Tuesday, February 7, 2012

Chicken research and Omega 3s-- best hope for prevention of ovarian cancer?

golden flax:
Linum usitatissimum

Ovarian cancer is a deadly disease, often referred to as the “silent killer” due to the late stage of detection when treatment options are limited and the prognosis of the patient is poor.  More than 24,000 women will be diagnosed with ovarian cancer in the United States in 2012, and it is likely that at least 16,000 women will die from this awful disease.  If ovarian cancer is detected in its early stages the prognosis is excellent and the 5 year survival rate is 95%.  But if the disease is discovered in later stages the 5 year survival rate is less than 30%.  Due to the lack of symptoms and early detection markers, ovarian cancer will go undiagnosed until women present with seemingly unrelated symptoms such as bloating or gastrointestinal distress, and upon further examination advanced disease is only then discovered.  Certainly one of the most important advances needed in ovarian cancer is a method for early detection.  Many of the most promising methods for early detection are unreliable with unacceptably high false positive rates, or are too expensive and impractical for population wide screening.  Thus an emerging emphasis in ovarian cancer research is on prevention, in lieu of reliable early detection. 

Progress in ovarian cancer research has been hampered by lack of suitable animal models.  Certainly there are many advances being made in the treatment of late stage ovarian cancer using rodent models.  But mice do not spontaneously get the disease; it has to be introduced via genetic manipulation, by exposure to chemical carcinogens, or by surgically implanting tumor xenografts into recipient mice.  Ovarian cancer is a complex disease with different subtypes that have distinct tissue-type appearances.  Specific genetic signatures have been described in each of these cancer subtypes, and genetically manipulating mice to mimic these gene signatures will result in the development of ovarian cancer in the mice that phenotypically resembles the subtype of ovarian cancer with that particular gene signature.  Great insight into the genetic lesions associated with the ovarian cancer subtypes has thus been derived.  None the less, the initial events that cause the disease remain obscure in these models because the investigators caused the cancer, in order to study therapy and progression.  Strikingly, the chicken is afflicted with ovarian cancer that closely resembles the human disease, and old laying hens contract the disease spontaneously.  The similarities between human and hen ovarian cancer include the spontaneous development of each of the tumor subtypes, gross pathological appearance of the disease with profuse abdominal ascites and extensive dissemination of metastases throughout the peritoneal cavity.  Moreover, hens, like women, lack any symptoms of early disease.  However, upon necropsy, early ovarian cancers in hens may be detected either upon gross inspection, or further detailed histological analysis will reveal early neoplasms, occult lesions, or pre neoplastic changes.  Analysis of these early lesions provides a unique opportunity to gain new insight into early stage ovarian cancers. 

The reason hens are believed to be such a good model, is that after two years of laying eggs, which happens nearly every day, the hen has ovulated 400 or so times, comparable to the menopausal woman.  Thus the hen after her 2nd year of lay has the same reproductive age as women at the end of their reproductive years. Approximately 50% of ovarian cancers in women are detected in women 62 years or older.  The incidence of ovarian cancer in hens is about 4% in 2 year old hens but when the hens are 4 or 5 years old nearly 50% of them have the disease.  Thus in this 2 year interval the progression of the entire disease can be studied.  The number of lifetime ovulations appears to be correlated with the incidence of ovarian cancer.  This observation forms the basis of the incessant ovulation theory, and posits that women usually get ovarian cancer after a life time of ovulations, which, is caused by the tear and repair of the ovarian surface.  Each time an egg is ovulated it bursts through the surface of the ovary where it is swept into the Fallopian tubes and transported to the uterus.  The surface cells undergo rapid repair and the wound of ovulation is healed.  These events create a pro-inflammatory environment rendering the surface cells susceptible to cancerous transformation.  After three or four hundred of these events the probability of cancer increases and then, on menopause when the ovaries become quiescent and the pituitary hormones (LH and FSH) are secreted excessively (unopposed by estrogen from the ovary), this signals to the ovarian surface cells and causes them to grow.  If any of the cells have acquired a mutation, then this may result in the initiation of ovarian cancer.  It starts on the surface cells of the ovary, and perhaps also in the fimbriae of the oviducts, and then the cancer begins.  It will likely remain dormant or grow very slowly for many years.  The hen, which ovulates every day, provides support for the incessant ovulation hypothesis. 

Working with the chicken model of ovarian cancer also provides the opportunity for large scale dietary intervention studies at relatively little cost.  In order to obtain statistically significant data on dietary effects, a large number of individuals in each diet group have to be studied.  Reasoning that the inflammatory conditions associated with ovulation might be target for prevention, we wanted to test the effectiveness of a diet rich in omega-3 fatty acids.  An effective way to increase omega-3 fatty acid consumption in hens is to feed them a diet enriched with flaxseed, the richest vegetable source of these potent, natural anti-inflammatory fats.  The "omega eggs" in the dairy case of the grocery store come from hens fed flaxseed to increase omega-3s in their eggs.  We were funded by the American Institute for Cancer Research (AICR) and then later by the National Center for Complementary and Alternative Medicine (an NIH institute) to explore the flaxseed diet on ovarian cancer.  We conducted an initial study in which we fed several hundred old hens flaxseed for one year.  We discovered many exciting things from this study.  The hens maintained the same lean weight throughout the study and the flax hens had much better overall health.  While over 50% of the control fed hens died of all causes combined only 20% of the flax hens died.  But the most exciting finding was that while there was no change in cancer incidence, the flax fed hens that did have ovarian cancer mostly only had early stage disease, but the control hens had predominantly late stage disease.   The flax diet significantly reduced the progression of the disease. Flaxseed not only improved the overall well being of the hens, it ameliorated the severity of ovarian cancer.   This gives us great hope that we might be turn ovarian cancer into a disease that women die WITH not from.   Awareness of the importance of diet rich in antioxidants and anti-inflammatory omega-3 fatty acids may be our first best hope for prevention, and suppression of this deadly disease.   Ongoing studies are designed to determine which components of flaxseed in addition to the omega-3s are important in the anti-cancer actions.   Studies are also examining the efficacy of fish oil derived omega-3s, as well as exploring the role of diet and metabolism in the anti-cancer actions of natural products.