Tumors Induce Complex DNA Damage in Distant Proliferative Tissues in Vivo
Induction of DNA damage in distant tissues of tumor-bearing mice correlates with the proliferative state of the tissue and depends on the cytokine CCL2, likely secreted by infiltrating macrophages.
In radiation biology, a bystander effect occurs when cells not directly exposed to ionizing radiation show increased genomic instability and impaired viability due to the release of signaling molecules by the irradiated cells in their vicinity. Christophe Redon, Ph.D., and colleagues in CCR’s Laboratory of Molecular Pharmacology, decided to ask whether a tumor itself could exhibit a similar effect. Their results were recently published in the Proceedings of the National Academy of Sciences.
The researchers designed in vivo experiments to test whether tumors, generated without exposure to radiation, could have bystander effects on normal cells. Using two strains of mice, they implanted one of three types of mouse tumors under the skin: melanoma, sarcoma, or intestinal carcinoma. Once the tumor mass reached 200 mg, the researchers examined several tissue types for markers of enhanced DNA damage using a system developed by William Bonner, Ph.D., a member of their lab. When compared to control mice, normal tissues of tumor-bearing animals showed an increased incidence of two types of DNA lesions—DNA double strand breaks (DSBs) and oxidatively-induced, clustered DNA lesions (OCDLs).
Intriguing differences were seen in the type and frequency of DNA lesions in the tissues examined. All tissues except for liver and kidney showed enhanced levels of OCDLs, whereas only those tissues that rapidly proliferate, including epithelia of the skin, hair follicles, and digestive tract, showed elevated numbers of DSBs. The investigators suggest that this pattern may be due to the conversion of OCDLs to DSBs during cell division, but they wanted to understand how the oxidative damage occurred in the first place.
A tumor could lead to elevated levels of DNA damage in distant tissues in more than one way. The tumors in this study were found to be infiltrated with mature macrophages and lymphocytes that can secrete a variety of cytokines and factors. The research team also found elevated numbers of activated macrophages within the distant affected tissues and identified several selectively enhanced cytokines in the tumor-bearing animals. This suggests that host macrophages that are activated in the tumor may be responsible for driving the distant DNA instability. Cancer cells themselves are also known to secrete a variety of signaling factors, which could directly cause the observed cellular DNA damage.
To distinguish between these two possible causes, the investigators implanted tumors from normal mice into animals lacking expression of one of the enhanced cytokines, CCL2. Under these conditions, no increase in OCDLs or DSBs was observed in tumor-bearing animals compared to controls. This finding suggests that it is the inflammatory signals from the host macrophages, not the tumor cells directly, that are responsible for inducing oxidative damage in tissues distant from the original tumor.
These results support a scenario whereby host macrophages activated in the tumor mass move throughout the body and secrete cytokines, including CCL2. This produces enhanced oxidative stress that ultimately triggers DNA damage in otherwise healthy tissues distant from the cancer. Stopping the release of these inflammatory signaling molecules could enhance tumor therapies. Additionally, these results provide a potential mechanism for the link between chronic inflammation and increased cancer risk.
Summary Posted: 10/2010
PNAS 2010 October 19 107(42):17992-7. PubMed Link
Reviewed by Donna Kerrigan
Note: All questions should be directed to TellCCR
- Immunotoxin Targeting Glypican-3 Effective against Liver Tumors
- Identifying a New Mechanism of HIV Core Formation
- p53 Regulates Bone Differentiation and Osteosarcoma Formation
- Small RNA Enhances Antitumor T-cell Therapy
- First-in-Human Study of Interleukin-15 as Immunotherapy for Metastatic Cancer
- Drosophila TDP1 Ortholog Important for Longevity and Nervous System Maintenance
- CAR T Cell Immunotherapy Promising in Refractory Leukemia
- Designing and Testing Functional RNA Nanoparticles
- Finding Order in Randomness: Single-Molecule Studies Reveal Stochastic RNA Processing
- Tumor-Protective Mechanism Identified from Premature Aging Disease
- Inhibiting NANOG Enhances Efficacy of BH3 Mimetics
- Investigating Genetic Alterations in Bladder Cancer
- Histone Variant Regulates DNA Repair via Chromatin Condensation
- DNA Damage Repair Factors have a Tumor Promoting Role in MLL-fusion Leukemia