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Background: Tumour repopulation initiated by residual tumour cells in response to cytotoxic therapy has been described clinically and biologically, but the mechanisms are unclear. Here, we aimed to investigate the mechanisms for the tumour‐promoting effect in dying cells and for tumour repopulation in surviving tongue cancer cells. Methods: Tumour repopulation in vitro and in vivo was represented by luciferase activities. The differentially expressed cytokines in the conditioned medium (CM) were identified using a cytokine array. Gain or loss of function was investigated using inhibitors, neutralising antibodies, shRNAs and ectopic overexpression strategies. Results: We found that dying tumour cells undergoing cytotoxic therapy increase the growth of living tongue cancer cells in vitro and in vivo. Dying tumour cells create amphiregulin (AREG)‐ and basic fibroblast growth factor (bFGF)‐based extracellular environments via cytotoxic treatment‐induced endoplasmic reticulum stress. This environment stimulates growth by activating lysine acetyltransferase 6B (KAT6B)‐dependent nuclear factor‐kappa B (NF‐κB) signalling in living tumour cells. As direct targets of NF‐κB, miR‐22 targets KAT6B to repress its expression, but long noncoding RNAs (lncRNAs) (XLOC_003973 and XLOC_010383) counter the effect of miR‐22 to enhance KAT6B expression. Moreover, we detected increased AREG and bFGF protein levels in the blood of tongue cancer patients with X‐box binding protein‐1 (XBP1) activation in tumours under cytotoxic therapy and found that XBP1 activation is associated with poor prognosis of patients. We also detected activation of miR‐22/lncRNA/KAT6B/NF‐κB signalling in recurrent cancers compared to paired primary tongue cancers. Conclusions: We identified the molecular mechanisms of cell death‐induced tumour repopulation in tongue cancer. Such insights provide new avenues to identify predictive biomarkers and effective strategies to address cancer progression. [ABSTRACT FROM AUTHOR]

Abstract Background Tumour repopulation initiated by residual tumour cells in response to cytotoxic therapy has been described clinically and biologically, but the mechanisms are unclear. Here, we aimed to investigate the mechanisms for the tumour‐promoting effect in dying cells and for tumour repopulation in surviving tongue cancer cells. Methods Tumour repopulation in vitro and in vivo was represented by luciferase activities. The differentially expressed cytokines in the conditioned medium (CM) were identified using a cytokine array. Gain or loss of function was investigated using inhibitors, neutralising antibodies, shRNAs and ectopic overexpression strategies. Results We found that dying tumour cells undergoing cytotoxic therapy increase the growth of living tongue cancer cells in vitro and in vivo. Dying tumour cells create amphiregulin (AREG)‐ and basic fibroblast growth factor (bFGF)‐based extracellular environments via cytotoxic treatment‐induced endoplasmic reticulum stress. This environment stimulates growth by activating lysine acetyltransferase 6B (KAT6B)‐dependent nuclear factor‐kappa B (NF‐κB) signalling in living tumour cells. As direct targets of NF‐κB, miR‐22 targets KAT6B to repress its expression, but long noncoding RNAs (lncRNAs) (XLOC_003973 and XLOC_010383) counter the effect of miR‐22 to enhance KAT6B expression. Moreover, we detected increased AREG and bFGF protein levels in the blood of tongue cancer patients with X‐box binding protein‐1 (XBP1) activation in tumours under cytotoxic therapy and found that XBP1 activation is associated with poor prognosis of patients. We also detected activation of miR‐22/lncRNA/KAT6B/NF‐κB signalling in recurrent cancers compared to paired primary tongue cancers. Conclusions We identified the molecular mechanisms of cell death‐induced tumour repopulation in tongue cancer. Such insights provide new avenues to identify predictive biomarkers and effective strategies to address cancer progression.

Simple Summary: Divergent results from trials of dose-escalation and acceleration suggest that optimal schedules have yet to be identified for radiotherapy of inoperable locally advanced non-small cell lung cancer. In this hypothesis-generating study radiation dose-response models were fitted to survival rates for 51 patient cohorts treated with schedules of varying total radiation dose, dose-per-fraction and duration. The best fit described repopulation running at 1.47 Gy/day for concurrent chemoradiotherapy and 0.30 Gy/day for radiotherapy alone and sequential chemoradiotherapy. The overall fitted tumour α/β ratio was 3.0 Gy. These findings imply that moderate hypofractionation of chemoradiation, within normal tissue toxicity limits, should be efficacious. (1) Purpose: We analysed overall survival (OS) rates following radiotherapy (RT) and chemo-RT of locally-advanced non-small cell lung cancer (LA-NSCLC) to investigate whether tumour repopulation varies with treatment-type, and to further characterise the low α/β ratio found in a previous study. (2) Materials and methods: Our dataset comprised 2-year OS rates for 4866 NSCLC patients (90.5% stage IIIA/B) belonging to 51 cohorts treated with definitive RT, sequential chemo-RT (sCRT) or concurrent chemo-RT (cCRT) given in doses-per-fraction ≤3 Gy over 16–60 days. Progressively more detailed dose-response models were fitted, beginning with a probit model, adding chemotherapy effects and survival-limiting toxicity, and allowing tumour repopulation and α/β to vary with treatment-type and stage. Models were fitted using the maximum-likelihood technique, then assessed via the Akaike information criterion and cross-validation. (3) Results: The most detailed model performed best, with repopulation offsetting 1.47 Gy/day (95% confidence interval, CI: 0.36, 2.57 Gy/day) for cCRT but only 0.30 Gy/day (95% CI: 0.18, 0.47 Gy/day) for RT/sCRT. The overall fitted tumour α/β ratio was 3.0 Gy (95% CI: 1.6, 5.6 Gy). (4) Conclusion: The fitted repopulation rates indicate that cCRT schedule durations should be shortened to the minimum in which prescribed doses can be tolerated. The low α/β ratio suggests hypofractionation should be efficacious. [ABSTRACT FROM AUTHOR]

Background: The effects of radiotherapy treatment delays vary considerably depending on several factors, including tumour type, tumour characteristics, extent of delay and the radiation schedule. Both delays during treatment and delays in starting treatment may have an impact on tumour outcomes. In developing countries, particularly, budget constraints and overwhelming patient numbers may contribute to long waiting lists that may affect treatment efficacy. Empirical evidence on which to base treatment decisions and to motivate for additional resources is important. Aim: The aim of this study was to review the evidence that radiotherapy treatment delays may affect tumour response in several common tumour types and to determine, where reported, estimates of specific, commonly applied parameters to incorporate time and proliferation. Setting: Clinical radiotherapy of solid tumours. Methods: A review of the literature from an online database and search engine using terms associated with treatment delays or interruptions for a range of common tumour types was conducted. Results: There is evidence in several of the tumour types reviewed, including those of the head and neck, breast, cervix, prostate, lung, colorectal, anus, brain and bladder, that delays in radiotherapy can affect treatment outcomes. While, in most cases, delays in treatment are detrimental, there are certain examples cited where delays between other modalities and radiotherapy may be beneficial. Conclusion: While levels of evidence vary, failure to take note of proliferative effects of tumours because of extensions in treatment may in many cases result in avoidable treatment failures. It is thus prudent for radiation oncology departments to have clear policies for avoiding and dealing with treatment delays.

Background: The effects of radiotherapy treatment delays vary considerably depending on several factors, including tumour type, tumour characteristics, extent of delay and the radiation schedule. Both delays during treatment and delays in starting treatment may have an impact on tumour outcomes. In developing countries, particularly, budget constraints and overwhelming patient numbers may contribute to long waiting lists that may affect treatment efficacy. Empirical evidence on which to base treatment decisions and to motivate for additional resources is important. Aim: The aim of this study was to review the evidence that radiotherapy treatment delays may affect tumour response in several common tumour types and to determine, where reported, estimates of specific, commonly applied parameters to incorporate time and proliferation. Setting: Clinical radiotherapy of solid tumours. Methods: A review of the literature from an online database and search engine using terms associated with treatment delays or interruptions for a range of common tumour types was conducted. Results: There is evidence in several of the tumour types reviewed, including those of the head and neck, breast, cervix, prostate, lung, colorectal, anus, brain and bladder, that delays in radiotherapy can affect treatment outcomes. While, in most cases, delays in treatment are detrimental, there are certain examples cited where delays between other modalities and radiotherapy may be beneficial. Conclusion: While levels of evidence vary, failure to take note of proliferative effects of tumours because of extensions in treatment may in many cases result in avoidable treatment failures. It is thus prudent for radiation oncology departments to have clear policies for avoiding and dealing with treatment delays. [ABSTRACT FROM AUTHOR]

Background/aim: Tumour repopulation is a major obstacle for successful cancer treatment. This study investigated whether anticancer agents contribute to tumour repopulation in TP53-mutated bile duct cancer cells., Materials and Methods: TP53-mutated HuCCT1 and HuH28 cells were exposed to anticancer agents, and recipient cells were exposed to their conditioned media or exosomes. The effect of inhibitors and siRNA-mediated gene silencing of p38 mitogen-activated protein kinase (MAPK) and of TP53 was analyzed by cell proliferation assays and western blotting., Results: Conditioned media from genotoxic agent-treated cells promoted proliferation of recipient cells (p<0.05), and this effect was abrogated by exosome inhibitors. Exosomes from gemcitabine- or cisplatin-treated cells increased cell proliferation by 1.6- to 2.2-fold (p<0.05) through p38 MAPK signalling. These effects of exosomes were inhibited by inhibition/silencing of p38 MAPK but not by TP53 silencing., Conclusion: Exosomal p38 MAPK plays a pivotal role in tumour repopulation in a TP53-independent manner., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)