Wednesday, November 19, 2008

CancerChix: Cancer research using the laying hen, Gallus Domesticus

Inflammation and oxidative stress in Ovarian Cancer

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 USA are diagnosed with ovarian cancer every year, and more than half of these women will die from their disease. Stage I ovarian cancer is curable in 95% of cases, but due to inadequate screening tools, ovarian cancer is usually detected at a late stage when the prognosis is poor. Most patients who present with ovarian cancer complain of GI problems, abdominal discomfort, feelings of being bloated an irregular-- not symptoms they would suspect were caused by ovarian cancer. Upon examination the distended abdomen is found to be due to a large accumulation of ascites fluid from the ovarian tumor. The cancer has progressed and metastasized throughout the abdominal cavity and the cancer cells are producing large volumes of the ascites fluid. After draining the fluid and surgical removal of the primary tumor and chemotherapy with taxol and carboplatin drugs, the disease will go into remission. about chemotherapy Sadly though, in more than 60% of the cases, the disease will return in a more aggressive and now chemoresistant way-- the growing tumors are no longer sensitive to the chemicals and continue to grow and spread until the women succumbs to the disease. It is indeed a very bad disease.

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.

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