Journal
CELL CYCLE
Volume 10, Issue 13, Pages 2059-2063Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.13.16233
Keywords
tumor stroma; microenvironment; aging; DNA damage; inflammation; NF kappa B; cancer metabolism; HIF1; autophagy; hypoxia; oxidative stress; personalized medicine
Categories
Funding
- W.W. Smith Charitable Trust
- Breast Cancer Alliance (BCA)
- American Cancer Society (ACS)
- NIH/NCI [R01-CA-080250, R01-CA-098779, R01-CA-120876, R01-AR-055660, R01-CA-70896, R01-CA-75503, R01-CA-86072, R01-CA-107382, P30-CA-56036]
- Susan G. Komen Breast Cancer Foundation
- Breast Cancer Alliance, Inc.
- Dr. Ralph and Marian C. Falk Medical Research Trust
- Margaret Q. Landenberger Research Foundation
- Pennsylvania Department of Health
- Breakthrough Breast Cancer in the UK
- European Research Council
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Cancer is thought to be a disease associated with aging. Interestingly, normal aging is driven by the production of ROS and mitochondrial oxidative stress, resulting in the cumulative accumulation of DNA damage. Here, we discuss how ROS signaling, NF kappa B- and HIF1-activation in the tumor micro-environment induces a form of accelerated aging, which leads to stromal inflammation and changes in cancer cell metabolism. Thus, we present a unified model where aging (ROS), inflammation (NF kappa B) and cancer metabolism (HIF1), act as co-conspirators to drive autophagy (self-eating) in the tumor stroma. Then, autophagy in the tumor stroma provides high-energy fuel and the necessary chemical building blocks, for accelerated tumor growth and metastasis. Stromal ROS production acts as a mutagenic motor and allows cancer cells to buffer-at a distance-exactly how much of a mutagenic stimulus they receive, further driving tumor cell selection and evolution. Surviving cancer cells would be selected for the ability to induce ROS more effectively in stromal fibroblasts, so they could extract more nutrients from the stroma via autophagy. If lethal cancer is a disease of accelerated host aging in the tumor stroma, then cancer patients may benefit from therapy with powerful antioxidants. Antioxidant therapy should block the resulting DNA damage, and halt autophagy in the tumor stroma, effectively cutting off the fuel supply for cancer cells. These findings have important new implications for personalized cancer medicine, as they link aging, inflammation and cancer metabolism with novel strategies for more effective cancer diagnostics and therapeutics.
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