Journal
CELL CYCLE
Volume 10, Issue 15, Pages 2440-2449Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.10.15.16870
Keywords
hydrogen peroxide; tumor stroma; microenvironment; aging; DNA damage; inflammation; NF kappa B; cancer metabolism; HIF1; autophagy; hypoxia; oxidative stress; seed and soil hypothesis
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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]
- Susan G. Komen Breast Cancer Foundation
- Dr. Ralph and Marian C. Falk Medical Research Trust
- NIH/NCI Cancer Center [P30-CA-56036]
- Margaret Q. Landenberger Research Foundation
- Pennsylvania Department of Health
- Breakthrough Breast Cancer in the UK
- European Research Council
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In 1889, Dr. Stephen Paget proposed the seed and soil hypothesis, which states that cancer cells (the seeds) need the proper microenvironment (the soil) for them to grow, spread and metastasize systemically. In this hypothesis, Dr. Paget rightfully recognized that the tumor microenvironment has an important role to play in cancer progression and metastasis. In this regard, a series of recent studies have elegantly shown that the production of hydrogen peroxide, by both cancer cells and cancer-associated fibroblasts, may provide the necessary fertilizer, by driving accelerated aging, DNA damage, inflammation and cancer metabolism, in the tumor microenvironment. By secreting hydrogen peroxide, cancer cells and fibroblasts are mimicking the behavior of immune cells (macrophages/neutrophils), driving local and systemic inflammation, via the innate immune response (NF kappa B). Thus, we should consider using various therapeutic strategies (such as catalase and/or other anti-oxidants) to neutralize the production of cancer-associated hydrogen peroxide, thereby preventing tumor-stroma co-evolution and metastasis. The implications of these findings for overcoming chemo-resistance in cancer cells are also discussed in the context of hydrogen peroxide production and cancer metabolism.
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