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Loss of mesenchymal bone morphogenetic protein signaling leads to development of reactive stroma and initiation of the gastric neoplastic cascade

View Article: PubMed Central - PubMed

ABSTRACT

Bmps are morphogens involved in various gastric cellular functions. Studies in genetically-modified mice have shown that Bmp disruption in gastric epithelial and stromal cell compartments leads to the development of tumorigenesis. Our studies have demonstrated that abrogation of gastric epithelial Bmp signaling alone was not sufficient to recapitulate the neoplastic features associated with total gastric loss of Bmp signaling. Thus, epithelial Bmp signaling does not appear to be a key player in gastric tumorigenesis initiation. These observations suggest a greater role for stromal Bmp signaling in gastric polyposis initiation. In order to identify the specific roles played by mesenchymal Bmp signaling in gastric homeostasis, we generated a mouse model with abrogation of Bmp signaling exclusively in the gastro-intestinal mesenchyme (Bmpr1aΔMES). We were able to expose an unsuspected role for Bmp loss of signaling in leading normal gastric mesenchyme to adapt into reactive mesenchyme. An increase in the population of activated-fibroblasts, suggesting mesenchymal transdifferentiation, was observed in mutant stomach. Bmpr1aΔMES stomachs exhibited spontaneous benign polyps with presence of both intestinal metaplasia and spasmolytic-polypeptide-expressing metaplasia as early as 90 days postnatal. These results support the novel concept that loss of mesenchymal Bmp signaling cascade acts as a trigger in gastric polyposis initiation.

No MeSH data available.


Related in: MedlinePlus

Inflammation does not precede the onset of the phenotypic modifications observed in Bmpr1aΔMES mice.(a) Staining against immune cells was performed on the corpus glands of 30-day and 90-day-old mutant and control mice. Staining against CD3 in 30-day-old mice showed no presence of T cells in the mucosa of controls while minimal staining is seen in mutant mice. Cross reactivity (green labelling above the mucosa) with food present in the control stomach lumen is observed. (b) Staining against CD3 in 90-day-old mice revealed a prominent presence of T cells in the mucosa of Bmpr1aΔMES mice whereas T cell still remained absent in control mice. Evans Blue served as counterstain (red staining). (c) Staining against F4/80 in 30-day-old mice showed no presence of macrophages in the mucosa of control mice where minimal staining is observed in mutants. (d) Staining against F4/80 in 90-day-old mice revealed a marked of presence of macrophages in stromal tissue of Bmpr1aΔMES mice while macrophage staining was not observed in control mice. Scale bar: 50 μm.
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f5: Inflammation does not precede the onset of the phenotypic modifications observed in Bmpr1aΔMES mice.(a) Staining against immune cells was performed on the corpus glands of 30-day and 90-day-old mutant and control mice. Staining against CD3 in 30-day-old mice showed no presence of T cells in the mucosa of controls while minimal staining is seen in mutant mice. Cross reactivity (green labelling above the mucosa) with food present in the control stomach lumen is observed. (b) Staining against CD3 in 90-day-old mice revealed a prominent presence of T cells in the mucosa of Bmpr1aΔMES mice whereas T cell still remained absent in control mice. Evans Blue served as counterstain (red staining). (c) Staining against F4/80 in 30-day-old mice showed no presence of macrophages in the mucosa of control mice where minimal staining is observed in mutants. (d) Staining against F4/80 in 90-day-old mice revealed a marked of presence of macrophages in stromal tissue of Bmpr1aΔMES mice while macrophage staining was not observed in control mice. Scale bar: 50 μm.

Mentions: The above results revealed parietal cell atrophy as well as a possible mucous barrier dysfunction that could lead to increased proliferation of microorganisms in the stomach lumen, thereby intensifying their contact with the epithelium. Such bacterial deregulation could result in chronic inflammation of the gastric mucosa. Accordingly, it is widely recognized that gastric metaplasia precedes neoplastic transformation of the stomach in response to chronic inflammation39. Analyses for the atypical presence of T lymphocytes (CD3) and macrophages (F4/80) revealed the absence of these immune cells from the gastric mucosa in control 30-day-old mice (Fig. 5a,c). Presence of a subtle staining for both cell types was found in 30-day-old mutants (Fig. 5a,c). A significant presence of T lymphocytes and macrophages was found once SPEM was already established at 90-days compared to controls (Fig. 5b,d). These results suggest that inflammation did not initiate SPEM in Bmpr1aΔMES gastric mucosa but was rather concomitant with the onset of the phenotypic alterations observed.


Loss of mesenchymal bone morphogenetic protein signaling leads to development of reactive stroma and initiation of the gastric neoplastic cascade
Inflammation does not precede the onset of the phenotypic modifications observed in Bmpr1aΔMES mice.(a) Staining against immune cells was performed on the corpus glands of 30-day and 90-day-old mutant and control mice. Staining against CD3 in 30-day-old mice showed no presence of T cells in the mucosa of controls while minimal staining is seen in mutant mice. Cross reactivity (green labelling above the mucosa) with food present in the control stomach lumen is observed. (b) Staining against CD3 in 90-day-old mice revealed a prominent presence of T cells in the mucosa of Bmpr1aΔMES mice whereas T cell still remained absent in control mice. Evans Blue served as counterstain (red staining). (c) Staining against F4/80 in 30-day-old mice showed no presence of macrophages in the mucosa of control mice where minimal staining is observed in mutants. (d) Staining against F4/80 in 90-day-old mice revealed a marked of presence of macrophages in stromal tissue of Bmpr1aΔMES mice while macrophage staining was not observed in control mice. Scale bar: 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5016723&req=5

f5: Inflammation does not precede the onset of the phenotypic modifications observed in Bmpr1aΔMES mice.(a) Staining against immune cells was performed on the corpus glands of 30-day and 90-day-old mutant and control mice. Staining against CD3 in 30-day-old mice showed no presence of T cells in the mucosa of controls while minimal staining is seen in mutant mice. Cross reactivity (green labelling above the mucosa) with food present in the control stomach lumen is observed. (b) Staining against CD3 in 90-day-old mice revealed a prominent presence of T cells in the mucosa of Bmpr1aΔMES mice whereas T cell still remained absent in control mice. Evans Blue served as counterstain (red staining). (c) Staining against F4/80 in 30-day-old mice showed no presence of macrophages in the mucosa of control mice where minimal staining is observed in mutants. (d) Staining against F4/80 in 90-day-old mice revealed a marked of presence of macrophages in stromal tissue of Bmpr1aΔMES mice while macrophage staining was not observed in control mice. Scale bar: 50 μm.
Mentions: The above results revealed parietal cell atrophy as well as a possible mucous barrier dysfunction that could lead to increased proliferation of microorganisms in the stomach lumen, thereby intensifying their contact with the epithelium. Such bacterial deregulation could result in chronic inflammation of the gastric mucosa. Accordingly, it is widely recognized that gastric metaplasia precedes neoplastic transformation of the stomach in response to chronic inflammation39. Analyses for the atypical presence of T lymphocytes (CD3) and macrophages (F4/80) revealed the absence of these immune cells from the gastric mucosa in control 30-day-old mice (Fig. 5a,c). Presence of a subtle staining for both cell types was found in 30-day-old mutants (Fig. 5a,c). A significant presence of T lymphocytes and macrophages was found once SPEM was already established at 90-days compared to controls (Fig. 5b,d). These results suggest that inflammation did not initiate SPEM in Bmpr1aΔMES gastric mucosa but was rather concomitant with the onset of the phenotypic alterations observed.

View Article: PubMed Central - PubMed

ABSTRACT

Bmps are morphogens involved in various gastric cellular functions. Studies in genetically-modified mice have shown that Bmp disruption in gastric epithelial and stromal cell compartments leads to the development of tumorigenesis. Our studies have demonstrated that abrogation of gastric epithelial Bmp signaling alone was not sufficient to recapitulate the neoplastic features associated with total gastric loss of Bmp signaling. Thus, epithelial Bmp signaling does not appear to be a key player in gastric tumorigenesis initiation. These observations suggest a greater role for stromal Bmp signaling in gastric polyposis initiation. In order to identify the specific roles played by mesenchymal Bmp signaling in gastric homeostasis, we generated a mouse model with abrogation of Bmp signaling exclusively in the gastro-intestinal mesenchyme (Bmpr1aΔMES). We were able to expose an unsuspected role for Bmp loss of signaling in leading normal gastric mesenchyme to adapt into reactive mesenchyme. An increase in the population of activated-fibroblasts, suggesting mesenchymal transdifferentiation, was observed in mutant stomach. Bmpr1aΔMES stomachs exhibited spontaneous benign polyps with presence of both intestinal metaplasia and spasmolytic-polypeptide-expressing metaplasia as early as 90 days postnatal. These results support the novel concept that loss of mesenchymal Bmp signaling cascade acts as a trigger in gastric polyposis initiation.

No MeSH data available.


Related in: MedlinePlus