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      Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases

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          Abstract

          The pressure towards innovation and creation of new model systems in regenerative medicine and cancer research has fostered the development of novel potential therapeutic applications. Kidney injuries provoke a high request of organ transplants making it the most demanding system in the field of regenerative medicine. Furthermore, renal cancer frequently threaten patients’ life and aggressive forms still remain difficult to treat. Ethical issues related to the use of embryonic stem cells, has fueled research on adult, patient-specific pluripotent stem cells as a model for discovery and therapeutic development, but to date, normal and cancerous renal experimental models are lacking. Several research groups are focusing on the development of organoid cultures. Since organoids mimic the original tissue architecture in vitro, they represent an excellent model for tissue engineering studies and cancer therapy testing. We established normal and tumor renal cell carcinoma organoids previously maintained in a heterogeneous multi-clone stem cell-like enriching medium. Starting from adult normal kidney specimens, we were able to isolate and propagate organoid 3D-structures composed of both differentiated and undifferentiated cells while expressing nephron specific markers. Furthermore, we were capable to establish organoids derived from cancer tissues although with a success rate inferior to that of their normal counterpart. Cancer cultures displayed epithelial and mesenchymal phenotype while retaining tumor specific markers. Of note, tumor organoids recapitulated neoplastic masses when orthotopically injected into immunocompromised mice. Our data suggest an innovative approach of long-term establishment of normal- and cancer-derived renal organoids obtained from cultures of fleshly dissociated adult tissues. Our results pave the way to organ replacement pioneering strategies as well as to new models for studying drug-induced nephrotoxicity and renal diseases. Along similar lines, deriving organoids from renal cancer patients opens unprecedented opportunities for generation of preclinical models aimed at improving therapeutic treatments.

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          Most cited references 79

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

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            Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.

            Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).
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              Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012.

              Cancer incidence and mortality estimates for 25 cancers are presented for the 40 countries in the four United Nations-defined areas of Europe and for the European Union (EU-27) for 2012. We used statistical models to estimate national incidence and mortality rates in 2012 from recently-published data, predicting incidence and mortality rates for the year 2012 from recent trends, wherever possible. The estimated rates in 2012 were applied to the corresponding population estimates to obtain the estimated numbers of new cancer cases and deaths in Europe in 2012. There were an estimated 3.45 million new cases of cancer (excluding non-melanoma skin cancer) and 1.75 million deaths from cancer in Europe in 2012. The most common cancer sites were cancers of the female breast (464,000 cases), followed by colorectal (447,000), prostate (417,000) and lung (410,000). These four cancers represent half of the overall burden of cancer in Europe. The most common causes of death from cancer were cancers of the lung (353,000 deaths), colorectal (215,000), breast (131,000) and stomach (107,000). In the European Union, the estimated numbers of new cases of cancer were approximately 1.4 million in males and 1.2 million in females, and around 707,000 men and 555,000 women died from cancer in the same year. These up-to-date estimates of the cancer burden in Europe alongside the description of the varying distribution of common cancers at both the regional and country level provide a basis for establishing priorities to cancer control actions in Europe. The important role of cancer registries in disease surveillance and in planning and evaluating national cancer plans is becoming increasingly recognised, but needs to be further advocated. The estimates and software tools for further analysis (EUCAN 2012) are available online as part of the European Cancer Observatory (ECO) (http://eco.iarc.fr). Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                ruggero.demaria@unicatt.it
                desiree.bonci@iss.it
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                27 February 2019
                27 February 2019
                March 2019
                : 10
                : 3
                Affiliations
                [1 ]ISNI 0000 0004 1760 5276, GRID grid.417520.5, IRCCS, Regina Elena National Cancer Institute, ; Rome, Italy
                [2 ]ISNI 0000 0000 9120 6856, GRID grid.416651.1, Department of Oncology and Molecular Medicine, , Istituto Superiore di Sanità, ; Rome, Italy
                [3 ]GRID grid.7841.a, Department of Internal Medicine and Medical Specialties, , “La Sapienza” University, ; Rome, Italy
                [4 ]ISNI 0000 0000 9120 6856, GRID grid.416651.1, RPPA Unit, Proteomics Area, Core Facilities, , Istituto Superiore di Sanità, ; Rome, Italy
                [5 ]ISNI 0000 0001 0941 3192, GRID grid.8142.f, Istituto di Patologia Generale Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, ; 00168 Rome, Italy
                [6 ]ISNI 0000 0004 1760 5276, GRID grid.417520.5, Oncological Urology Department, , Regina Elena National Cancer Institute, ; Rome, Italy
                [7 ]ISNI 0000 0001 0120 3326, GRID grid.7644.1, Department of Bioscience, Biotechnology and Biopharmaceutics, , University of Bari, ; Bari, Italy
                [8 ]ISNI 0000 0001 0727 6809, GRID grid.414125.7, Genetics and Rare Diseases Research Division, , Ospedale Pediatrico Bambino Gesù, ; Rome, Italy
                [9 ]ISNI 0000 0000 9120 6856, GRID grid.416651.1, National AIDS Center, , Istituto Superiore di Sanità, ; Rome, Italy
                [10 ]ISNI 0000 0004 1763 1124, GRID grid.5611.3, Section of Oncology, Department of Medicine, , University of Verona School of Medicine, ; Verona, Italy
                [11 ]Verona University, Hospital Trust, Verona, Italy
                [12 ]GRID grid.452490.e, Department of Urology, , Humanitas University, ; Turin, Italy
                [13 ]Scientific Vice-Direction, Fondazione Policlinico Universitario “A. Gemelli” - I.R.C.C.S. Largo Francesco Vito 1-8, 00168 Rome, Italy
                1453
                10.1038/s41419-019-1453-0
                6393468
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                Cell biology

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