Stromal cell-derived factor-1 overexpression induces gastric dysplasia through expansion of stromal myofibroblasts and epithelial progenitors

Abstract

Objective Stromal cell-derived factor-1 (SDF-1/CXCL12), the main ligand for CXCR4, is overexpressed in human cancer. This study addressed the precise contribution of SDF-1 to gastric carcinogenesis. Design SDF-1 transgenic mice were created and a Helicobacter-induced gastric cancer model was used in combination with H/K-ATPase-IL-1β mice. Gastric tissue was analysed by histopathology and cells isolated from the stomach were analysed by molecular biological methods. Results Analysis of the H/K-ATPase/SDF-1 transgenic (SDF-Tg) mice showed that SDF-1 overexpression results in significant gastric epithelial hyperproliferation, mucous neck cell hyperplasia and spontaneous gastric dysplasia (wild-type mice 0/15 (0%) vs SDF-Tg mice 4/14 (28.6%), p=0.042, Fisher exact test) but has minimal effects on inflammation. SDF-Tg mice also showed a dramatic expansion of α-smooth muscle actin-positive myofibroblasts and CXCR4-expressing gastric epithelial cells in the progenitor zone, both of which preceded the development of significant gastritis or dysplasia. Gremlin 1-expressing mesenchymal stem cells, the putative precursors of myofibroblasts, were also increased within the dysplastic stomachs of SDF-Tg mice and showed chemotaxis in response to SDF-1 stimulation. SDF-1 overexpression alone resulted in minimal recruitment of haematopoietic cells to the gastric mucosa, although macrophages were increased late in the disease. When SDF-Tg mice were crossed with H/K-ATPase-IL-1β mice or infected with Helicobacter felis, however, there were dramatic synergistic effects on recruitment of bone marrow-derived cells and progression to preneoplasia. Conclusion Activation of the SDF-1/CXCR4 axis can contribute to early stages of carcinogenesis primarily through recruitment of stromal cells and modulation of the progenitor niche.

Obesity acceleratesHelicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response

“…29 Infected and uninfected mice were fed either a HFD (45% of calories from fat, Research Diets 12451) or a standard chow diet (CD, 13% of calories from fat, PicoLab Rodent Diet 20) ad libitum. HFD was begun 3 weeks postinfection (PI).…”

Bone marrow cells as precursors of the tumor stroma

“…αSMA positive CAFs, perhaps the best-established marker of CAFs, are generated through a number of complementary mechanisms. Chemokines such as stromal cell-derived factor 1 (SDF-1/CXCL12) recruit fibroblast precursors expressing CXCR4, possibly MSCs and potentially fibrocytes, into the stroma from distant sites [1,43]. In the context of additional desmoplastic factors, including PDGF and TGF-β, these precursors differentiate into αSMA expressing CAFs.…”

Gastritis Promotes an Activated Bone Marrow-Derived Mesenchymal Stem Cell with a Phenotype Reminiscent of a Cancer-Promoting Cell

“…We may account for the rapid infiltration of BM-stromal cells to the stomach by the increased expression of SDF-1 receptor CXCR4. Recent work using SDF-1 transgenic mice establishes a relationship between SDF-1-mediated recruitment of stromal cell populations within the stomach [6]. We and others have observed that the SDF1 receptor CXCR4 may be a target of the Shh signaling pathway [46](Donnelly and Zavros unpublished data).…”

“…When isolated from healthy mice and injected by tail vein into recipients chronically infected with H. felis , MSCs reverse the preneoplastic morphological changes present in the gastric epithelium and return normal histological appearance [5]. In contrast, studies show that endogenous MSCs exposed to the local and systemic pro-inflammatory milieu for the duration of H. felis infection contribute to a population of cancer-associated fibroblasts (CAFs) and acquire a phenotype that promotes the progression of gastric cancer development [2,6]. In vivo data on the mechanism initiating this transformative process is limited.…”