发育异常干细胞的可塑性作为癌前胃黏膜发生肿瘤转化的驱动力。
Dysplastic Stem Cell Plasticity Functions as a Driving Force for Neoplastic Transformation of Precancerous Gastric Mucosa.
机构信息
Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina at Chapel Hill, Raleigh, North Carolina; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
出版信息
Gastroenterology. 2022 Oct;163(4):875-890. doi: 10.1053/j.gastro.2022.06.021. Epub 2022 Jun 11.
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 2 putative dysplastic stem cell (DSC) populations, CD44v6/CD133/CD166 (double positive [DP]) and CD44v6/CD133/CD166 (triple positive [TP]), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of noncancerous Trop2/CD133/CD166 DSCs initially developed in the transition from precancerous metaplasia to dysplasia in the stomach.
METHODS
Dysplastic organoids established from active Kras-induced mouse stomachs were used 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 casein kinase 1 alpha (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 toward multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Last, 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.
背景与目的
异型增生具有很高的癌症发展风险；然而，异型增生发展为癌症的细胞机制尚不清楚。我们之前已经鉴定出两种可能的异型增生干细胞（DSC）群体，即 CD44v6/CD133/CD166（双阳性[DP]）和 CD44v6/CD133/CD166（三阳性[TP]），它们可能有助于胃异型增生的细胞异质性。在这里，我们研究了非癌性 Trop2/CD133/CD166 DSC 的功能作用和细胞可塑性，这些 DSC 最初在癌前化生向胃异型增生的转变过程中发展。
方法
从活性 Kras 诱导的小鼠胃中建立异型增生类器官，用于 DSC 的转录组分析、体外分化和体内致瘤性评估。通过下一代测序检查 DSC 克隆进化过程中的细胞异质性和遗传改变。使用组织微阵列鉴定人异型增生中的 DSC。我们还使用鼠和人异型增生类器官评估了酪蛋白激酶 1α（CK1α）调节对 DSC 活性的影响。
结果
我们发现 DP-DSC 和 TP-DSC 之间的分子谱具有高度相似性，但 DP-DSC 在分化和生存中的活性更高，通过 Wnt 配体非依赖性 CK1α/β-连环蛋白信号维持异型增生细胞谱系。异种移植研究表明，DP-DSC 克隆进化为多种胃腺癌，并通过获得额外的遗传突变和招募肿瘤微环境促进肿瘤细胞异质性。最后，通过靶向 CK1α 控制了鼠和人异型增生类器官的生长和存活。
结论
这些发现表明 DSC 是新的胃起始癌细胞，负责肿瘤转化，是早期诱导胃癌的有前途的干预靶点。
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