Open AccessSmall subset of Wnt‐activated cells is an initiator of regrowth in colorectal cancer organoids after irradiation
Author(s) -
Endo Hiroko,
Kondo Jumpei,
Onuma Kunishige,
Ohue Masayuki,
Inoue Masahiro
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14683
Subject(s) - wnt signaling pathway , radiosensitivity , organoid , cancer research , stem cell , radiation sensitivity , cancer stem cell , colorectal cancer , biology , stem cell marker , regeneration (biology) , cancer , cellular differentiation , cancer cell , microbiology and biotechnology , radiation therapy , medicine , irradiation , signal transduction , gene , genetics , physics , nuclear physics
Most colorectal cancers (CRCs) are differentiated adenocarcinomas, which maintain expression of both stemness and differentiation markers. This observation suggests that CRC cells could retain a regeneration system of normal cells upon injury. However, the role of stemness in cancer cell regeneration after irradiation is poorly understood. Here, we examined the effect of radiation on growth, stemness, and differentiation in organoids derived from differentiated adenocarcinomas. Following a sublethal dose of irradiation, proliferation and stemness markers, including Wnt target genes, were drastically reduced, but differentiation markers remained. After a static growth phase after high dose of radiation, regrowth foci appeared; these consisted of highly proliferating cells that expressed stem cell markers. Radiosensitivity and the ability to form foci differed among the cancer tissue‐originated spheroid (CTOS) lines examined and showed good correlation with in vivo radiation sensitivity. Pre‐treating organoids with histone deacetylase inhibitors increased radiation sensitivity; this increase was accompanied by the suppression of Wnt signal‐related gene expression. Accordingly, Wnt inhibitors increased organoid radiosensitivity. These results suggested that only a small subset of, but not all, cancer cells with high Wnt activity at the time of irradiation could give rise to foci formation. In conclusion, we established a radiation sensitivity assay using CRC organoids that could provide a novel platform for evaluating the effects of radiosensitizers on differentiated adenocarcinomas in CRC.