference significantly suppressed cell proliferation, reduced the number of persister cells after anticancer drug treatment and interfered with tumor growth in a mouse xenograft model. Mechanistically, ALDH1A3 depletion affected gene expression of the mammalian target of rapamycin (mTOR) cell survival pathway, which coincided with a decrease in the activating phosphorylation of S6 kinase. Temsirolimus, an mTOR inhibitor, reduced the number of 5FU‐tolerant persister cells. High ALDH1A3 expression correlated with worse prognosis of gastric cancer patients. These observations indicate that the ALDH1A3‐mTOR axis could be a novel therapeutic target to eradicate drug‐tolerant gastric cancer cells.
“…Реже других желудочный , 22]. По литературным данным частота встречаемости желудочного иммунофенотипа при дифференцированном РРЖ колеблется от 7,9% до 23,9%[14,23] и даже может достигать 52,38%[9]. В нашем исследовании при дифференцированном типе РРЖ желудочный иммунофенотип встречался в 9,8% случаев (9/91), кишечный -в 47,2% (43/91).Важность исследования муцинового профиля РРЖ объясняется тем, что дифференцированный РРЖ (по классификации Nakamura K.), особенно диаметром менее 2 см, является общепринятым критерием в показаниях к эндоскопической резекции РРЖ, предложенной JGCA[4].…”
Муциновый иммуногистохимический профиль раннего рака желудка (РРЖ) обладает определенными клинико-морфологическими особенностями, которые не зависят от гистологического типа опухоли. В нашем исследовании мы определили распространение и прогностическое значение муцинового профиля РРЖ. На операционном материале 227 случаев РРЖ было проведено иммуногистохимическое исследование с определением экспрессии маркеров к муцинам MUC 5 АС, MUC6, MUC2 и CD10. Варианты муцинового иммунофенотипа были классифицированы как желудочный, кишечный, смешанный и нулевой иммунофенотипы в соответствии с иммунопозитивностью вышеуказанных маркеров. РРЖ с желудочным иммунофенотипом характеризовался более агрессивными морфологическими признаками-достоверно чаще (по сравнению с кишечным фенотипом) встречался при 0 III макроскопическом типе, при изъязвленном типе, при недифференцированном гистологическом типе по классификации Nakamura K., диффузном типе по классификации Lauren Р. и перстневидноклеточном гистологическом типе РРЖ по классификации JGCA. Также при РРЖ с желудочным иммунофенотипом наблюдался более высокий уровень метастазирования по сравнению с кишечным (20,6% против 11,7%), а частота метастазирования при дифференцированном типе РРЖ с желудочным иммунофенотипом была заметно выше, чем при кишечном (9/2; 22,3% против 40/3; 7,0%), однако данные не достигли значимости вследствие небольшого количества выборки. РРЖ с кишечным иммунофенотипом характеризовался более благоприятными морфологическими признаками и достоверно чаще встречался при внутрислизистой локализации, 0 I макроскопическом типе, дифференцированном типе по классификации Nakamura K., интестинальном типе по классификации Lauren Р. и при высокодифференцированной аденокарциноме по классификации JGCA и имел самую низкую частоту изъязвления. Результаты показывают, что муциновый профиль РРЖ связан с прогрессированием опухоли. Желудочный иммунофенотип РРЖ был ассоциирован более агрессивные морфологические характеристики, чем кишечный. Ключевые слова: ранний рак желудка, муциновый иммунофенотип.
Background and Aim
Gastric cancer (GC) is one of the most common cancers worldwide, with a high incidence rate in Korean men. However, comparative studies are scarce on the pathologic findings and treatment effects of GC in patients aged less than 40 years. We evaluated the characteristics and pathologic findings of GC patients aged younger and older than 40 years.
Methods
We retrospectively analyzed 2307 patients diagnosed with GC between January 2010 and May 2018. Eighty‐eight (3.8%) and 2219 (96.2%) patients were younger and older than 40 years, respectively. The patients were divided into younger (
n
= 70) and older (
n
= 62) age groups through propensity matching.
Results
Overall, compared to the younger group, the older group (
n
= 2219) had a significantly higher proportion of male patients (66.7%
vs
39.8%;
P
< 0.001) and patients who underwent endoscopic submucosal dissection (ESD) (2.3%
vs
23.1%;
P
< 0.001). However, young patients more often underwent operations compared to older patients (78.4%
vs
60.1%;
P
= 0.001). In the propensity‐matched group, older patients more often showed differentiated carcinoma, including well‐differentiated (5.7%
vs
11.3%) and moderately differentiated (1.4%
vs
32.3%). However, younger patients more often showed signet ring cell carcinoma (SRC) (70.0%
vs
25.8%). In multivariate analysis,
Helicobacter pylori
infection (odds ratio, 12.643; 95% confidence interval, 1.068–1449.665;
P
= 0.044) independently correlated with SRC risk.
Conclusions
Patients below 40 years were more likely to undergo surgery compared to ESD, and pathologic findings were more common in SRC. Therefore, more active screening and
H. pylori
eradication are needed even in patients aged less than 40 years.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.