Friday, June 1, 2012

Report on CCOCR 2012

Report on the Canadian Conference on Ovarian Cancer Research May 27-30, 2012

These are exciting times in ovarian cancer research.  We just attended the Canadian Conference on Ovarian Cancer Research (CCOCR  in Quebec City, Quebec, Canada and the theme of the conference was “Where there is a molecular path, there is a way.”  Surprisingly there were only three or four presentations which utilized animal models, the rest of the conference including oral, poster and plenary talks were based on clinical research.  The further analysis of ovarian cancer subtypes and defining each of the subtypes by their genomic signatures, phenotypic and morphological  features, and anatomical location to give insight into the potential site from which the cancers originate, but more importantly, to devise effective “personalized” therapies.  It now appears that ovarian cancer may be described as possibly 8 distinct cancers.  Impressive technology is being brought to bear on this disease.  The use of next-generation, massively parallel deep sequencing of the tumors brings new insight into the complex changes underlying the cancers.  Instead of considering the cancers from the viewpoint of single gene mutations, it is clear that pathways instead of individual genes need to be targeted.  Combined targeted therapies are bringing improved patient outcomes—but these are often marginal gains.  Increasing progression free survival by 3 months is still considered a major therapeutic advance.  Beyond gene signatures, investigations reveal alteration in copy number of certain genes and specific chromosomal rearrangements.   Certain of these cancer subtypes feature considerable genomic instability, especially the biggest killer of them all, “high grade serous” cancer—of which more than 70% of ovarian cancer victims succumb. 

Yet lacking from these enlightened discussions and state-of-the art technological advances is an increase in our understanding of the underlying cause of ovarian cancer.  While it appears that the fimbriae of the Fallopian tube is the origin of high grade serous cancers which are proposed to spread from tube to ovary to the peritoneum, it remains an open question—what event caused the neoplastic transformation in the first place?  The so called incessant ovulation hypothesis, proposed in 1971 by Fathalla is no longer favored by the gynecologic oncologists, largely because of the postulate that the ovarian surface epithelium the OSE is the origin of the disease.  This idea is challenged the evidence that serous disease my arise from the tubal epithelium, and also the emerging idea that other forms of the disease may arise from endometriosis associated lesions.  The gifted gynecologic surgeons who are “debulking” these cancers observe the similarity in appearance and presentation of the endometrioid cancer with the endometriomas and propose a causal relationship.  The molecular signature of the endometrial cancers and the endometrioid ovarian tumors supports the clonal origins of the disease and help the physicians devise targeted combinatorial therapies for the afflicted women. 

We still favor the basic postulate set forth in the incessant ovulation hypothesis—that ovulation is an inflammatory event and the associated oxidative stress and inflammation is the molecular insult that initiates the transformation.  The endometriosis origin when examined carefully also supports inflammation as the prime driver of the disease—moreover, only endometriomas are associated with endometrioid type of ovarian cancer, and these are endometriosis lesions on the ovary itself—so called “chocolate cysts.”  The fimbriae is in close physical proximity to the surface of the ovary and the insult associated with ovulation exposes the tubal epithelium to the same inflammatory milieu as the OSE.  Tubal, endometriotic or ovarian surface—the inflammatory insult is the common culprit.

Chemoresistance, recurring disease, poor prognosis—all the unfortunate hallmarks of ovarian cancer.  Molecular medicine advances the therapeutic options and outcomes are improving.  Yet there is no better cure for the disease than prevention.  And here is probably the single most important feature of the chicken model of ovarian cancer—it provides the opportunity to devise effective interventions that are potentially able to prevent the disease in the first place.  Furthermore, the hens provide us with a tool to look at the very first initiating events.  What prevents ovarian cancer?  Reducing the number of life time ovulations is the best intervention thus far described.  Parity, breast feeding, steroidal contraceptives—all lead to significant reductions in cancer incidence.  Reducing the inflammation associated with ovulation maybe another effective preventative.  Also reducing the inflammation associated with endometriosis is also likely to have important effects on ovarian cancer reduction.  And we propose that dietary intervention with natural foods rich in antioxidants with anti-inflammatory properties will provide the population with a significant reduction in ovarian cancers when adopted.  This hypothesis has substantial support from dietary intervention studies in hens, and provides the foundation for clinical trials in women.

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.  

Sunday, January 29, 2012

True Science: The Woman on the Street test.

These are very exciting times in the Hales lab. Bolstered by the promising results from our pilot one year flax feeding study our work has gained some media exposure. The idea that simple dietary changes like including flax seed and other rich source of omega-3 and natural antioxidants can result in significant improvements in ovarian cancer prognosis really speaks to people. Hope springs eternal, as they say, and being able to make ovarian cancer a disease women die with, but not from, brings hope to us all. This is important work and we have had great fortune in receiving major NIH funding to continue the studies. The National Center for Complementary and Alternative Medicine (NCCAM, an NIH Center) and the National Cancer Institute (NCI) have both recently funded our research. The NCCAM funded project exams the different constituents of flax seed to assess their relative contributions to the therapeutic actions of flax seed-- the omega-3 fatty acids in the germ of the seed, or the phytoestrogen antioxidants in the hull? We propose that they act synergistically to quell the inflammation and ameliorate the progression of ovarian cancer. If flax oil supplemented with lignan proves to be the most effective, a new therapeutic regimen could be tested in the clinic. It may prove that the omega-3 is the most important ingredient. To test this we will be looking at the effects of fish oil derived omega 3s to contrast and compare to flax seed derived omega 3s. These studies are funded by the NCI.

News of this funding has prompted a flurry of media attention:

Monday, January 18, 2010

Dietary intervention for the prevention and treatment of Ovarian Cancer: just the flax, mamm

A typical Western diet, which is high in meats and low in vegetables, may be positively associated with ovarian cancer incidence. An imbalance of omega 3 (OM-3FA) and omega 6 (OM-6FA) fatty acids contributes to excess cancer risk. Studies indicate that populations that consume high amounts of OM-3FA have lower incidences of breast, prostate and colon cancers than do those that consume less OM-3FA. Thus increasing the consumption of OM-3FA may be a nontoxic way to prevent or suppress ovarian cancer, augment cancer therapy and to significantly increase life span. Flaxseed is an excellent source of dietary fiber, the OM-3FA a-linolenic acid (ALA), and phytoestrogen lignans. ALA is the precursor for the essential omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) The lignans in flaxseed secoisolariciresinol (SECO) secoisolariciresinol diglycoside (SDG) are metabolized in the digestive tract to enterodiol (END) and enterolactone (ENL), which are potent anti-estrogens that have been shown to have anti-proliferative and pro-apoptotic activities in certain cancers. Consumption of the phytoestrogen lignans has been associated with alterations in gene expression and estrogen metabolism which may result in decreased disease risk.

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

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.

This post was copied from the original at