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Monday, January 18, 2010
Model of Flax action in the prevention and suppression of cancer: omega-3 fatty acids in the seed germ and phytoestrogen lignan in the seed hull act synergistically on separate pathwaysAs research into the role of nutrition in cancer continues, it is increasingly evident that nutrition plays a major role in cancer. It has been estimated by the American Institute for Cancer Research that 30-40 percent of all cancers can be prevented by appropriate diets, physical activity and maintenance of appropriate body weight . Obesity, nutrient sparse foods such as concentrated sugars and refined flour products, low fiber intake, consumption of red meat, and imbalance of omega 3 (OM-3FA) and omega 6 (OM-6FA) fats all contribute to excess cancer risk. OM-3FA and OM-6FA are polyunsaturated fats that are referred to as essential fatty acids because they cannot be synthesized by mammals and must be obtained from the diet.
The OM-3FAs a-linolenic acid (ALA; 18:3n:3), eicosapentaenoic acid (EPA; 20:5n:3), and docosahexaenoic acid (DHA; 22:6n:3) have been shown in animal studies to protect from cancer, while the OM-6FAs linoleic acid (LA; 18:2n:6), and arachidonic acid(AA; 20:4n:6) have been shown to be cancer promoting fats. EPA and DHA are both found primarily in oily cold-water fish such as tuna, salmon, and mackerel. ALA is found primarily in dark green leafy vegetables, flax seed oils, and certain vegetable oils. GI enzymes convert ALA to EPA and DHA, and all three OM-3FAs are important to human health. Excessive amounts of OM-6FAs and a very high OM-6FA/OM-3FA ratio have been linked with pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases. The ratio of OM-6FA to OM-3FA in modern diets is approximately 15:1, whereas ratios of 2:1 to 4:1 have been associated with reduced mortality from cardiovascular disease, suppressed inflammation, and decreased risk of cancer. OM-3FAs reduce inflammation and OM-6FAs tend to promote inflammation. OM-3FA have been shown to have a protective effect against ovarian cancer in population based studies. In fact, OM-3FA have been proposed as possible non-toxic chemopreventative agents for epithelial ovarian cancer. Recently, OM-3FA were shown to inhibit the proliferation, induce apoptosis, and suppress VEGF production in ovarian cancer cells in vitro—biological endpoints for chemopreventative trials. Moreover, it is clear that OM-3FAs have demonstrated significant anti-proliferative effects in vitro in many cancer cell lines, most notably breast and colon. Clearly there is an important need for preclinical studies to definitively evaluate the efficacy of OM-3FA as a chemopreventative regimen for ovarian cancer.
Wednesday, November 19, 2008
The current focus of research in the lab is on the etiology of Ovarian Cancer. This project utilizes the laying hen Gallus domesticus, the only animal model for spontaneous ovarian epithelial carcinoma. The focus of our research is on understanding the role that extrinsic factors, inflammation and oxidative stress play in the pathogenesis of hormonal carcinogenesis. Projects include evaluation of dietary intervention in the prevention of ovarian cancer using flax seed enriched diets, the richest vegetable source of omega-3 fatty acids and lignans which are phytoestrogens that block estrogen actions; dietary intervention with broccoli which contains potent antioxidants; understanding the role of CYP1B1 which converts estrogen directly into a genotoxic carcinogen, independently from binding to the estrogen receptor. Recent publications from our lab have examined the prostaglandin producing enzymes called cyclooxygenases (COX-1 and COX-2): "Cyclooxygenases expression and distribution in the normal ovary and their role in ovarian cancer in the domestic hen (Gallus domesticus)", and on CYP1B1 in ovarian cancer in the hen model . We have established a very fruitful collaboration with Janice Bahr at UIUC, the world's foremost expert on the reproductive biology of the chicken, who gives us access to the experimental poultry farm at UIUC where our experimental hens are housed. Drs. Barau and Luborsky at Rush Univeristy Medical Center in Chicago provide essential insight and expertise in the laying hen model, especially Dr. Barau who studied with Dr. Yoshimura in Japan, the foremost expert on avian immunology. We are now publishing at a brisk pace in collaboration with the UIUC and Rush groups. Our first important goal is the validation of the hen model for ovarian cancer. In 'Histopathology of ovarian tumors in laying hens, a preclinical model of human ovarian cancer" (International Journal of Gynecological Cancer, 2009 in press). We document the histopathological similarity between human and hen ovarian cancer.
As we prepare our presentations, either posters for meetings or various talks either me or one o my students might give, we say in a light-hearted way "Ovarian cancer is a really bad disease." This of course is the the devastating truth, but our statement is a synopsis, a short hand way of doling out the facts about this deadly disease. More than 24,000 women in the
While there has been significant progress in curing other forms of cancer, ovarian cancer lags behind. The key to the cure is early detection-- for breast, prostate and colon cancers, early detection and treatment provide the patient with an excellent prognosis for long term cancer free survival. And certain other cancers are entirely preventable-- lung cancer is the single most preventable disease correlated to not smoking or quiting cigarette smoking. Cervical cancer is caused by human papalloma virus and vaccination against HPV is very successful in preventing the disease. Cancer biologists have exploited animal models to understand the etiology or cause of these diseases, and have been able to test therapies and perfect therapies while gaining further insight into these cancers. But ovarian cancer research has been hampered by a lack of suitable animal models. In the past ten years several important rodent models for ovarian cancer have been developed in which a tumor suppressor is knocked out and an oncogene is targeted to the ovary-- but these transgenic models are by their nature blind to the cause of the cancer. Ovarian cancer is of epithelial origin, arising from the specialized tissue that covers the ovary, the so called ovarian surface epithelium. Certain of the transgenic models have successfully targeted the surface epithelium by injection of oncogenes under the ovarian bursa, and the resulting disease closely mimics the human disease. These models provide a testing ground for therapies and enable investigation into the progression of later stage disease-- where all of the therapies are targeted. But the cause of the disease can not be determined from this approach.
With the exception of the laying hen, no other accessible animal model recapitulates the human disease. Laying hens get ovarian cancer spontaneously and it is of epithelial origin, just like in humans. The prevailing theory about the cause of ovarian cancer is the so called "incessant ovulation theory" set forth by Fathalla in 1971. The theory postulates that continuous "tear and repair" of the ovarian surface epithelium, which happens every time an egg is ovulated, provides a rich environment for the initiation of the cancer. Ovulation has long been considered to be an inflammatory process, analogous to wound healing. The mature follicle ruptures, bursting through the surface epithelium releasing the egg which is swept into the oviduct. The process is the same in chickens as in humans. In chickens, though, this happens every day-- yes every time a chicken lays an egg it was necessarily preceded by ovulation. Of course what happens to the ovulated oocyte is remarkably different in the chicken. In the oviduct the yolk is surrounded by albumin and then in the shell gland, analogous to the uterus, the hard shell is formed. The post ovulatory ovary is different too-- in the mammal a corpus luteum is formed, and if the egg gets fertilized, the corpus luteum will provide estrogen and progesterone to prepare the uterus for implantation and maintain the early embryo. Fertilized or not, the chicken's egg gets laid, or in the parlance of the poultry scientist, undergoes oviposition.
Despite the differences between the hen and women, the process at the surface of the ovary are essentially identical. Since hen's ovulate every day, by the time they've completed their second year of lay, they have approximately the same reproductive age as a menopausal woman, each having ovulated 450 to 500 times. That is a lot of tear and repair and it is a this time that both women and hens are usually afflicted with ovarian cancer. The incidence in a 2 year old hen is 4%, but in a 6 year old hen, the incidence of ovarian cancer approaches 50%. This provides a relatively short period of time in which the entire disease can be studied. We've made substantial progress already in defining the earlies steps in ovarian cancer in the hen, and them after examining surgical specimens from women, have observed very similar events. Our long term goal to is characterize these events, determine what factors and mediators are involved in driving these first early steps, and then devise a screening strategy based on our understanding of the mechanism through which normal surface epithelial cells become transformed into malignant ovarian cancer cells.
Another advantage of working with the hen, is the opportunity to do large scale interventions are relatively little cost-- compared to doing similar studies in rodents. Stay tuned for a subsequent post in where I will describe these intervention strategies based on functional food enriched diets.
This post was copied from the original at http://virtualbuck.blogspot.com