Dale Buck Hales, PhD
Inflammation and oxidative stress contribute to numerous pathologies including cancer and decreased reproductive health. Our studies examine the mechanisms through which immune-endocrine interactions contribute to hormonal carcinogenesis and control steroid hormone biosynthesis, metabolism and action.
Ovarian cancer is the leading cause of death from gynecological malignancies due to the late stage at which it is usual detected. With the exception of the laying hen no other animals are inflicted with spontaneous ovarian surface epithelial cancer that replicates the human disease. Using the chicken as a model for ovarian cancer our studies examine the role of inflammation and oxidative stress in etiology of ovarian cancer. Our studies involve dietary intervention strategies and examine basic mechanisms of cancer pathogenesis.
Our recent studies have shown that feeding cancer prone hens a diet enriched with 10% flaxseed for one year caused a significant reduction in the severity of cancer in hens which were afflicted. This result not only holds promise for therapeutic applications of flaxseed or its biologically active constituents --omega-3 fatty acids in the seed germ or the phytoestrogen antioxidants in the hull, but also gives us new insight into the pathobiology of ovarian cancer. We have shown that the flax diet causes a significant reduction in inflammatory prostaglandin (PGE2), suggesting that the progression of ovarian cancer is driven by inflammation. The initial long term feeding study, which employed hens that had completed their second year of lay, caused significant reduction in severity of the disease, and an improvement of overall wellbeing of the chickens, but did not reduce the incidence of spontaneous epithelial ovarian cancer in the hens. Reasoning that the cumulative damage of 400 ovulations had already created the pro-carcinogenic microenvironment in the ovarian surface epithelium --in fact, many of the birds which were recruited to the study likely were already harboring occult disease --thus prevention was not possible, but amelioration of the disease was the achievable with the intervention. Based on this logic we conducted a 5 yearlong study feeding hens flaxseed from the time of their first lay, when they were about 6 months old. At 6 month intervals for 4 years 20 hens from the control and flax fed groups were analyzed. The hens were cancer free until they reached 2.5 years of age, coincident with the time we had initiated the prior study. At the age when cancer was first evident, was when prostaglandin levels and expression of the cyclooxygenase enzymes began to increase --in parallel to the increase in cancer. Importantly, the flax-fed hens had a significant decrease in cancer incidence, and the flax-fed hens with cancer presented with decreased severity. Our current studies are examining the individual contribution of flax derived omega-3 fatty acids vs. phytoestrogen lignans to the chemo-preventative and chemo-suppressive effects of whole flaxseed. Studies examine alterations in three classes of surrogate endpoints --inflammation (prostaglandin pathways); estrogen metabolism, and signaling, and oxidative stress pathways.
Our studies also examine the mechanisms through which inflammation adversely affects the reproductive capacity via perturbation of gonadal steroid biosynthesis. These studies have revealed that there is a biphasic inhibition of testosterone production: an acute inhibition due to reactive oxygen mediated perturbation of Leydig cell mitochondria, and a prolonged, cytokine-mediated transcriptional repression of steroidogenic enzyme gene expression. Oxidant mediated senescence likely contributes to declining reproductive capacity and performance in the aging male, and understanding the mechanisms through which inflammation and oxidative stress affect testosterone biosynthesis will provide the basis for therapeutic modalities for natural methods of preventing androgenic senescence.
2011-2017 National Center for Complementary and Alternative Medicine NIH 1R01 AT005295-01 (PI Hales) “Flax seed therapy for the prevention of ovarian cancer.” $1,840,000
2014-2017 Team Science Grant, Simmons Cancer Institute at SIU, Co-Pi (Brard, Hales, K Hales) “Flaxseed as maintenance therapy for ovarian cancer patients in remission” $100,000