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Evidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells.

ABSTRACT: Renal angiomyolipomas (AML) contain an admixture of clonal tumour cells with features of several different mesenchymal lineages, implying the existence of an unidentified AML neoplastic stem cell. Biallelic inactivation of TSC2 or TSC1 is believed to represent the driving event in these tumours. Here we show that TSC2 knockdown transforms senescence-resistant cultured mouse and human renal epithelial cells into neoplastic stem cells that serially propagate renal AML-like tumours in mice. mTOR inhibitory therapy of mouse AML allografts mimics the clinical responses of human renal AMLs. Deletion of Tsc1 in mouse renal epithelia causes differentiation in vivo into cells expressing characteristic AML markers. Human renal AML and a renal AML cell line express proximal tubule markers. We describe the first mouse models of renal AML and provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells, uncovering an unexpected pathological differentiation plasticity of the proximal tubule.

SUBMITTER: Goncalves AF

PROVIDER: S-EPMC5684212 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Evidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells.

Gonçalves Ana Filipa AF Adlesic Mojca M Brandt Simone S Hejhal Tomas T Harlander Sabine S Sommer Lukas L Shakhova Olga O Wild Peter J PJ Frew Ian J IJ

Nature communications 20171113 1

Renal angiomyolipomas (AML) contain an admixture of clonal tumour cells with features of several different mesenchymal lineages, implying the existence of an unidentified AML neoplastic stem cell. Biallelic inactivation of TSC2 or TSC1 is believed to represent the driving event in these tumours. Here we show that TSC2 knockdown transforms senescence-resistant cultured mouse and human renal epithelial cells into neoplastic stem cells that serially propagate renal AML-like tumours in mice. mTOR in ...[more]

PMID: 29133867

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Project description:Exposure to genotoxic stresses such as radiation and tobacco smoke can cause increased cancer incidence rate as reflected in an in depth meta-analysis of data for women and breast cancer incidence. Published reports have indicated that exposures to low dose radiation and tobacco smoke are factors that contribute to the development of breast cancer. However, there is a scarcity of information on the combinatorial effects of low dose radiation and tobacco smoke on formation and progression of breast cancer. The combination of these two genotoxic insults can induce significant damage to the genetic material of the cells resulting in neoplastic transformation.To study the effects of low dose ionizing radiation and tobacco smoke on breast cells, MCF 10A cells were treated either with radiation (Rad - 0.1 Gray) or cigarette smoke condensate (Csc - 10 microgram/ml of medium) or a combination of Rad + Csc. Following treatments, cells were analyzed for cell cycle distribution patterns and the ability to extrude the Hoechst 33342 dye. In addition, in vitro invasion and migration as well as mammosphere formation assays were performed. Finally, differential gene expression profiles were generated from the individual and combination treatment.Exposure of MCF 10A cells to the combination of radiation plus cigarette smoke condensate generated a neoplastic phenotype. The transformed phenotype promoted increased mammosphere numbers, altered cell cycle phases with a doubling of the population in S phase, and increased invasion and motility. Also, exclusion of Hoechst 33342 dye, a surrogate marker for increased ABC transporters, was observed, which indicates a possible increase in drug resistance. In addition, changes in gene expression include the up regulation of genes encoding proteins involved in metabolic pathways and inflammation.The results indicate that when normal breast cells are exposed to low dose radiation in combination with cigarette smoke condensate a phenotype is generated that exhibits traits indicative of neoplastic transformation. More importantly, this is the first study to provide a new insight into a possible etiology for breast cancer formation in individuals exposed to low dose radiation and tobacco smoke.

Dataset Information

Evidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells.

Publications

Evidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells.

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