Small subset of Wnt‐activated cells is an initiator of regrowth in colorectal cancer organoids after irradiation

Abstract

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.

Cancer Stem Cell Biomarkers Predictive of Radiotherapy Response in Rectal Cancer: A Systematic Review

“…Preoperative RT, administered as a conventional fractionated RT (45 Gy to the pelvis, followed by 5.4 Gy in 3 fractions to the tumour) has been recognised to play a key role in the standard multidisciplinary treatment of RC, by reducing local recurrence and increasing survival [51][52][53]. However, tumour response to RT differs considerably among patients, with several tumour types, including RC [39]. A significant number of patients exhibiting a complete response to neoadjuvant therapy experience local regrowth or metastatic dissemination, which is strongly associated with the capability of CSCs to resist treatment and promote cancer progression [48].…”

“…To date, there are no indicators able to distinguish RC resistance and neoadjuvant treatment [40]. Therefore, identifying specific biomarkers to predict patient response to RT can help in planning a strategy aimed at targeting not only the tumour bulk, but also the sensibility of CSCs to RT, in order to avoid therapeutic failure and unnecessary treatments [20,31,39,40]. This review analysed the most recent studies focused on the characteristics of CSCs and therapeutic sensitivity targeting CSC radiosensitivity/radioresistance, through the detection of RT-response predictive biomarkers.…”

“…Radioresistance, either intrinsic or acquired (leading to the development of adaptive responses induced by the irradiation itself), represents a barrier to overcome in order to improve both prognosis and treatment efficacy. The emerging role of CSCs in tumour response to RT has promoted the investigation of the molecular mechanisms underlying radioresistance in these cells [39,41]. To date, studies on cellular radiosensitivity in vitro have identified several cell-surface biomarkers of CSCs, showing differences between marker-negative and positive cells, the latter generally being more radioresistant.…”

“…These studies laid the foundation for the subsequent research on CSCs in radiation oncology, suggesting the importance of the number of tumour-initiating cells as prognostic factors for tumour radiocurability [15,[34][35][36][37][38]. The detection of biomarkers that characterize CSCs may play a crucial role in predicting the clinical outcome of radiotherapy-treated patients (Table 2) [39]. Currently, CD133 represents the main biomarker for the identification of putative CSCs in various types of cancer, including RC [39,40].…”

“…The detection of biomarkers that characterize CSCs may play a crucial role in predicting the clinical outcome of radiotherapy-treated patients (Table 2) [39]. Currently, CD133 represents the main biomarker for the identification of putative CSCs in various types of cancer, including RC [39,40]. As CD133 is associated with poor clinical outcomes, evaluation of the sensitivity to radiation therapy in RC may serve to predict a possible complete or partial tumour response to RT, thus avoiding unnecessary treatments [20,31,40].…”