2024-03-29T04:48:41Z
https://nagoya.repo.nii.ac.jp/oai
oai:nagoya.repo.nii.ac.jp:00029321
2023-01-16T04:22:26Z
499:500:501
Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis
Mizutani, Yasuyuki
96038
Kobayashi, Hiroki
96039
Iida, Tadashi
96040
Asai, Naoya
96041
Masamune, Atsushi
96042
Hara, Akitoshi
96043
Esaki, Nobutoshi
96044
Ushida, Kaori
96045
Mii, Shinji
96046
Shiraki, Yukihiro
96047
Ando, Kenju
96048
Weng, Liang
96049
Ishihara, Seiichiro
96050
Ponik, Suzanne M.
96051
Conklin, Matthew W.
96052
Haga, Hisashi
96053
Nagasaka, Arata
96054
Miyata, Takaki
96055
Matsuyama, Makoto
96056
Kobayashi, Tomoe
96057
Fujii, Tsutomu
96058
Yamada, Suguru
96059
Yamaguchi, Junpei
96060
Wang, Tongtong
96061
Woods, Susan L.
96062
Worthley, Daniel
96063
Shimamura, Teppei
96064
Fujishiro, Mitsuhiro
96065
Hirooka, Yoshiki
96066
Enomoto, Atsushi
96067
Takahashi, Masahide
96068
Meflin
cancer-associated fibroblasts
pancreatic cancer
pancreatic stellate cells
tumor microenvironment
lysyl oxidase
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.
ファイル公開:2020/10/01
journal article
American Association for Cancer Research
2019-10
application/pdf
application/pdf
Cancer Research
20
79
5367
5381
0008-5472
https://nagoya.repo.nii.ac.jp/record/29321/files/Mizutani_et_al_for_repository.pdf
https://nagoya.repo.nii.ac.jp/record/29321/files/Mizutani_et_al_Suppl_Data.pdf
eng
https://doi.org/10.1158/0008-5472.CAN-19-0454