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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

Loss of mesenchymal Bmp signaling leads to gastric hypochlorhydria and modulates gastrin and somatostatin cell populations.(a) Proton pump staining associated with parietal cells performed on mutant and control stomachs showed a decrease in the number of parietal cells in 30-day-old mutant stomach (b) with a noticeable loss by 90 days. (c) Statistical analysis of the number of H+/K+-ATPase positive cells revealed a significant decrease in parietal cells of the gland units in 30-day-old Bmpr1aΔMES mice and in 90-day-old Bmpr1aΔMES mice (n = 5). (d) Measurement of basal (PBS) and stimulated (histamine) gastric acid secretion in 16-hour fasted 90-days-old mice showed that basal and histamine-induced intragastric acidity was significantly lower (higher pH) in both conditions in Bmpr1aΔMES mice compared to controls (n = 6). (e) Staining against gastrin (green staining) showed a decrease in the number of this sub-population of endocrine cells in 90-day-old Bmpr1aΔMES stomachs compared with controls. (f) Positive gastrin-labeled cells were counted from the antrum of control and mutant animals and statistical analysis revealed a significant decrease in number of gastrin cells in Bmpr1aΔMES mice (n = 6). (g) Staining against somatostatin (green staining) performed on 90-day-old Bmpr1aΔMES and control corpus and (h) antrum revealed a decrease in positively-labeled somatostatin cells in mutant mice. (i) Statistical analysis also confirmed the significant decrease in the number of somatostatin-positive cells in Bmpr1aΔMES mice (n = 6). Evans Blue served as counterstain for all immunofluorescences (red staining). Scale bar: 50 μm. Two-way ANOVA (b,e,g), Mann-Whitney (c); *p < 0.05; **p < 0.01; ***p < 0.001.
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f3: Loss of mesenchymal Bmp signaling leads to gastric hypochlorhydria and modulates gastrin and somatostatin cell populations.(a) Proton pump staining associated with parietal cells performed on mutant and control stomachs showed a decrease in the number of parietal cells in 30-day-old mutant stomach (b) with a noticeable loss by 90 days. (c) Statistical analysis of the number of H+/K+-ATPase positive cells revealed a significant decrease in parietal cells of the gland units in 30-day-old Bmpr1aΔMES mice and in 90-day-old Bmpr1aΔMES mice (n = 5). (d) Measurement of basal (PBS) and stimulated (histamine) gastric acid secretion in 16-hour fasted 90-days-old mice showed that basal and histamine-induced intragastric acidity was significantly lower (higher pH) in both conditions in Bmpr1aΔMES mice compared to controls (n = 6). (e) Staining against gastrin (green staining) showed a decrease in the number of this sub-population of endocrine cells in 90-day-old Bmpr1aΔMES stomachs compared with controls. (f) Positive gastrin-labeled cells were counted from the antrum of control and mutant animals and statistical analysis revealed a significant decrease in number of gastrin cells in Bmpr1aΔMES mice (n = 6). (g) Staining against somatostatin (green staining) performed on 90-day-old Bmpr1aΔMES and control corpus and (h) antrum revealed a decrease in positively-labeled somatostatin cells in mutant mice. (i) Statistical analysis also confirmed the significant decrease in the number of somatostatin-positive cells in Bmpr1aΔMES mice (n = 6). Evans Blue served as counterstain for all immunofluorescences (red staining). Scale bar: 50 μm. Two-way ANOVA (b,e,g), Mann-Whitney (c); *p < 0.05; **p < 0.01; ***p < 0.001.

Mentions: Parietal cells in the oxyntic glands play a decisive role in gastric function and homeostasis38. Immunostaining of H+/K+-ATPase associated with the proton pump of parietal cells was performed and showed a decrease in number of labeled acid-secreting parietal cells in Bmpr1aΔMES mice compared to control littermates (Fig. 3a,b). Parietal cell counts revealed a significant 1.37-fold decrease in parietal cells in Bmpr1aΔMES mice at 30 days reaching a 2.81-fold decrease at 90 days (Fig. 3c). In 16-hour fasted 90-day-old mice, basal intragastric acidity was significantly lower by 1.24-fold in Bmpr1aΔMES mice (higher pH) compared to controls (Fig. 3d). Bmpr1aΔMES mice were unresponsive to histamine treatment whereas gastric acidity increased (drop in pH) in histamine-treated control animals. Gastric acid secretion is regulated by endocrine signals through the gastrin-histamine messenger pathway, among others38. Morphometric analysis of immunostained stomach pyloric antrums surprisingly revealed a significant decrease in the number of gastrin-expressing cells in Bmpr1aΔMES mice starting at 30 days (2.1-fold) and progressing by 90 days (4.5-fold) compared to controls (Fig. 3e,f).


Loss of mesenchymal bone morphogenetic protein signaling leads to development of reactive stroma and initiation of the gastric neoplastic cascade
Loss of mesenchymal Bmp signaling leads to gastric hypochlorhydria and modulates gastrin and somatostatin cell populations.(a) Proton pump staining associated with parietal cells performed on mutant and control stomachs showed a decrease in the number of parietal cells in 30-day-old mutant stomach (b) with a noticeable loss by 90 days. (c) Statistical analysis of the number of H+/K+-ATPase positive cells revealed a significant decrease in parietal cells of the gland units in 30-day-old Bmpr1aΔMES mice and in 90-day-old Bmpr1aΔMES mice (n = 5). (d) Measurement of basal (PBS) and stimulated (histamine) gastric acid secretion in 16-hour fasted 90-days-old mice showed that basal and histamine-induced intragastric acidity was significantly lower (higher pH) in both conditions in Bmpr1aΔMES mice compared to controls (n = 6). (e) Staining against gastrin (green staining) showed a decrease in the number of this sub-population of endocrine cells in 90-day-old Bmpr1aΔMES stomachs compared with controls. (f) Positive gastrin-labeled cells were counted from the antrum of control and mutant animals and statistical analysis revealed a significant decrease in number of gastrin cells in Bmpr1aΔMES mice (n = 6). (g) Staining against somatostatin (green staining) performed on 90-day-old Bmpr1aΔMES and control corpus and (h) antrum revealed a decrease in positively-labeled somatostatin cells in mutant mice. (i) Statistical analysis also confirmed the significant decrease in the number of somatostatin-positive cells in Bmpr1aΔMES mice (n = 6). Evans Blue served as counterstain for all immunofluorescences (red staining). Scale bar: 50 μm. Two-way ANOVA (b,e,g), Mann-Whitney (c); *p < 0.05; **p < 0.01; ***p < 0.001.
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f3: Loss of mesenchymal Bmp signaling leads to gastric hypochlorhydria and modulates gastrin and somatostatin cell populations.(a) Proton pump staining associated with parietal cells performed on mutant and control stomachs showed a decrease in the number of parietal cells in 30-day-old mutant stomach (b) with a noticeable loss by 90 days. (c) Statistical analysis of the number of H+/K+-ATPase positive cells revealed a significant decrease in parietal cells of the gland units in 30-day-old Bmpr1aΔMES mice and in 90-day-old Bmpr1aΔMES mice (n = 5). (d) Measurement of basal (PBS) and stimulated (histamine) gastric acid secretion in 16-hour fasted 90-days-old mice showed that basal and histamine-induced intragastric acidity was significantly lower (higher pH) in both conditions in Bmpr1aΔMES mice compared to controls (n = 6). (e) Staining against gastrin (green staining) showed a decrease in the number of this sub-population of endocrine cells in 90-day-old Bmpr1aΔMES stomachs compared with controls. (f) Positive gastrin-labeled cells were counted from the antrum of control and mutant animals and statistical analysis revealed a significant decrease in number of gastrin cells in Bmpr1aΔMES mice (n = 6). (g) Staining against somatostatin (green staining) performed on 90-day-old Bmpr1aΔMES and control corpus and (h) antrum revealed a decrease in positively-labeled somatostatin cells in mutant mice. (i) Statistical analysis also confirmed the significant decrease in the number of somatostatin-positive cells in Bmpr1aΔMES mice (n = 6). Evans Blue served as counterstain for all immunofluorescences (red staining). Scale bar: 50 μm. Two-way ANOVA (b,e,g), Mann-Whitney (c); *p < 0.05; **p < 0.01; ***p < 0.001.
Mentions: Parietal cells in the oxyntic glands play a decisive role in gastric function and homeostasis38. Immunostaining of H+/K+-ATPase associated with the proton pump of parietal cells was performed and showed a decrease in number of labeled acid-secreting parietal cells in Bmpr1aΔMES mice compared to control littermates (Fig. 3a,b). Parietal cell counts revealed a significant 1.37-fold decrease in parietal cells in Bmpr1aΔMES mice at 30 days reaching a 2.81-fold decrease at 90 days (Fig. 3c). In 16-hour fasted 90-day-old mice, basal intragastric acidity was significantly lower by 1.24-fold in Bmpr1aΔMES mice (higher pH) compared to controls (Fig. 3d). Bmpr1aΔMES mice were unresponsive to histamine treatment whereas gastric acidity increased (drop in pH) in histamine-treated control animals. Gastric acid secretion is regulated by endocrine signals through the gastrin-histamine messenger pathway, among others38. Morphometric analysis of immunostained stomach pyloric antrums surprisingly revealed a significant decrease in the number of gastrin-expressing cells in Bmpr1aΔMES mice starting at 30 days (2.1-fold) and progressing by 90 days (4.5-fold) compared to controls (Fig. 3e,f).

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.


Related in: MedlinePlus