figure
posted on 2023-12-05, 14:20 authored by Andrea R. Daniel, Chang Su, Nerissa T. Williams, Zhiguo Li, Jianguo Huang, Omar Lopez, Lixia Luo, Yan Ma, Lorraine da Silva Campos, Sara R. Selitsky, Jennifer L. Modliszewski, Siyao Liu, Rosa Hernansaiz-Ballesteros, Yvonne M. Mowery, Diana M. Cardona, Chang-Lung Lee, David G. Kirsch Radiation-induced chronic injuries increase the risk of sarcomagenesis. A, The final injury scores of the control and p53KD mice that received 30 or 40 Gy are plotted. The final injury scores of mice that did not develop a radiation-induced sarcoma (blue) are compared with the scores of mice that did develop a radiation-induced sarcoma (red). P value is from a t test. B, Kaplan–Meier curves show radiation-induced sarcoma-free survival of the control and p53KD mice irradiated with 30 or 40 Gy to the hind limb. Mice with chronic injury scores equal to or less than 3 are compared with mice with chronic injury scores greater than 3. P value is from a cox proportional hazards model.
Funding
DOD | USA | MEDCOM | CDMRP | DOD Peer Reviewed Cancer Research Program (PRCRP)
HHS | NIH | NIAID | Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID)
HHS | NIH | NCI | Basic Research Laboratory (BRL)
Whitehead Scholar award
History
ARTICLE ABSTRACT
Approximately half of patients with cancer receive radiotherapy and, as cancer survivorship increases, the low rate of radiation-associated sarcomas is rising. Pharmacologic inhibition of p53 has been proposed as an approach to ameliorate acute injury of normal tissues from genotoxic therapies, but how this might impact the risk of therapy-induced cancer and normal tissue injuries remains unclear. We utilized mice that express a doxycycline (dox)-inducible p53 short hairpin RNA to reduce Trp53 expression temporarily during irradiation. Mice were placed on a dox diet 10 days prior to receiving 30 or 40 Gy hind limb irradiation in a single fraction and then returned to normal chow. Mice were examined weekly for sarcoma development and scored for radiation-induced normal tissue injuries. Radiation-induced sarcomas were subjected to RNA sequencing. Following single high-dose irradiation, 21% of animals with temporary p53 knockdown during irradiation developed a sarcoma in the radiation field compared with 2% of control animals. Following high-dose irradiation, p53 knockdown preserves muscle stem cells, and increases sarcoma development. Mice with severe acute radiation-induced injuries exhibit an increased risk of developing late persistent wounds, which were associated with sarcomagenesis. RNA sequencing revealed radiation-induced sarcomas upregulate genes related to translation, epithelial–mesenchymal transition (EMT), inflammation, and the cell cycle. Comparison of the transcriptomes of human and mouse sarcomas that arose in irradiated tissues revealed regulation of common gene programs, including elevated EMT pathway gene expression. These results suggest that blocking p53 during radiotherapy could minimize acute toxicity while exacerbating late effects including second cancers.
Strategies to prevent or mitigate acute radiation toxicities include pharmacologic inhibition of p53 and other cell death pathways. Our data show that temporarily reducing p53 during irradiation increases late effects including sarcomagenesis.
