Histopathological features of the proper gastric glands in FVB/N-background mice carrying constitutively-active aryl-hydrocarbon receptor

Abstract

Background Aryl-hydrocarbon receptor (AhR) is a multiple ligand-activated transcription factor that has important roles in xenobiotic, physiological, or pathological functions. Transgenic mice systemically expressing constitutively-active AhR (CA-AhR) have been created to mimic activated AhR signaling in vivo. However, their detailed histopathological features are unclear. In the present study, we generated CA-AhR-expressing FVB/N mice (FVB-CA-AhR mice) and clarified their phenotypes in detail. Methods Male and female FVB-CA-AhR and wild-type mice were histopathologically examined from 6 to 33 weeks of age. Results Among the systemic organs, only the stomachs in FVB-CA-AhR mice showed pathological changes including cystic structures beneath the serosa; in addition, stomach weights increased with age. Histopathologically, cystic structures and alcian blue-positive metaplasia were observed in the mucosa of the proper gastric glands, and these two histometric parameters were positively correlated. Furthermore, proliferating cells shifted from the isthmus to the base of the glands, and parietal cells decreased. Age-related histopathological changes were clearer in females than in males. Importantly, in FVB-CA-AhR mice, intramucosal cysts developed as extramucosal cysts beneath the serosa, penetrating the lamina muscularis mucosae and the muscularis propria. Their incidence reached 100% in 28-week-old male mice and 33-week-old female mice. Extramucosal cysts contained alcian blue-, Griffonia simplicifolia lectin II-, or trefoil factor 2-positive cells, suggesting a stomach origin for the cysts and spasmolytic polypeptide-expressing metaplasia-like lesions. Conclusions Disease onset occurred earlier in FVB-CA-AhR mice than previously reported in C57BL/6-derived CA-AhR mice. Importantly, the histopathological features were partly similar with gastritis cystica profunda in humans and animals. Excessive activation of AhR signaling aggravated abnormalities in the gastric mucosa and were affected by both genetic- and sex-related factors. Electronic supplementary material The online version of this article (10.1186/s12876-019-1009-x) contains supplementary material, which is available to authorized users.

Recurrent exon-deleting activating mutations in AHR act as drivers of urinary tract cancer

“…In particular, hAHR Q383H leads to more sensitized ligand-dependent activation while hAHR Δe8-9 leads to ligand-independent constitutive activation of the AhR pathway thereby promoting bladder cells to adopt a transformed undifferentiated proliferative phenotype allowing anchorage-independent growth. This is in line with previous work showing that AHR overexpression can lead to malignant transformation of epithelial cells and the oncogenic potential of constitutively activated AhR in mice (Brooks and Eltom 2011;Andersson et al 2002;Dantsuka et al 2019).…”

“…In this study, we show high prevalence of AHR alterations in urinary tract cancers and provide functional validations to support that these aberrations are oncogenic and drive urinary tract cancer. These findings are in line with mouse studies that have shown that AHR overexpression or pathway activation can lead to malignant transformation of epithelial cells 38–40 . A variety of molecular signaling pathways have been previously linked to AHR-mediated tumorigenesis whether or not in a cancer type-specific background and/or driven by AHR agonists 13,41 .…”

Recurrent exon-deleting activating mutations in AHR act as drivers of urinary tract cancer

“…In this study, we show high prevalence of AHR alterations in urinary tract cancers and provide functional validations to support that these aberrations are oncogenic and drive urinary tract cancer. These ndings are in line with mouse studies that have shown that AHR overexpression or pathway activation can lead to malignant transformation of epithelial cells [38][39][40] . A variety of molecular signaling pathways have been previously linked to AHR-mediated tumorigenesis whether or not in a cancer type-speci c background and/or driven by AHR agonists 13,41 .…”

Structural variation in genomes and its role in disease

“…In particular, the AHR Q383H mutant leads to more sensitized activation while the AHR Δe8-9 mutant leads to constitutive activation of the AhR pathway thereby promoting bladder cells to adopt a transformed undifferentiated proliferative phenotype allowing anchorage-independent growth. This is in line with previous work showing that AhR overexpression can lead to malignant transformation of epithelial cells and the oncogenic potential of constitutively activated AhR in mice 128,129,142 .…”

“…AhR activity in cancer has cancer-and cell-type specific associations with cancer characteristics such as invasion, migration, cancer stem cell properties, and survival 127 . Furthermore, transgenic mice that expressed a constitutively activated AhR using a tissue-restricted expression vector had a reduced life span and developed tumors in the glandular part of the stomach 128,129 .…”