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Intestinal Stem Cell Markers in the Intestinal Metaplasia of Stomach and Barrett's Esophagus.

Jang BG, Lee BL, Kim WH - PLoS ONE (2015)

Bottom Line: Notably, we found that ISC markers-including OLFM4 and EPHB2-are positively associated with the CDX2 expression in non-tumorous gastric tissues.In conclusion, we identified that LGR5+ cells in gastric IM and BE coexpress ISC markers, and exhibit the same expression profile as those found in normal intestinal crypts.Taken together, these results implicate an intestinal-like stem cell population in the pathogenesis of IM, and provide an important basis for understanding the development and maintenance of this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Jeju National University Hospital, Jeju, South Korea.

ABSTRACT
Gastric intestinal metaplasia (IM) is a highly prevalent preneoplastic lesion; however, the molecular mechanisms regulating its development remain unclear. We have previously shown that a population of cells expressing the intestinal stem cell (ISC) marker LGR5 increases remarkably in IM. In this study, we further investigated the molecular characteristics of these LGR5+ cells in IM by examining the expression profile of several ISC markers. Notably, we found that ISC markers-including OLFM4 and EPHB2-are positively associated with the CDX2 expression in non-tumorous gastric tissues. This finding was confirmed in stomach lesions with or without metaplasia, which demonstrated that OLFM4 and EPHB2 expression gradually increased with metaplastic progression. Moreover, RNA in situ hybridization revealed that LGR5+ cells coexpress several ISC markers and remained confined to the base of metaplastic glands, reminiscent to that of normal intestinal crypts, whereas those in normal antral glands expressed none of these markers. Furthermore, a large number of ISC marker-expressing cells were diffusely distributed in gastric adenomas, suggesting that these markers may facilitate gastric tumorigenesis. In addition, Barrett's esophagus (BE)-which is histologically similar to intestinal metaplasia-exhibited a similar distribution of ISC markers, indicating the presence of a stem cell population with intestinal differentiation potential. In conclusion, we identified that LGR5+ cells in gastric IM and BE coexpress ISC markers, and exhibit the same expression profile as those found in normal intestinal crypts. Taken together, these results implicate an intestinal-like stem cell population in the pathogenesis of IM, and provide an important basis for understanding the development and maintenance of this disease.

No MeSH data available.


Related in: MedlinePlus

ISC marker expression in normal antrum, IM, and gastric adenoma.Representative H&E staining and in situ hybridization in IM and gastric adenoma with low grade dysplasia. LGR5+ cells in normal antrum are devoid of ISC marker expression (A), whereas those in I-type IM located at the base of glands coexpress ASCL2, EPHB2, and OLFM4 (B). Relative increase of LGR5+ cell population with ISC marker expression (C) in gastric adenoma. Magnification: A (except H & E staining) ×100, B ×400; C ×200.
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pone.0127300.g003: ISC marker expression in normal antrum, IM, and gastric adenoma.Representative H&E staining and in situ hybridization in IM and gastric adenoma with low grade dysplasia. LGR5+ cells in normal antrum are devoid of ISC marker expression (A), whereas those in I-type IM located at the base of glands coexpress ASCL2, EPHB2, and OLFM4 (B). Relative increase of LGR5+ cell population with ISC marker expression (C) in gastric adenoma. Magnification: A (except H & E staining) ×100, B ×400; C ×200.

Mentions: To determine if a direct relationship existed between LGR5 and ISC markers in IM, we examined whether their coexpression by RNA in situ hybridization. The expression of LGR5, ASCL2, EPHB2, and OLFM4 were first examined in a normal human small intestine section to validate this technique, and were found to localize specifically to cells within the stem cell niche of intestinal crypts as expected (S2 Fig). Since LGR5+ cells in normal intestinal crypts also express ISC markers, we theorized that LGR5+ cells in IM might also exhibit a similar expression pattern. Thus, we repeated the procedure on consecutive sections of endoscopic submucosal dissection specimens (n = 5), each of which contained multiple foci of GI- or I-type IM amongst non-tumorous tissue. A small number of LGR5+ cells at the base of normal antral glands were devoid of ISC marker expression (Fig 3A), whereas those in I-type IM showed expressed all three markers (Fig 3B). Moreover, GI-type IM lesions displayed the same expression profile overall except for that ISC marker expression was located above the remaining gastric glands, rather than restricted to the basal areas (S3 Fig). This expression pattern was consistently observed in all samples. These findings indicate that LGR5+ cells in IM differ from those in normal antrum in the expression of ISC markers that are usually restricted to cells within the intestinal crypts. Interestingly, IM derived from the fundic glands, where LGR5+ cells are not normally present, produced the same results (S4 Fig). Thus, it seems likely that the population of LGR5+ cells in IM does not result from the proliferation of preexisting LGR5+ cells, but is rather an emergence of LGR5+ cells with acquired differentiation potential, suggesting that an intestinal-like stem cell population is established in IM. In addition, gastric adenomas (n = 5) also expressed high levels of ISC markers throughout the lesions, rather than confined to the glandular crypts (Fig 3C). As shown in Fig 3, this accumulation of ISC marker-expressing cells over the metaplasia to dysplasia sequence is implicative of the participation of intestinal type stem cells in gastric tumorigenesis and additional studies to investigate the link between intestinal stem cell markers and gastric tumor development are certainly warranted.


Intestinal Stem Cell Markers in the Intestinal Metaplasia of Stomach and Barrett's Esophagus.

Jang BG, Lee BL, Kim WH - PLoS ONE (2015)

ISC marker expression in normal antrum, IM, and gastric adenoma.Representative H&E staining and in situ hybridization in IM and gastric adenoma with low grade dysplasia. LGR5+ cells in normal antrum are devoid of ISC marker expression (A), whereas those in I-type IM located at the base of glands coexpress ASCL2, EPHB2, and OLFM4 (B). Relative increase of LGR5+ cell population with ISC marker expression (C) in gastric adenoma. Magnification: A (except H & E staining) ×100, B ×400; C ×200.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440782&req=5

pone.0127300.g003: ISC marker expression in normal antrum, IM, and gastric adenoma.Representative H&E staining and in situ hybridization in IM and gastric adenoma with low grade dysplasia. LGR5+ cells in normal antrum are devoid of ISC marker expression (A), whereas those in I-type IM located at the base of glands coexpress ASCL2, EPHB2, and OLFM4 (B). Relative increase of LGR5+ cell population with ISC marker expression (C) in gastric adenoma. Magnification: A (except H & E staining) ×100, B ×400; C ×200.
Mentions: To determine if a direct relationship existed between LGR5 and ISC markers in IM, we examined whether their coexpression by RNA in situ hybridization. The expression of LGR5, ASCL2, EPHB2, and OLFM4 were first examined in a normal human small intestine section to validate this technique, and were found to localize specifically to cells within the stem cell niche of intestinal crypts as expected (S2 Fig). Since LGR5+ cells in normal intestinal crypts also express ISC markers, we theorized that LGR5+ cells in IM might also exhibit a similar expression pattern. Thus, we repeated the procedure on consecutive sections of endoscopic submucosal dissection specimens (n = 5), each of which contained multiple foci of GI- or I-type IM amongst non-tumorous tissue. A small number of LGR5+ cells at the base of normal antral glands were devoid of ISC marker expression (Fig 3A), whereas those in I-type IM showed expressed all three markers (Fig 3B). Moreover, GI-type IM lesions displayed the same expression profile overall except for that ISC marker expression was located above the remaining gastric glands, rather than restricted to the basal areas (S3 Fig). This expression pattern was consistently observed in all samples. These findings indicate that LGR5+ cells in IM differ from those in normal antrum in the expression of ISC markers that are usually restricted to cells within the intestinal crypts. Interestingly, IM derived from the fundic glands, where LGR5+ cells are not normally present, produced the same results (S4 Fig). Thus, it seems likely that the population of LGR5+ cells in IM does not result from the proliferation of preexisting LGR5+ cells, but is rather an emergence of LGR5+ cells with acquired differentiation potential, suggesting that an intestinal-like stem cell population is established in IM. In addition, gastric adenomas (n = 5) also expressed high levels of ISC markers throughout the lesions, rather than confined to the glandular crypts (Fig 3C). As shown in Fig 3, this accumulation of ISC marker-expressing cells over the metaplasia to dysplasia sequence is implicative of the participation of intestinal type stem cells in gastric tumorigenesis and additional studies to investigate the link between intestinal stem cell markers and gastric tumor development are certainly warranted.

Bottom Line: Notably, we found that ISC markers-including OLFM4 and EPHB2-are positively associated with the CDX2 expression in non-tumorous gastric tissues.In conclusion, we identified that LGR5+ cells in gastric IM and BE coexpress ISC markers, and exhibit the same expression profile as those found in normal intestinal crypts.Taken together, these results implicate an intestinal-like stem cell population in the pathogenesis of IM, and provide an important basis for understanding the development and maintenance of this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Jeju National University Hospital, Jeju, South Korea.

ABSTRACT
Gastric intestinal metaplasia (IM) is a highly prevalent preneoplastic lesion; however, the molecular mechanisms regulating its development remain unclear. We have previously shown that a population of cells expressing the intestinal stem cell (ISC) marker LGR5 increases remarkably in IM. In this study, we further investigated the molecular characteristics of these LGR5+ cells in IM by examining the expression profile of several ISC markers. Notably, we found that ISC markers-including OLFM4 and EPHB2-are positively associated with the CDX2 expression in non-tumorous gastric tissues. This finding was confirmed in stomach lesions with or without metaplasia, which demonstrated that OLFM4 and EPHB2 expression gradually increased with metaplastic progression. Moreover, RNA in situ hybridization revealed that LGR5+ cells coexpress several ISC markers and remained confined to the base of metaplastic glands, reminiscent to that of normal intestinal crypts, whereas those in normal antral glands expressed none of these markers. Furthermore, a large number of ISC marker-expressing cells were diffusely distributed in gastric adenomas, suggesting that these markers may facilitate gastric tumorigenesis. In addition, Barrett's esophagus (BE)-which is histologically similar to intestinal metaplasia-exhibited a similar distribution of ISC markers, indicating the presence of a stem cell population with intestinal differentiation potential. In conclusion, we identified that LGR5+ cells in gastric IM and BE coexpress ISC markers, and exhibit the same expression profile as those found in normal intestinal crypts. Taken together, these results implicate an intestinal-like stem cell population in the pathogenesis of IM, and provide an important basis for understanding the development and maintenance of this disease.

No MeSH data available.


Related in: MedlinePlus