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.
Highlights
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
While it has not yet been conclusively proven, there is some evidence that these epithelial structures may be tumour-derived[13,14], implying that the putative AML or AMLEC neoplastic stem cell may have the capacity to differentiate into renal epithelial cells in some cases
We further showed that some cells in human renal AMLs, as well as a renal AML cell line, exhibit molecular features of renal proximal tubular epithelial cells
Summary
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. It is possible that another renal cell type could become transformed and reprogrammed to form a neoplastic AML stem cell In this context is noteworthy that a rare variant of AML, called AMLEC (AML with epithelial cysts) contains epithelial tubular or cystic structures[12]. While it has not yet been conclusively proven, there is some evidence that these epithelial structures may be tumour-derived[13,14], implying that the putative AML or AMLEC neoplastic stem cell may have the capacity to differentiate into renal epithelial cells in some cases. These findings argue that renal AMLs might derive from proximal tubule epithelial cells
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