Dataset Information

Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy.

ABSTRACT: In cancer treatment, apoptosis is a well-recognized cell death mechanism through which cytotoxic agents kill tumor cells. Here we report that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. Furthermore, activated caspase 3, a key executioner in apoptosis, is involved in the growth stimulation. One downstream effector that caspase 3 regulates is prostaglandin E(2) (PGE(2)), which can potently stimulate growth of surviving tumor cells. Deficiency of caspase 3 either in tumor cells or in tumor stroma caused substantial tumor sensitivity to radiotherapy in xenograft or mouse tumors. In human subjects with cancer, higher amounts of activated caspase 3 in tumor tissues are correlated with markedly increased rate of recurrence and death. We propose the existence of a cell death-induced tumor repopulation pathway in which caspase 3 has a major role.

SUBMITTER: Huang Q

PROVIDER: S-EPMC3132290 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy.

Huang Qian Q Li Fang F Liu Xinjian X Li Wenrong W Shi Wei W Liu Fei-Fei FF O'Sullivan Brian B He Zhimin Z Peng Yuanlin Y Tan Aik-Choon AC Zhou Ling L Shen Jingping J Han Gangwen G Wang Xiao-Jing XJ Thorburn Jackie J Thorburn Andrew A Jimeno Antonio A Raben David D Bedford Joel S JS Li Chuan-Yuan CY

Nature medicine 20110703 7

In cancer treatment, apoptosis is a well-recognized cell death mechanism through which cytotoxic agents kill tumor cells. Here we report that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. Furthermore, activated caspase 3, a key executioner in apoptosis, is involved in the growth stimulation. One downstream effector that caspase 3 regulates is prostaglandin E(2) (PGE(2)), which can potentl ...[more]

PMID: 21725296

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Project description:Optimal treatment planning for fractionated external beam radiation therapy requires inputs from radiobiology based on recent thinking about the "five Rs" (repopulation, radiosensitivity, reoxygenation, redistribution, and repair). The need is especially acute for the newer, often individualized, protocols made feasible by progress in image guided radiation therapy and dose conformity. Current stochastic tumor control probability (TCP) models incorporating tumor repopulation effects consider "stem-like cancer cells" (SLCC) to be independent, but the authors here propose that SLCC-SLCC interactions may be significant. The authors present a new stochastic TCP model for repopulating SLCC interacting within microenvironmental niches. Our approach is meant mainly for comparing similar protocols. It aims at practical generalizations of previous mathematical models.The authors consider protocols with complete sublethal damage repair between fractions. The authors use customized open-source software and recent mathematical approaches from stochastic process theory for calculating the time-dependent SLCC number and thereby estimating SLCC eradication probabilities. As specific numerical examples, the authors consider predicted TCP results for a 2 Gy per fraction, 60 Gy protocol compared to 64 Gy protocols involving early or late boosts in a limited volume to some fractions.In sample calculations with linear quadratic parameters α = 0.3 per Gy, α∕β = 10 Gy, boosting is predicted to raise TCP from a dismal 14.5% observed in some older protocols for advanced NSCLC to above 70%. This prediction is robust as regards: (a) the assumed values of parameters other than α and (b) the choice of models for intraniche SLCC-SLCC interactions. However, α = 0.03 per Gy leads to a prediction of almost no improvement when boosting.The predicted efficacy of moderate boosts depends sensitively on α. Presumably, the larger values of α are the ones appropriate for individualized treatment protocols, with the smaller values relevant only to protocols for a heterogeneous patient population. On that assumption, boosting is predicted to be highly effective. Front boosting, apart from practical advantages and a possible advantage as regards iatrogenic second cancers, also probably gives a slightly higher TCP than back boosting. If the total number of SLCC at the start of treatment can be measured even roughly, it will provide a highly sensitive way of discriminating between various models and parameter choices. Updated mathematical methods for calculating repopulation allow credible generalizations of earlier results.

Project description:PurposePrevious literature has reported contradicting results regarding the relationship between tumor volume changes during radiotherapy treatment for non-small cell lung cancer (NSCLC) patients and locoregional recurrence-free rate or overall survival. The aim of this study is to validate the results from a previous study by using a different volume extraction procedure and evaluating an external validation dataset.MethodsFor two datasets of 94 and 141 NSCLC patients, gross tumor volumes were determined manually to investigate the relationship between tumor volume regression and locoregional control using Kaplan-Meier curves. For both datasets, different subgroups of patients based on histology and chemotherapy regimens were also investigated. For the first dataset (n?=?94), automatically determined tumor volumes were available from a previously published study to further compare their correlation with updated clinical data.ResultsA total of 70 out of 94 patients were classified into the same group as in the previous publication, splitting the dataset based on median tumor regression calculated by the two volume extraction methods. Non-adenocarcinoma patients receiving concurrent chemotherapy with large tumor regression show reduced locoregional recurrence-free rates in both datasets (p?<?0.05 in dataset 2). For dataset 2, the opposite behavior is observed for patients not receiving chemotherapy, which was significant for overall survival (p?=?0.01) but non-significant for locoregional recurrence-free rate (p?=?0.13).ConclusionThe tumor regression pattern observed during radiotherapy is not only influenced by irradiation but depends largely on the delivered chemotherapy schedule, so it follows that the relationship between patient outcome and the degree of tumor regression is also largely determined by the chemotherapy schedule. This analysis shows that the relationship between tumor regression and outcome is complex, and indicates factors that could explain previously reported contradicting findings. This, in turn, will help guide future studies to fully understand the relationship between tumor regression and outcome.

Dataset Information

Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy.

Publications

Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy.

Similar Datasets

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