| Autor: |
Jimin Min, Changqing Zhang, R. Jarrett Bliton, Brianna Caldwell, Leah Caplan, Kimberly S. Presentation, Do-Joong Park, Seong-Ho Kong, Hye Seung Lee, M. Kay Washington, Woo-Ho Kim, Ken S. Lau, Scott T. Magness, Hyuk-Joon Lee, Han-Kwang Yang, James R. Goldenring, Eunyoung Choi |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Gastroenterology |
| ISSN: |
1528-0012 |
| Popis: |
BACKGROUND & AIMS: Dysplasia carries a high risk of cancer development, however, the cellular mechanisms for dysplasia evolution to cancer are obscure. We have previously identified two putative dysplastic stem cell (DSC) populations, CD44v6(neg)/CD133(+)/CD166(+) (DP) and CD44v6(+)/CD133(+)/CD166(+) (TP), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of non-cancerous Trop2(+)/CD133(+)/CD166(+) DSCs initially developed in the transition from pre-cancerous metaplasia to dysplasia in the stomach. METHODS: Dysplastic organoids established from active Kras-induced mouse stomachs were utilized for transcriptome analysis, in vitro differentiation and in vivo tumorigenicity assessments of DSCs. Cell heterogeneity and genetic alterations during clonal evolution of DSCs were examined by next-generation sequencing. Tissue microarrays were used to identify DSCs in human dysplasia. We additionally evaluated the effect of CK1α regulation on the DSC activities using both mouse and human dysplastic organoids. RESULTS: We identified a high similarity of molecular profiles between DP- and TP-DSCs, but more dynamic activities of DP-DSCs in differentiation and survival for maintaining dysplastic cell lineages through Wnt ligand-independent CK1α/β-catenin signaling. Xenograft studies demonstrated that the DP-DSCs clonally evolve towards multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Lastly, growth and survival of both mouse and human dysplastic organoids were controlled by targeting CK1α. CONCLUSIONS: These findings indicate that the DSCs are de novo gastric cancer-initiating cells responsible for neoplastic transformation and a promising target for intervention in early induction of gastric cancer. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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