Different in vivo and in vitro transformation of intestinal stem cells in mismatch repair deficiency
| Autor: | Knut Krohn, Markus Loeffler, Peter Buske, Gabriela Aust, Henry Löffler-Wirth, Christiane Kerner, Karen Rother, T Kreutzmann, Jens Przybilla, Joerg Galle, K Keysselt |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Cancer Research DNA Repair Biology medicine.disease_cause DNA Mismatch Repair Mice 03 medical and health sciences 0302 clinical medicine Growth factor receptor Genetics Organoid medicine Animals Humans neoplasms Molecular Biology Germ-Line Mutation Cell Proliferation Mice Knockout Cell growth nutritional and metabolic diseases Microsatellite instability Cell cycle medicine.disease Molecular biology digestive system diseases Intestines Cell Transformation Neoplastic MutS Homolog 2 Protein 030104 developmental biology 030220 oncology & carcinogenesis Neoplastic Stem Cells Microsatellite Instability DNA mismatch repair Stem cell Colorectal Neoplasms Carcinogenesis |
| Zdroj: | Oncogene. 36:2750-2761 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2016.429 |
| Popis: | Mutations in mismatch repair (MMR) genes result in microsatellite instability (MSI) and early onset of colorectal cancer. To get mechanistic insights into the time scale, sequence and frequency of intestinal stem cell (ISC) transformation, we quantified MSI and growth characteristics of organoids of Msh2-deficient and control mice from birth until tumor formation and related them to tissue gene expression. Although in Msh2-deficient organoids MSI continuously increased from birth, growth characteristics remained stable at first. Months before tumor onset, normal Msh2-deficient tissue contained tumor precursor cells forming organoids with higher MSI, cystic growth and growth rates resembling temporarily those of tumor organoids. Consistently, Msh2-deficient tissue exhibited a tumor-like gene signature. Normal Msh2-deficient organoids showed increased inheritable transient cyst-like growth, which became independent of R-spondin. ISC transformation proceeded faster in vitro than in vivo independent of the underlying genotype but more under MMR deficiency. Transient cyst-like growth but not MSI was suppressed by aspirin. In summary, as highlighted by organoids, molecular alterations continuously proceeded long before tumor onset in MMR-deficient intestine, thus increasing its susceptibility for ISC transformation. |
| Databáze: | OpenAIRE |
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