NDLI: Acquired radioresistance in cancer associated fibroblasts is concomitant with enhanced antioxidant potential and DNA repair capacity

Content Provider	Springer Nature : BioMed Central
Author	Domogauer, Jason D. de Toledo, Sonia M. Howell, Roger W. Azzam, Edouard I.
Abstract	Background Cancer-associated fibroblasts (CAFs) are a major component of the cancer stroma, and their response to therapeutic treatments likely impacts the outcome. We tested the hypothesis that CAFs develop unique characteristics that enhance their resistance to ionizing radiation. Methods CAFs were generated through intimate coculture of normal human fibroblasts of skin or lung origin with various human cancer cell types using permeable microporous membrane inserts. Fibroblasts and cancer cells are grown intimately, yet separately, on either side of the insert’s membrane for extended times to generate activated fibroblast populations highly enriched in CAFs. Results The generated CAFs exhibited a decrease in Caveolin-1 protein expression levels, a CAF biomarker, which was further enhanced when the coculture was maintained under in-vivo-like oxygen tension conditions. The level of p21Waf1 was also attenuated, a characteristic also associated with accelerated tumor growth. Furthermore, the generated CAFs experienced perturbations in their redox environment as demonstrated by increases in protein carbonylation, mitochondrial superoxide anion levels, and modulation of the activity of the antioxidants, manganese superoxide dismutase and catalase. Propagation of the isolated CAFs for 25 population doublings was associated with enhanced genomic instability and a decrease in expression of the senescence markers β-galactosidase and p16INK4a. With relevance to radiotherapeutic treatments, CAFs in coculture with cancer cells of diverse origins (breast, brain, lung, and prostate) were resistant to the clastogenic effects of 137Cs γ rays compared to naïve fibroblasts. Addition of repair inhibitors of single- or double-stranded DNA breaks attenuated the resistance of CAFs to the clastogenic effects of γ rays, supporting a role for increased ability to repair DNA damage in CAF radioresistance. Conclusions This study reveals that CAFs are radioresistant and experience significant changes in indices of oxidative metabolism. The CAFs that survive radiation treatment likely modulate the fate of the associated cancer cells. Identifying them together with their mode of communication with cancer cells, and eradicating them, particularly when they may exist at the margin of the radiotherapy planning target volume, may improve the efficacy of cancer treatments. Video Abstract
Related Links	https://biosignaling.biomedcentral.com/counter/pdf/10.1186/s12964-021-00711-4.pdf
Ending Page	17
Page Count	17
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s12964-021-00711-4
Journal	Cell Communication and Signaling
Issue Number	1
Volume Number	19
Language	English
Publisher	BioMed Central
Publisher Date	2021-02-26
Access Restriction	Open
Subject Keyword	Cell Biology Protein-Ligand Interactions Receptors Cytokines and Growth Factors Cancer associated fibroblasts Radiotherapy Radioresistance Oxidative metabolism DNA repair Intercellular communication
Content Type	Text
Resource Type	Article
Subject	Biochemistry Cell Biology Molecular Biology
Journal Impact Factor	8.2/2023
5-Year Journal Impact Factor	8/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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