||5R01CA237895-03 Interpret this number
||Vanderbilt University Medical Center
||Time-Dependent and Bidirectional Effect of Oxidative Stress - a Missing Piece of the Free Radical Theory of Cancer and Its Potential Implications
Conventional wisdom says that antioxidants should lower cancer risk by neutralizing cell-
damaging, cancer-causing oxidative stress. However, despite the compelling biochemical evidence that ties
oxidative damage to carcinogenesis for in vitro systems, almost all large randomized clinical trials have shown
that antioxidant supplementation provides no clear benefit and even increases cancer risk. These
disappointing and seemingly contradictory results have puzzled the public and researchers for decades. Even
more controversial is whether antioxidant supplementation is safe and effective for cancer survivors. An
estimated 15.5 million Americans in 2016 were cancer survivors, and up to 81% of them used antioxidant
supplements to promote healing. However, we do not understand whether and to what extent post-treatment
oxidative stress is associated with cancer prognosis. We recently conducted a molecular epidemiological study
of colorectal cancer (CRC). We found the first piece of evidence in humans that the association between
oxidative stress and CRC risk was bidirectional, with both beneficial and deleterious effects. Moreover, these
bidirectional effects were time-dependent. Specifically, in earlier phases of cancer development, high oxidative
stress was associated with increased risk of CRC, whereas in later phases, it was associated with decreased
risk. Correspondingly, we found that the association between antioxidant intake and CRC risk was also time-
dependent and varied by baseline oxidative stress. In the pilot study, we found that among patients with more
advanced cancer, their systemic levels of oxidative stress were actually lower. Furthermore, cancer patients
with higher post-treatment levels of oxidative stress had odds of living longer, after comprehensively adjusting
for clinical parameters. In this proposed study, we will conduct a large case-cohort study, building upon three
Asian and European cohorts to determine whether our novel findings—the time-dependent and bidirectional
effects of oxidative stress and antioxidants on CRC, first observed in Chinese women (discovery phase)—can
be replicated in both sexes and in different ethnic populations (replication phase). Comprehensive
assessments of oxidative stress in pre-diagnostic urine samples will be performed. We will also conduct a
follow-up study of CRC cases from whom both pre-diagnostic and post-treatment urine samples have been
collected. We will examine whether higher levels of systemic post-treatment oxidative stress are associated
with better CRC survival, while comprehensively accounting for pre-diagnostic oxidative stress and other
clinical parameters. We expect that this study, with its focus on the time-dependent and bidirectional
association between oxidative stress and CRC, will provide novel insights into the role of oxidative stress in
carcinogenesis, the first evidence linking oxidative stress and clinical outcomes of CRC, and much needed
information for identification of population subsets for chemoprevention. Thus, this study will have high
translational potential to lead to tailored strategies for CRC prevention and patient care.
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