1. Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells
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Hans-Joachim Anders, Alessandro Antonelli, Tiziano Lottini, Andrea Minervini, Marco Carini, Francesco Guzzi, Paola Romagnani, Mauro Gacci, Alessandro Sisti, Carolina Conte, Fabrizio Di Maida, Mario Rotondi, Samuela Landini, Marco Allinovi, Maria Elena Melica, Rosa Maria Roperto, Francesco Porpiglia, Vincenzo Ficarra, Benedetta Mazzinghi, Sergio Serni, Sabrina Giglio, George J. Netto, Maria Rosaria Raspollini, Maria Lucia Angelotti, Letizia De Chiara, Sara Nardi, Giulia Antonelli, Davide Facchiano, Alberto Magi, Riccardo Schiavina, Elena Lazzeri, Helen Liapis, Andrea Mari, Roberto Semeraro, Christian Fynbo Christiansen, Laura Lasagni, Anna Julie Peired, Peired A.J., Antonelli G., Angelotti M.L., Allinovi M., Guzzi F., Sisti A., Semeraro R., Conte C., Mazzinghi B., Nardi S., Melica M.E., De Chiara L., Lazzeri E., Lasagni L., Lottini T., Landini S., Giglio S., Mari A., Di Maida F., Antonelli A., Porpiglia F., Schiavina R., Ficarra V., Facchiano D., Gacci M., Serni S., Carini M., Netto G.J., Roperto R.M., Magi A., Christiansen C.F., Rotondi M., Liapis H., Anders H.-J., Minervini A., Raspollini M.R., and Romagnani P.
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Adenoma ,0301 basic medicine ,papillary renal cell carcinoma ,medicine.disease_cause ,urologic and male genital diseases ,DISEASE ,PATHWAY ,PROTECTS ,Mice ,03 medical and health sciences ,0302 clinical medicine ,AKI ,NOTCH1 ,REGENERATION ,Renal cell carcinoma ,Biomarkers, Tumor ,ABLATION ,medicine ,Carcinoma ,Animals ,Progenitor cell ,RECURRENCE ,Carcinoma, Renal Cell ,RECEPTOR ,Papillary renal cell carcinomas ,business.industry ,Stem Cells ,Papillary Adenoma ,Acute kidney injury ,renal carcinoma ,General Medicine ,Acute Kidney Injury ,medicine.disease ,TUMORS ,Kidney Neoplasms ,3. Good health ,NOTCH ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,GROWTH ,Neoplasm Recurrence, Local ,Stem cell ,Carcinogenesis ,business - Abstract
Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.
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