Apposition of Fibroblasts With Metaplastic Gastric Cells Promotes Dysplastic Transition.

Gastroenterology

Section of Surgical Sciences, Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Nashville Veterans Affairs Medical Center, Nashville, Tennessee. Electronic address:

Published: August 2023

AI Article Synopsis

  • The study investigates how changes in the stroma, particularly fibroblast heterogeneity, contribute to the development of gastric cancer from metaplasia, which is a precursor stage.
  • Using advanced single-cell transcriptomics, the researchers identified four distinct subsets of fibroblasts in gastric tissue that vary in distribution during different disease stages.
  • The findings suggest that interactions between specific fibroblast subsets and metaplastic epithelial cells promote transitions towards dysplasia, potentially accelerating the progression of gastric cancer.

Article Abstract

Background & Aims: Elements of field cancerization, including atrophic gastritis, metaplasia, and dysplasia, promote gastric cancer development in association with chronic inflammation. However, it remains unclear how stroma changes during carcinogenesis and how the stroma contributes to progression of gastric preneoplasia. Here we investigated heterogeneity of fibroblasts, one of the most important elements in the stroma, and their roles in neoplastic transformation of metaplasia.

Methods: We used single-cell transcriptomics to evaluate the cellular heterogeneity of mucosal cells from patients with gastric cancer. Tissue sections from the same cohort and tissue microarrays were used to identify the geographical distribution of distinct fibroblast subsets. We further evaluated the role of fibroblasts from pathologic mucosa in dysplastic progression of metaplastic cells using patient-derived metaplastic gastroids and fibroblasts.

Results: We identified 4 subsets of fibroblasts within stromal cells defined by the differential expression of PDGFRA, FBLN2, ACTA2, or PDGFRB. Each subset was distributed distinctively throughout stomach tissues with different proportions at each pathologic stage. The PDGFRα subset expanded in metaplasia and cancer compared with normal, maintaining a close proximity with the epithelial compartment. Co-culture of metaplasia- or cancer-derived fibroblasts with gastroids showing the characteristics of spasmolytic polypeptide-expressing metaplasia-induced disordered growth, loss of metaplastic markers, and increases in markers of dysplasia. Culture of metaplastic gastroids with conditioned media from metaplasia- or cancer-derived fibroblasts also promoted dysplastic transition.

Conclusions: These findings indicate that fibroblast associations with metaplastic epithelial cells can facilitate direct transition of metaplastic spasmolytic polypeptide-expressing metaplasia cell lineages into dysplastic lineages.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10375042PMC
http://dx.doi.org/10.1053/j.gastro.2023.04.038DOI Listing

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