In the colon, myofibroblasts are primary contributors in the establishment of the microenvironment involved in tissue homeostasis. Alterations in myofibroblast functions lead to changes resulting in a toxic microenvironment nurturing tumorigenesis. Bone morphogenetic proteins (Bmps) are morphogens known to play key roles in adult gut homeostasis. Studies in genetically-modified mice have shown that Bmp disruption in all cell layers leads to the development of gut polyposis. In contrast, our studies showed that loss of Bmp exclusively in the gastrointestinal epithelium resulted in increased epithelial proliferation without polyposis initiation, thus suggesting a key role for mesenchymal Bmp signaling in polyposis initiation. In order to identify the role of mesenchymal Bmp signaling on the microenvironment and its impact on colonic mucosa, a mouse model was generated with suppression of Bmp signaling exclusively in myofibroblasts (Bmpr1aDMES). Bmpr1aDMES mice exhibited increased subepithelial proliferation with changes in cellular composition leading to the development of a primed stroma with modulation of extracellular matrix proteins, immune cells and cytokines as early as 90 days of age. This microenvironmental deregulation was associated with increased polyposis initiation at one year of age. These results are the first to demonstrate that mesenchymal Bmpr1a inactivation alone is sufficient to prompt an expansion of myofibroblasts leading to the development of a reactive mesenchyme that contributes to polyposis initiation in the colon. These findings support the novel concept that inhibition of Bmp signaling in mesenchymal cells surrounding the normal epithelium leads to important changes instructing a toxic microenvironment sufficient to induce colonic polyposis.For decades, colorectal cancer (CRC) has been studied at the epithelial level with the aim of identifying signaling pathways, potential markers and/or genetic mutations able to recapitulate the carcinogenesis cascade. 1,2 Traditionally, the mesenchyme was thought to be a passive structural partner adjacent to the diseased epithelium. However, it is now acknowledged that genetic and signaling changes in the epithelium alone are insufficient to encompass the complete cascade. The microenvironment and its associated stromal cells surrounding the diseased epithelium play a key role in tumor initiation and progression. 3,4 It has also been shown that the cancerous reactive mesenchyme observed in CRC is characterized by the presence of an abnormal number of professional and nonprofessional cells that contribute to the dysregulation of extracellular matrix (ECM) deposition and of cytokine and growth factor expression. 5 Myofibroblasts are a unique group of smooth muscle-like fibroblasts in the lamina propria of the gut and are considered as major contributors of the microenvironment found to interact directly with the epithelium. 6 Myofibroblasts can arise from multiple origins, such as mesenchymal stem cells, fibrocytes or bone marrow-derived cells. [6][7]...

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.

Conditions leading to unrepaired DNA double‐stranded breaks are potent inducers of genetic instability. Systemic conditions may lead to fluctuation of hydrogen ions in the cellular microenvironment, and we show that small variations in extracellular pH , termed suboptimal pH e, can decrease the efficiency of DNA repair in the absence of intracellular pH variation. Recovery from bleomycin‐induced DNA double‐stranded breaks in fibroblasts proceeded less efficiently at suboptimal pH e values ranging from 7.2 to 6.9, as shown by the persistence of repair foci, reduction of H4K16 acetylation, and chromosomal instability, while senescence or apoptosis remained undetected. By allowing escape from these protective mechanisms, suboptimal pH e may therefore enhance the genotoxicity of double‐stranded breaks, leading to genetic instability.

No abstract

No abstract

No abstract

No abstract

No abstract