Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis.

Autor:	Mizutani Y; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Kobayashi H; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.; School of Medicine, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Iida T; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Asai N; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan., Masamune A; Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan., Hara A; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Esaki N; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Ushida K; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Mii S; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Shiraki Y; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Ando K; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Weng L; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Ishihara S; Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan., Ponik SM; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin., Conklin MW; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin., Haga H; Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan., Nagasaka A; Division of Anatomy, Department of Human Development and Fostering, Meikai University School of Dentistry, Sakado, Japan., Miyata T; Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Matsuyama M; Division of Molecular Genetics, Shigei Medical Research Institute, Okayama, Japan., Kobayashi T; Division of Molecular Genetics, Shigei Medical Research Institute, Okayama, Japan., Fujii T; Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan., Yamada S; Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan., Yamaguchi J; Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan., Wang T; School of Medicine, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Woods SL; School of Medicine, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Worthley D; School of Medicine, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Shimamura T; Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Fujishiro M; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Hirooka Y; Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan., Enomoto A; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan. enomoto@iar.nagoya-u.ac.jp mtakaha@med.nagoya-u.ac.jp., Takahashi M; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan. enomoto@iar.nagoya-u.ac.jp mtakaha@med.nagoya-u.ac.jp.; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2019 Oct 15; Vol. 79 (20), pp. 5367-5381. Date of Electronic Publication: 2019 Aug 22.
DOI:	10.1158/0008-5472.CAN-19-0454
Abstrakt:	Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression. SIGNIFICANCE: Meflin marks and functionally contributes to a subset of cancer-associated fibroblasts that exert antitumoral effects. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5367/F1.large.jpg. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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