Student Tokyo University of Agriculture and Technology, Japan
Abstract: Multi-stage carcinogenesis theory is known as the process by which healthy cells repeatedly accumulate genetic mutations and transform into malignant tumors. Still, genetic mutation varies among individuals and cancers, and in some cases, carcinogenesis can occur without mutation. Therefore, carcinogenesis factors may have been also related to the senescence of stem cells in the organs in old age. Previous studies reported experimental models of carcinogenesis induced by chemical substances or cancer-related gene mutations, but there has not been an established carcinogenesis model using aged animal-derived cells. Therefore, the current study focused on establishing aged (19-month-old) mice organoids (AMO) and comparing their histopathological characteristics with young (4-weeks-old) mice organoids (YMO). Kidney, lung, gall bladder, and bladder tissue were extracted from aged or young mice and used to generate organoids. The relationship between stem cells and carcinogenesis between AMO and YMO in different organ organoids was genetically evaluated. RNA sequencing was performed using AMO and YMO to explore signaling pathways that were specifically activated in AMO compared to YMO. Changes in morphology and aging-related gene markers were assessed by HE staining and IHC. Organoids were successfully derived and the morphological differences were evident between AMO and YMO, especially for gallbladder and bladder organoids. Expressions of MUC3, and CK19 in gallbladder organoids, and UPK3A, CK7, and CK5 in bladder organoids were downregulated in AMO, compared to YMO. RNA sequencing revealed that some age-related signaling pathways were significantly more activated in AMO than in YMO. It would be expected that organoids derived from aged mice will have usefulness in the future to elucidate the mechanism of aging and the process of age-related carcinogenesis.
