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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.


Bmp-deficient activated-fibroblasts lead to gastric ECM remodeling.Immunostaining (in green) against basement membrane (a) collagen-I, (b) collagen-IV and (c) fibronectin was performed in the corpus gland of 90-day-old control and mutant mice. Collagen-I, collagen-IV and fibronectin deposition were increased in Bmpr1aΔMES mice compared to controls. Evans Blue served as counterstain for all immunofluorescences (red staining). (d) Western blot analyses in 90-day-old mice revealed a decrease in matrix metalloproteinase 3 (Mmp-3) in Bmpr1aΔMES mice compared to controls. Actin served as loading control. Densitometry analysis of exposed films using ImageJ revealed a significant decrease in Mmp-3 expression compared to controls (n = 4). Mann-Whitney; *p < 0.05. Scale bar: 50 μm.
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f7: Bmp-deficient activated-fibroblasts lead to gastric ECM remodeling.Immunostaining (in green) against basement membrane (a) collagen-I, (b) collagen-IV and (c) fibronectin was performed in the corpus gland of 90-day-old control and mutant mice. Collagen-I, collagen-IV and fibronectin deposition were increased in Bmpr1aΔMES mice compared to controls. Evans Blue served as counterstain for all immunofluorescences (red staining). (d) Western blot analyses in 90-day-old mice revealed a decrease in matrix metalloproteinase 3 (Mmp-3) in Bmpr1aΔMES mice compared to controls. Actin served as loading control. Densitometry analysis of exposed films using ImageJ revealed a significant decrease in Mmp-3 expression compared to controls (n = 4). Mann-Whitney; *p < 0.05. Scale bar: 50 μm.

Mentions: A pathological reactive mesenchyme is frequently populated by an abnormal number of activated-fibroblasts. Given that such reactive mesenchyme leads to the production of a toxic microenvironment with deregulated levels/types of cytokines, growth factors and massive remodeling of the ECM thus promoting the pathological state in the epithelium14333437, we next analyzed the potential alteration of ECM composition in Bmpr1aΔMES mice. Immunostaining against collagen-I, collagen-IV and fibronectin confirmed the increased deposition of these ECM proteins in 90-days-old Bmpr1aΔMES mice compared to controls (Fig. 7a–c, respectively). Lastly, Western blot analyses on corpus from whole stomach extract revealed a significant 3.72-fold down-modulation in stromelysin-1 (Mmp3), an important matrix-remodeling endopeptidase (Fig. 7d).


Loss of mesenchymal bone morphogenetic protein signaling leads to development of reactive stroma and initiation of the gastric neoplastic cascade
Bmp-deficient activated-fibroblasts lead to gastric ECM remodeling.Immunostaining (in green) against basement membrane (a) collagen-I, (b) collagen-IV and (c) fibronectin was performed in the corpus gland of 90-day-old control and mutant mice. Collagen-I, collagen-IV and fibronectin deposition were increased in Bmpr1aΔMES mice compared to controls. Evans Blue served as counterstain for all immunofluorescences (red staining). (d) Western blot analyses in 90-day-old mice revealed a decrease in matrix metalloproteinase 3 (Mmp-3) in Bmpr1aΔMES mice compared to controls. Actin served as loading control. Densitometry analysis of exposed films using ImageJ revealed a significant decrease in Mmp-3 expression compared to controls (n = 4). Mann-Whitney; *p < 0.05. Scale bar: 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Bmp-deficient activated-fibroblasts lead to gastric ECM remodeling.Immunostaining (in green) against basement membrane (a) collagen-I, (b) collagen-IV and (c) fibronectin was performed in the corpus gland of 90-day-old control and mutant mice. Collagen-I, collagen-IV and fibronectin deposition were increased in Bmpr1aΔMES mice compared to controls. Evans Blue served as counterstain for all immunofluorescences (red staining). (d) Western blot analyses in 90-day-old mice revealed a decrease in matrix metalloproteinase 3 (Mmp-3) in Bmpr1aΔMES mice compared to controls. Actin served as loading control. Densitometry analysis of exposed films using ImageJ revealed a significant decrease in Mmp-3 expression compared to controls (n = 4). Mann-Whitney; *p < 0.05. Scale bar: 50 μm.
Mentions: A pathological reactive mesenchyme is frequently populated by an abnormal number of activated-fibroblasts. Given that such reactive mesenchyme leads to the production of a toxic microenvironment with deregulated levels/types of cytokines, growth factors and massive remodeling of the ECM thus promoting the pathological state in the epithelium14333437, we next analyzed the potential alteration of ECM composition in Bmpr1aΔMES mice. Immunostaining against collagen-I, collagen-IV and fibronectin confirmed the increased deposition of these ECM proteins in 90-days-old Bmpr1aΔMES mice compared to controls (Fig. 7a–c, respectively). Lastly, Western blot analyses on corpus from whole stomach extract revealed a significant 3.72-fold down-modulation in stromelysin-1 (Mmp3), an important matrix-remodeling endopeptidase (Fig. 7d).

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 (Bmpr1a&Delta;MES). 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. Bmpr1a&Delta;MES 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.