Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
The webinar started with a brief introduction of attendees , most who are breast cancer survivors. Survivingbreastcancer.org is an organization committed to supplying women affected with breast cancer up to date information, including podcasts, webinars, and information for treatment, care, and finding support and support groups.
Some of the comments of survivors:
being strong
making sure to not feel overwhelmed on initial diagnosis
get good information
sometimes patients have to know to ask for genetic testing as physicians may not offer it
Laura Carfang discussed her study results presented at a bioethics conference in Clearwater, FL on issues driving breast cancer patient’s as well as at-risk women’s decision making process for genetic testing. The study was a phenomenological study in order to determine, through personal lived experiences, what are pivotal choices to make genetic testing decisions in order to improve clinical practice.
The research involved in depth interviews with 6 breast cancer patients (all women) who had undergone breast cancer genetic testing.
Main themes coming from the interviews
information informing decisions before diagnosis: they did not have an in depth knowledge of cancer or genetics or their inherent risk before the diagnosis.
these are my genes and I should own it: another common theme among women who were just diagnosed and contemplating whether or not to have genetic testing
information contributing to decision making after diagnosis: women wanted the option, and they wanted to know if they carry certain genetic mutations and how it would guide their own personal decision to choose the therapy they are most comfortable with and gives them the best chance to treat their cancer (the decision and choice is very personal)
communicating to family members and children was difficult for the individual affected; women found that there were so many ramifications about talking with family members (how do I tell children, do family members really empathize with what I am going through). Once women were tested they felt a great strain because they now were more concerned with who in their family (daughters) were at risk versus when they first get the diagnosis the bigger concern was obtaining information.
Decision making to undergo genetic testing not always linear but a nonlinear process where women went from wanting to get tested for the information to not wanting to get tested for reasons surrounding negative concerns surrounding knowing results (discrimination based on results, fear of telling family members)
Complex decision making involves a shift or alteration in emotion
The Mayo Clinic has come out with full support of genetic testing and offer to any patient.
Additional resources discussed was a book by Leslie Ferris Yerger “Probably Benign” which discusses misdiagnoses especially when a test comes back as “probably benign” and how she found it was not.
Once upon a time, Merck was looking to candidate omarigliptin—a once-weekly DPP-4 diabetes med—to build up declining sales of its Januvia/Janumet franchise.
But no more. Late last week, the pharma giant quietly announced that it had dropped the Phase III prospect it once regarded as a key cog in its diabetes plans.
So why the change of heart? A new report from healthcare analytics firm Advera Health Analytics found that the weekly therapy came along with more serious side effects than Januvia in two studies. Omarigliptin turned up higher rates of prostate cancer and cardiovascular and hepatobiliary issues, or problems with the liver, pancreas or digestive system, it found. And that kind of profile could have made the drug a hard sell.
Merck says the decision didn’t result from any safety or efficacy concerns. Instead, it may have taken a look at the diabetes landscape and seen a difficult future for the DPP-4 contender.
Such a conclusion would come as no surprise, considering recent developments in the diabetes world. Last year, SGLT2 med Jardiance from Eli Lilly and Boehringer Ingelheim made headlines when it became the first diabetes med to cut down on the combined risk of heart attack, stroke and cardiovascular-related death. Last month, GLP-1 product Victoza from Novo Nordisk accomplished the same feat. And those outcomes leave DPP-4s—which have shown that they don’t increase the risk of serious cardiovascular events, but don’t reduce it, either—out in the cold.
And omarigliptin’s once-weekly advantage may not have done enough to change that, considering the long-acting GLP-1 options out there. Eli Lilly is already marketing once-weekly Trulicity, and Novo is in Phase III with its own long-lasting GLP-1, semaglutide.
But that’s not to say Merck will be left in the dust. With omarigliptin off its hands, the company plans to double down on its pipeline efforts, which include ertugliflozin–an SGLT2 prospect of its own.
Report from Ohio State University
COLUMBUS, Ohio – When Ohio State University cancer researchers first began studying a large sect of Amish living in Ohio, they theorized they would find higher incidence rates of cancer. That’s because Amish religious beliefs and traditions limit contact with mainstream society, and intermarriage within this relatively small population could increase the incidence of cancer-related gene mutations.
Instead, they found just the opposite, said Dr. Judith Westman, division director of Human Genetics at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James).
The study of Amish suggests that clean living can lead to healthier life. Overall cancer rates in this population were 60 percent of the age-adjusted rate for Ohio and 56 percent of the national rate. The incidence of tobacco-related cancers in the Amish adults was 37 percent of the rate for Ohio adults, and the incidence of non-tobacco-related cancer was 72 percent.
“The Amish are at an increased risk for a number of genetic disorders but they probably have protection against many types of cancer both through their lifestyle – there is very little tobacco or alcohol use and limited sexual partners – and through genes that may reduce their susceptibility to cancer,” said Westman, who co-authored the study with OSUCCC-James researcher Amy K. Ferketich, who specializes in epidemiology.
The findings were reported in a recent issue of the journal Cancer Causes & Control. The study, which spanned 1996-2003 and is the first of its kind, looked at the incidence of 24 types of cancer in the Amish population. Of the 24 types of cancer studied, the incidence of seven of them – cervical, laryngeal, lung, oral cavity/pharyngeal, melanoma, breast and prostate – was low enough compared with the Ohio rate to be statistically significant.
Westman and Ferketich chose to study the Amish to gain a better understanding of the contributions of environment and genetics to developing cancer. Ohio is home to the largest Amish population in the world, and of the approximately 26,000 Amish living in Holmes County, all descended from the same 100 people who immigrated here 200 years ago.
Researchers interviewed 92 Amish families as part of a cross-sectional household survey and charted their family cancer histories obtaining cancer information on all relatives back three generations and as far forward as possible. For example, researchers interviewing a set of grandparents could gather cancer information on both their ancestors and descendants, said Ferketich.
The study population consisted of 9,992 Amish adults residing in the Holmes County area. Researchers also collected death certificates and cross-checked cancer cases reported to the Ohio Cancer Incidence and Surveillance System. Between 1996 and 2003, there were 191 incident cancer cases identified.
“Because this is a small, relatively closed population, we needed to interview just 92 families to cover 90 percent of the population in Holmes County,” said Ferketich.
The low cancer incidence in the Ohio Amish may be partially explained by lifestyle factors such as limited tobacco consumption and lack of sexual promiscuity. The Amish, as a whole, consume very little tobacco and alcohol, and they lead active, labor-intensive lives as farmers, construction laborers and factory workers.
“One of the things we can learn from the Amish is that they don’t typically smoke or use tobacco products,” Westman said. “They have limited sexual partners and monogamous relationships, so they don’t have some of the cancers that are related to sexual promiscuity.”
Even skin cancer rates are lower for Amish, despite the fact though many Amish make their living working outdoors where they are exposed to sunlight and UV rays.
“They are typically covered and dress to work in the sun the way that is recommended by wearing wide-brimmed hats and generally wearing long sleeves to protect their arms,” Westman said.
Other Ohio State researchers involved in the study include Steven N. MacEachern, J.R. Wilkins III, Robert T. Pilarski, Rebecca Nagy, Stanley Lemeshow, Albert de la Chapelle and Clara D. Bloomfield.
The study was funded by the Ohio Division of the American Cancer Society, National Institutes of Health and the Leukemia Clinical Research Foundation.
Affiliation at the time of the award: NHMRC Helicobacter pylori Research Laboratory,
QEII Medical Centre, Nedlands, Australia, University of Western Australia, Perth, Australia
The Nobel Prize in Physiology or Medicine 2005 was awarded jointly to Barry J. Marshall and J. Robin Warren
“for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease”
Nobel Lecture, December 8, 2005 by Barry J. Marshall NHMRC
Heliobacter pyroli Research Laboratory, QEII Medical Centre, Nedlands, WA 6009, Australia.
SUMMARY
After preliminary studies in 1981, Marshall and Warren conducted a study in which the new bacterium, Helicobacter pylori, was cultured. In that series, 100% of 13 patients with duodenal ulcer were found to be infected. The hypothesis that peptic ulcer was caused by a bacterial infection was not accepted without a fight. Most experts believed that Helicobacter was a harmless commensal infecting people who had ulcers for some other reason. In response, Marshall drank a culture of Helicobacter to prove that the bacteria could infect a healthy person and cause gastritis. The truth behind peptic ulcers was revealed; i.e. very young children acquired the Helicobacter organism, a chronic infection which caused a lifelong susceptibility to peptic ulcers. Marshall developed new treatments for the infection and diagnostic tests which allowed the hypothesis to be evaluated and proven. After 1994 Helicobacter was generally accepted as the cause of most gastroduodenal diseases including peptic ulcer and gastric cancer. As a result of this knowledge, treatment is simply performed and stomach surgery has become a rarity
HELICOBACTER – THE EASE AND DIFFICULTY OF A NEW DISCOVERY
Nobel Lecture, December 8, 2005 by J. Robin Warren Perth, WA 6000, Australia.
This is the story of my discovery of Helicobacter. At various times I have been asked: did I steal the discovery; did I find it by accident; did it follow some brilliant research work; or was it serendipity. My answer to most of these is a definite “No.” Obviously, as with any new discovery, there is an element of luck, but I think my main luck was in finding something so important. I think the best term is serendipity; I was in the right place at the right time and I had the right interests and skills to do more than just pass it by. First, let us examine this. Before 1970, well-fixed specimens of gastric mucosa were rarely seen in clinical practice. Biopsies, taken with the rigid gastroscope or the suction method, were very uncommon. Gastrectomy specimens are clamped at each end, with the contents inside. They fix slowly from the outside. Meanwhile the mucosa autolyzes and any organisms disappear. Autopsy specimens are even worse. Most surgical specimens were taken to remove tumours or ulcers and pathology descriptions centred on this rather than the fine histology of the mucosa. If they described gastritis at all, pathologists gave it names such as ‘superficial’ or ‘atrophic,’ which showed little real relationship to the histology. Since the early days of medical bacteriology, over one hundred years ago, it was taught that bacteria do not grow in the stomach. When I was a student, this was taken as so obvious as to barely rate a mention. It was a “known fact,” like “everyone knows that the earth is flat.” Known facts can be dangerous; to quote Sherlock Holmes (Conan Doyle, The Boscombe Valley Mystery) “There is nothing more deceptive than an obvious fact.” As my knowledge of medicine and then pathology increased, I found that there are often exceptions to “known facts.” In the stomach, organisms, usually yeast or fungus, often grow in the necrotic debris in ulcers or tumours. Unusual infections sometimes do involve the gastric wall. Once I saw tuberculosis. Bacteria, floating above the mucus layer on the epithelium, are often seen in gastric biopsies. They appear to be mixed varieties, probably just passing through, dead, or contaminants; they are relatively sparse in cultures. The introduction of the flexible endoscope changed all this. It enabled gastroenterologists to biopsy many of their patients. Small biopsies, placed 293 immediately into formalin, fixed well. Instead of rare, these became some of our most frequent biopsies. Whitehead accurately described them in 1972. He described ‘active’ changes, which become important in my story. His pictures of this (figure 1) show intraepithelial polymorph infiltration in the necks of the gastric glands and a remarkable distortion of the foveolar (surface) epithelium. These features proved to be quite common and easy to diagnose.
They were remarkably consistent in appearance, although often much more focal or mild than in the original illustrations (figure 2 and 3). The changes were superficial, usually involving only the epithelium. Whitehead devised a classification based on the features he actually saw and described. Most of these features are mentioned in the diagnosis. This allows any associations between histology and other clinical features to be noted. I was very impressed with Whitehead’s work. I simplified his classification for my own use (table), and the pathology of the stomach suddenly seemed to make sense. The diagnosis describes in one short line the features actually seen. Microbiological stains are excellent for staining bacteria in smears, especially from a clean culture. However, histology shows a complex mass of tissue structures that also stain.
To see bacteria, it is necessary to contrast them with the tissue. Gram positive organisms and acid fast organisms contrast with tissue sections. Warthin-Starry silver stain of tissue shows spirochaetes (in Figure 2. The surface (foveolar) epithelium to the right shows a focus of gross epithelial irregularity, of the type described by Whitehead. Elsewhere the epithelium shows only mild non-specific changes. In many biopsies the changes are often much milder than shown here (H&E x100)….. Table.
Figure 3. The section is cut obliquely through the necks of the gastric glands. This shows numerous gland necks in transverse section, lined by foveolar type epithelium. Glands are visible in the lower area, lined by smaller mucus-secreting cells. Polymorphonuclear leucocytes infiltrate the epithelium of the neck of one gland (arrow). There are also individual PMN’s in other gland necks (arrow heads). Sometimes a few of these is all that is found, and the infiltration is often focal, as shown here (H&E x100). 296
My simplification of Whitehead’s Classification of Gastritis Pathology Description Severity Mild, Moderate, Severe ‘Active’ Active (if present) Type of Inflammation Acute, Chronic etc. Other features present Atrophy, Metaplasia, Dysplasia, Reduced mucus secretion Using this table, the diagnosis may be written as a single line. In the following example, replace the headings (in brackets) with the appropriate descriptive terms. Diagnosis: (Severity) – (Active?) – (Type) – gastritis – (with any other features). 295 syphilitic chancres) and bipolar Donovan bodies (the Gram negative bacilli in granuloma inguinale). I was interested in microbiological stains. After seeing several cases of granuloma inguinale in which the bacteria were clearly visible with the silver stain, I was experimenting with this stain on other Gram negative organisms, with variable success. Thus, I was a young pathologist when high quality gastric biopsies became frequent. By 1979, I had a particular interest in gastric pathology, based on Whitehead’s work and, in particular, his description of active gastritis. I was interested in bacterial stains, especially the use of silver stains for Gram negative bacilli. In addition, electron microscopy had recently started in our department. I found this interesting, giving another dimension to histology. Finally, I was interested in drawing specimens, and also in photography, both of which helped me to discern detail.
DISCOVERY: THE EASY PART
My adventure with Helicobacter began in June 1979. A routine biopsy showed severe active chronic gastritis (figure 4).
Figure 4. My first case. The epithelium shows gross cobblestone change, most marked to the right, resembling Whitehead’s ‘active’ change. A thin blue line on the surface shows bacteria at high power (H&E x100). 297
Figure 5. Diagram from my first case shows active changes in the infected epithelium (below). Normal (above) shows a flat surface and well aligned basal nuclei.
Figure 6. My first case. High power view with the silver stain shows numerous curved bacilli on the distorted epithelium (Warthin Starry x 1000). 298 Figure 8. Electron microscopy, low power, of normal foveolar epithelium shows a flat surface with numerous tiny microvilli just visible.
Figure 7. My first case. High power electron microscopy shows the top of two epithelial cells bulging out, with small curved bacilli closely applied to the surface. Few microvilli are seen. 299
The epithelium showed gross cobblestone change, very similar to Whitehead’s description. Nuclei were out of alignment. Mucus secretion showed a marked patchy reduction. Focal intraepithelial polymorphonuclear leucocytes were present (figure 5). There were numerous lymphocytes and plasma cells in the stroma. A thin blue line was visible on the surface, which on high power I thought consisted of numerous bacteria. My colleagues could not see them, so I stained them with the Warthin-Starry silver stain and numerous bacteria were easily visible at low power. At high power (figure 6), they were obviously small curved and spiral bacilli, closely applied to the epithelial surface and often arranged in palisades. I took tissue from the wax block used for standard histology and obtained the electron microscopy. The images were of good quality and showed the bacteria well (figure 7). There were small curved bacilli closely applied to the surface. Some were attached to microvilli. The top of the cells bulged out. Mucus secretion was reduced. Bacteria were infiltrating between the bulging tops of the cells. They were not obviously penetrating past the cell junctions; however they may do so, because occasional bacterial fragments were present in the superficial stroma. Electron microscopy demonstrates the normal anatomy of the columnar (foveolar) epithelium and the mechanism of the active change. The normal epithelium shows a flat surface, but there are numerous tiny microvilli (figure 8). The microvilli contain bundles of filaments that attach to the top of them. These filaments normally extend through the cells and attach to the cell base, giving the cells a rigid structure. This fixes their shape and also maintains their internal architecture, with basal nuclei and superficial mucus secretion. The normal columnar epithelium can be scraped from the mucosal surface, smeared onto a glass slide and still retain its columnar structure on cytological examination. Helicobacter pylori attach to the microvilli (figure 9) and often flatten and destroy the microvilli. The filaments become detached and the cells loose their structure. They behave in an amoeboid fashion, with nuclei floating through the cytoplasm and the surface bulging out. My colleagues finally believed the bacteria were there. However, they doubted their importance, and challenged me to find any more cases. I thought they were worthy of further study (figure 10) so I continued to search and, to my surprise, I found them in quite a significant number of biopsies. The number increased with experience. Many cases showed only mild pathology, but the basic changes were still present. Eventually I was finding them in about a third of the gastric biopsies. Another interesting feature gradually became apparent as my experience increased. I found the bacteria were easily visible on many surgical specimens. They were only seen along the cut edge of the specimens, where a narFigure 9. Very high power electron microscopy shows how the bacteria attach to the surface microvilli and flatten them. Bundles of filaments are visible within the microvilli to the left. 300 row strip of mucosa came into rapid contact with the formalin fixative. In addition, they were often mixed with a variable number of spherical organisms, particularly slightly further (2–3 mm) from the cut edge. It soon became apparent that the spherical organisms were the degenerating form of Helicobacter. This strip of ‘mixed’ organisms, only seen along the cut edge of the specimen, probably helps explain the absence of past reports. They would undoubtedly be seen as contaminants. We found these specimens a very useful source of positive control specimens when performing the bacterial stain…
In 1982, we obtained biopsies for culture and histology from 100 consecutive outpatients referred for gastroscopy. Most of them complained of peptic symptoms or pain, so this could not be investigated. They all completed a detailed clinical protocol that listed every symptom Barry could think of. The results were totally unexpected. First, the bacteria were not related to any significant symptoms, only bad breath and burping. The gastroscopy reports were surprising. They showed that the gastric infection was most closely related to duodenal ulcer. Most gastric ulcers were associated with the infection, but every patient with a duodenal ulcer was infected. “Gastritis,” as observed on gastroscopy, was not related to either the histology or the bacteria. At first, no bacteria were cultured. Finally, plates incubated for five days over the Easter holiday showed a culture of a new type of bacteria, not described previously. The microbiology technicians had previously treated our research culture plates as routine cultures and discarded negative plates at 48 hours. After this, the plates were allowed to mature, and several more cultures were obtained. The bacteria showed many features of Campylobacter, but they were unusual and were eventually considered to be a new genus, now termed Helicobacter. I sent a letter to the Lancet in 1983, a summary of the work I had done before I met Barry (ref 1). Barry sent an accompanying letter describing our joint work. He also presented our findings at the Brussels Campylobacter conference. Martin Skirrow, who chaired the conference, was very impressed with our work. We sent our definitive paper to the Lancet in 1984 (ref 2)….
Helicobacter patients show considerable variation. I was involved with these early examples. • Barry gave himself a severe active gastritis, to the disgust of his wife, in an attempt to fulfil Koch’s postulates. • Morris, in New Zealand, gave himself chronic gastritis and took years to cure it. • My wife developed arthritis and as soon as she took NSAIDs she developed severe epigastric pain. Stopping the NSAIDs reversed this. And again. I sent her to Barry, who found Helicobacter, treated it and she was able to take the NSAIDs. Do not take it for granted that NSAIDs are the only guilty party. • Most patients are symptomless. This was actually one of our major difficulties. I was an example. After she was treated, my wife complained that I had bad breath. I was positive for H pylori and after treatment marital bliss returned….
In 1986, we undertook a double blind trial to find the effect of treatment of Helicobacter pylori infection on ulcer relapse (ref 3). All patients received treatment for their ulcers. They received antibacterial therapy or placebo for Helicobacter infection. All were examined by multiple gastroscopies and biopsies for 12 months and again after 7 years. This provided me with excellent material for the study of the pathology related to Helicobacter and, also, the pathology of duodenal ulcers. I quantified the grade of gastritis on a 0–36 scale by giving a value 0–9 for each of the main four features seen with active gastritis: intraepithelial polymorphs; typical epithelial distortion; reduced mucinogenesis in the foveolar epithelium; increased stromal lymphoid cells (a non-specific change seen with all chronic inflammation). This gave easily obtainable and remarkably consistent grades of gastritis for each case. From these results I made a histogram to show the grades of inflammation before and after eradication of H pylori (figure 11). The grade of gastritis when Helicobacter pylori was present was usually above 20.
Figure 11. Histogram, comparing gastritis before and after eradication of H pylori. The normal range is (0–14), in the absence of pre-existing disease or infection.
Biopsies were taken 2 weeks after treatment. After successful eradication of H pylori, the active changes disappeared very quickly, and the grades in the histogram for these patients were mainly below 20. The true normal range is 0–14, but our cases show treated active gastritis, many biopsies taken only 2 weeks after treatment, not random normal samples. The stromal lymphoid cell infiltration disappeared more slowly, over about twelve months or more. The absolute difference between the two groups is very impressive. There is some overlap, but the difference in the gastric pathology with and without Helicobacter pylori is incontrovertible (figure 11). One interesting feature was the consistency of the results over time. Repeated biopsies from each patient showed remarkably constant histological features throughout the 7 years of the study, as long as the bacteria remained. The active changes vanished as soon as the bacteria were eradicated, within weeks. This strongly suggests the bacteria caused these changes. ‘Active’ changes are almost never seen in the absence of H pylori. Other changes remained longer, particularly structural damage such as scarring, and epithelial changes such as gland atrophy, metaplasia and dysplasia.
DUODENAL ULCER
We were surprised to find duodenal ulcer so closely related to Helicobacter. However, further investigation shows that most duodenal ulcers can be viewed as distal pyloric ulcers. They are in the duodenal cap and the pyloric mucosa normally extends through the pylorus (figure 12). Biopsies from the proximal border of all duodenal ulcers in this study showed either gastric mucosa or scarred mucosa, consistent with a gastric origin and with no apparent Brunner’s glands, as seen in duodenal mucosa. The pyloric mucosa is very mobile and easily moves some distance through the pylorus. When the stomach contracts, a mixture of food fragments and corrosive gastric juice squirts through the pylorus. Perhaps it is not surprising that ulcers are so common here, especially when the epithelium is damaged by infection and active inflammation.
Figure 11. Histogram, comparing gastritis before and after eradication of H pylori. The normal range is (0–14), in the absence of pre-existing disease or infection. 304
CONCLUSION Now, the importance of Helicobacter is generally recognised, particularly with regard to duodenal ulcer. As a pathologist, I am disappointed that active gastritis is not considered worthy of treatment. I see it in all infected stomachs, although often mild. Unfortunately, it does not cause many symptoms and nobody is interested. In conclusion, we now know that Helicobacter had been seen and largely ignored for over 100 years. I saw them 25 years ago and linked them with active gastritis. Barry Marshall and I cultured the bacteria and linked them to duodenal ulcer. In various different ways over the next few years we proved these relationships.
People who harbor ulcer-causing bacteria in their stomachs may be protected against some diarrheal diseases, according to an Israeli study.
Some previous studies had suggested that being infected with the bacterium, Helicobacter pylori, increases the risk of diarrhea, while others have reported finding the opposite, said researchers from Tel Aviv University.
“Our findings suggest an active role of H. pylori in the protection against diarrheal diseases,” wrote lead author Dani Cohen in the journal Clinical Infectious Diseases.
The bacterium is especially common throughout the developing world, but only causes symptoms in a minority of those it infects. People with chronic H. pylori infections are known to have an increased risk of stomach cancer and related diseases.
One in six cancer deaths around the world are caused by infections that could have been prevented or treated, according to a new study in the journal The Lancet.
Researchers from International Agency for Research on Cancer, France, found that about 1.9 million cancer deaths that occurred in 2008 were caused by the human papillomavirus (HPV), hepatitis B and C, or Helicobacter pylori.
For men in particular, 80 percent of the infection-related cancers were liver and gastric cancers. In women, about half of the infection-related cancers were cervical cancer, according to the study.
A new phase of the Breast Cancer and the Environment Research Program (BCERP), focused on prevention, is being launched at the National Institutes of Health. Grant-funded researchers will now work across scientific disciplines, involve new racially and ethnically diverse communities, and expand the study of risk factors that precede breast cancer, such as breast density.
These new directions reflect recommendations made by the Interagency Breast Cancer and Environmental Research Coordinating Committee (IBCERCC) in 2013. IBCERCC was congressionally mandated to review the state of the science around breast cancer and environmental influences by the Breast Cancer and Environmental Research Act. Recommendations included prioritizing prevention, involving transdisciplinary research teams, engaging public stakeholders, collaborating across federal agencies, and communicating the science to the public.
This broadened research focus will add to the growing knowledge of environmental and genetic factors that may influence breast cancer risk across the lifespan. The six new BCERP projects, plus a new coordinating center promoting cross-project collaboration, are jointly funded by the National Institute of Environmental Health Sciences (NIEHS) and the National Cancer Institute. All projects involve strong partnerships between researchers and organizations focused on breast cancer prevention or environmental health.
The new research will be conducted at the following institutions
Brigham and Women’s Hospital, Boston
City of Hope/Beckman Research Institute, Duarte, California
Columbia University, New York City
Georgetown Lombardi Comprehensive Cancer Center, Washington, D.C.
Michigan State University, Lansing
University of Massachusetts, Amherst
University of Wisconsin – Madison (Coordinating Center)
“The beauty of this research is that scientific discoveries and community observations inform each other, in order to dive deeper into the complex causes of breast cancer,” said Gwen Collman, Ph.D., director of NIEHS Division of Extramural Research and Training.
The focus on minority and socio-economically disadvantaged women is an important step in addressing disparities in breast cancer outcomes. Although African-American women are diagnosed with breast cancer less often than white women, more aggressive cancers and breast cancer deaths are more common among African-American women.
Another new direction for BCERP is research on the role of breast density as a possible intermediate risk factor for breast cancer. Dense breast tissue is one of the most common risk factors for breast cancer. Identifying links between environmental exposures and high breast density may provide new insights into prevention.
“These priorities reflect our continued commitment to breast cancer prevention,” noted Caroline Dilworth, Ph.D., BCERP program lead at NIEHS. “Our goal is to build on the high quality science we’ve been funding for more than a decade, while also being responsive to the expert recommendations of the IBCERCC report.”
Grant Numbers: U01ES026130, U01ES026137, U01ES026122, U01ES026132, U01ES026119, U01ES026140, U01ES026127
NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.
The National Cancer Institute leads the National Cancer Program and the NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at http://www.cancer.gov or call NCI’s Cancer Information Service at 1-800-4-CANCER.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Other posts on this site on Cancer and Early Detection include
Cancer Biology and Genomics for Disease Diagnosis (Vol. I) Now Available for Amazon Kindle
Reporter: Stephen J Williams, PhD
Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series C: e-Books on Cancer & Oncology
This e-Book is a comprehensive review of recent Original Research on Cancer & Genomics including related opportunities for Targeted Therapy written by Experts, Authors, Writers. This ebook highlights some of the recent trends and discoveries in cancer research and cancer treatment, with particular attention how new technological and informatics advancements have ushered in paradigm shifts in how we think about, diagnose, and treat cancer. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation.The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012. All new articles on this subject, will continue to be incorporated, as published with periodical updates.
We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon. All forthcoming BioMed e-Book Titles can be viewed at:
Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.
Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:
delivering curation and summary interpretations of latest findings and innovations
on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
providing a social platform for scientists and clinicians to enter into discussion using social media
compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform
This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.
Table of Contents for Cancer Biology and Genomics for Disease Diagnosis
Preface
Introduction The evolution of cancer therapy and cancer research: How we got here?
Part I. Historical Perspective of Cancer Demographics, Etiology, and Progress in Research
Chapter 1: The Occurrence of Cancer in World Populations
Chapter 2. Rapid Scientific Advances Changes Our View on How Cancer Forms
Chapter 3: A Genetic Basis and Genetic Complexity of Cancer Emerge
Chapter 4: How Epigenetic and Metabolic Factors Affect Tumor Growth
Chapter 5: Advances in Breast and Gastrointestinal Cancer Research Supports Hope for Cure
Part II. Advent of Translational Medicine, “omics”, and Personalized Medicine Ushers in New Paradigms in Cancer Treatment and Advances in Drug Development
Chapter 6: Treatment Strategies
Chapter 7: Personalized Medicine and Targeted Therapy
Part III.Translational Medicine, Genomics, and New Technologies Converge to Improve Early Detection
Chapter 8: Diagnosis
Chapter 9: Detection
Chapter 10: Biomarkers
Chapter 11: Imaging In Cancer
Chapter 12: Nanotechnology Imparts New Advances in Cancer Treatment, Detection, & Imaging
Epilogue by Larry H. Bernstein, MD, FACP: Envisioning New Insights in Cancer Translational Biology
Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk
Reporter/Curator: Stephen J. Williams, Ph.D.
Article-7.2.6. Ethical Concerns in Personalized Medicine BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk
Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing[1]
Direct-to-consumer (DTC) genetic testing and genetic health information in 2007 with the advent of personalized testing services by companies who offered microarray-based genotyping of single-nucleotide-polymorphisms (SNP) which had strong correlations to disease risk. Three companies started to offer such services directly to the consumer:
A common test which is offered analyzes the consumers BRCA1/2 mutation status. Three mutations in the BRCA gene are known to predispose women to hereditary breast and ovarian cancer: BRCA1 185delAG, BRCA1 538insC, and BRCA2 617delT. These BRCA1 mutation confer a 60% breast cancer risk and a 40% risk of ovarian cancer while the BRCA2 mutation confers a breast cancer risk of 50% and 20% risk of ovarian cancer.
However, the commercial availability of this genetic disease-risk associated testing has led to certain ethical issues concerning communication and responses of risk information by:
Consumers who request BRCA1/2 testing (focus of the Francke article
BRCA1/1 testing and communication of results to minors and relatives (Bradbury: see below)
There has been much opinion, either as commentary in literature, meeting proceedings, or communiques from professional societies warning that this type of “high-impact” genetic information should not be given directly to the consumer as consumers will not fully understand the information presented to them, be unable to make proper risk-based decisions, results could cause panic and inappropriate action such as prophylactic oophorectomy or unwarranted risk-reduction mastectomy, or false reassurance in case of negative result and reduced future cancer screening measures taken by the consumer. However, there have been few studies to investigate these concerns.
A report by Dr. Uta Francke in the open access journal PeerJ, assesses and quantifies the emotional and behavioral reactions of consumers to their 23andMe Personal Genome Service® report of the three BRCA mutations known to be associated with high risk for breast/ovarian cancer. One hundred thirty six (136) individuals, who tested positive for BRCA1 and/or BRCA2 mutations as well as 160 users of the service, who tested mutation-free were invited to participate in phone interviews addressing personal and family history of cancer, decision and timing of viewing the BRCA report, recollection of results, emotional responses, perception of personal cancer risk, information sharing, and actions taken. Thirty two (32) mutation carriers (16 female and 16 male) and 31 non-carriers responded to the phone questionnaire.
Questions were based on the following themes:
When you purchased the 23andME Personal Genome Service® were you aware that it included testing for mutations that predispose to breast and ovarian cancer?
Were you aware that having Ashkenazi Jewish ancestry influences your risk of carrying one of the three mutations?
Have you or a first or second degree relative been diagnosed with breast, ovarian or any other cancer?
What did you learn from your results?
Were you surprised by the result?
How did you feel about this information (extremely, moderately, somewhat upset or extremely relieved)?
Results: Eleven women and 14 men had received an unexpected result that they are carriers of one of the three mutations however none of them reported extreme anxiety and only four reported moderate anxiety which did not last long. Participants were at least 8 years of age. Five women and six men described their reaction as neutral. Most carrier women sought medical advice and four underwent risk-reducing procedures. Some to the male carriers felt burdened to share their test results with their female relatives, which led to additional screenings of relatives. Almost all of the mutation-positive customers appreciated learning their BRCA mutational status.
Other highlights of the results include:
More women got tested if they had a first or second degree relative previously diagnosed with breast/ovarian cancer
Ten mutation-positive individuals who were surprised at the test results cited the lack of family history of breast/ovarian cancer as the reason for their surprise. The rest who were surprised at their positive test results believed that the frequency of these mutations were low in the general population so they shouldn’t have been affected.
For the mutation-positive group, none of the 32 reported as being “extremely upset”.
Interestingly, on male who learned, for the first time, he was a positive carrier for BRCA mutation, reported feeling “relieved” because his daughter who was also tested by 23andMe had not acquired his mutation.
A brief interview with Dr. Francke follows:
Q: In your results you had noted that none of the mutation carriers showed extreme anxiety about their reports however there were many of Ashkenazi descent who was well aware of the increased risk to breast cancer. In another study by Dr. Angela Bradbury, anxieties and communication to their children depended on mutation status and education status. Do you feel that most women in your study were initially aware they could be in a high risk category for cancer, whether breast, ovarian, or other?
Dr. Francke: As we show in Table 1, 6 of 16 women and 6 of 16 men who found out that they were BRCA mutation carriers had not been aware that being of Ashkenazi descent confers an increased risk of breast/ovarian cancer. In Table S1, we show that 6 of these 32 people did not self-identify as Ashkenazi. Q: The reporting and communication of test results to offspring and genetic testing of offspring as a result of positive tests has been under much debate. I had noticed that there was a high proportion of relatives who went for screening after learning of a family members BRCA testing, whether it showed a mutation or not. Some studies have shown that offspring of carriers may misinterpret genetic testing results and take inappropriate action, such as considering having early testing before age 25. It appears some anxiety may be due to misinformation and lack of genetic counseling. Should these test results be considered in guidelines for oncologist such as NCCN guidelines with respect to informing family members using genetic counselors as an intermediary?
Dr. Francke: The “high proportion of relatives who went for screening after learning of a family member’s BRCA testing”, were only those related to a BRCA-positive person. Most of the BRCA testing of relatives was done through health care providers at Myriad as these people were eligible for insurance coverage of the test. In our interviews we found no evidence for inappropriate action of carriers or non-carriers. With one exception, we found no evidence for misinterpretation or “anxiety due to lack of genetic counseling”. In our online reports we recommend genetic counseling for all customers who have questions about their results.
Q: I was also particularly interested the male carrier felt a heightened burden to tell their offspring. This has been suggested in other studies. I would assume the mothers and not the fathers would feet more pressure to tell their children. Is there a reason for this? Dr. Francke: The heightened burden reported by the male carriers was mostly about the realization of the risk for their daughters, not so much about to telling their offspring. Female carriers were primarily concerned about their own health risk and management, and decision-making about preventive measures – therefore, the risk for offspring appeared to be of secondary concern for them.
However, the availability of this type of predictive genetic testing for hereditary cancer has raised some ethical issues regarding the communication of risk and genetic results to family members and especially offspring, specifically whether informing minors would incur unnecessary testing, anxiety among minors of parents who tested positive for genetic risk-factors, or even premature risk-reduction surgeries or medical interventions.
The aforementioned ethical issues concerning communicating results of BRCA mutational testing to offspring was addressed by two large studies conducted by Dr. Angela Bradbury M.D. and colleagues at Fox Chase Cancer Center Family Risk Assessment Program(now she is at University of Pennsylvania) and University of Chicago Cancer Risk Clinic. These studies evaluated the parental opinions regarding BRCA1/2 testing of minors, and how parents communicate BRCA1/2 genetic testing with their children.
In the JCO article (Parent Opinions Regarding the Genetic Testing of Minors for BRCA1/2)[2], Bradbury and colleagues used semistructured interviews (yes/no questions and open-ended questions) of 246 parents at Fox Chase and University of Chicago, who underwent BRCA1/2 whether they supported testing of minors in general and testing of their own offspring. Parents were asked, “If you were deciding, do you think children under 18 years old should be given the opportunity to be tested” and followed by the open-ended question: “Why do (don’t) you support the genetic testing of minors for BRCA1/2?”.
Results: In response to the first question (Would you support testing in minors) 37% of parents supported testing of minors in the general population. The follow-up open-ended question revealed that 4% support testing minors in some or all circumstances. This decision was independent of parent sex or race. 44% of parents would test their own offspring. Parents who opposed testing in minors thought testing would cause fear and anxiety for their children but those who supported unconditional testing (regardless of whether they were positive for the BRCA mutation or not) mentioned that the medical information would foster better health behaviors in their offspring. 21% of parents who opposed testing minors, in general, actually supported testing of their own children. Interestingly parents who tested positive for the BRCA1 overwhelmingly (64%) opposed testing of minors, in general. In addition, statistical analysis of the open-ended questions revealed that parents who did not have a college degree, had a negative test result, and were non white favored testing of their own children. The authors had suggested larger studies before any guidelines were given as to whether testing in minors of BRCA mutation carriers should be standard.
In a recent publication by Dr. Bradbury and colleagues (Knowledge and perceptions of familial and genetic risks for breast cancer risk in adolescent girls)[3], studied how adolescent girls understood and responded to breast cancer risk by interviewing 11-19 year-old girls at high-risk and population-risk for breast cancer. Although most girls said they were aware of increased risk because either a family member had or was predisposed to breast cancer (66 %) only 17 % of girls were aware of BRCA1/2 genes. Mother was the most frequently reported source of information for breast cancer among both high-risk (97 %) and population-risk (89 %) girls. The study also showed that most girls who believe they are at high-risk could alter their lifestyles or change dietary habits to lower their risk.
In an adjacent study in the journal Cancer[4], Bradbury and colleagues at Fox Chase Cancer Center had gauged the frequency with which parents had told their children of their BRCA1/2 teat results and how their children felt about the results.
When parents disclose BRCA1/2 test results: Their communication and perceptions of offspring response[4]
Semi-structured interviews were conducted with parents who had BRCA1/2 testing and at least 1 child <25 YO. A total of 253 parents completed interviews (61% response rate), reporting on 505 offspring. Twenty-nine percent of parents were BRCA1/2 mutation carriers. Three hundred thirty-four (66%) offspring learned of their parent’s test result. Older offspring age (P ≤ .01), offspring gender (female, P = .05), parents’ negative test result (P = .03), and parents’ education (high school only, P = .02) were associated with communication to offspring. The most frequently reported initial offspring responses were neutral (41%) or relief (28%). Thirteen percent of offspring were reported to experience concern or distress (11%) in response to parental communication of their test results. Distress was more frequently perceived among offspring learning of their parent’s BRCA1/2 positive or variant of uncertain significance result.
CONCLUSIONS:
Many parents communicate their BRCA1/2 test results to young offspring. Parents’ perceptions of offspring responses appear to vary by offspring age and parent test result. A better understanding of how young offspring respond to information about hereditary risk for adult cancer could provide opportunities to optimize adaptive psychosocial responses to risk information and performance of health behaviors, in adolescence and throughout an at-risk life span.
Many Parents Share Genetic Test Findings With Kids
By Steven Reinberg HealthDay Reporter
Mar. 23
FRIDAY, Aug. 17 (HealthDay News) — As genetic testing for diseases becomes more commonplace, the impact of those findings on family members may be underestimated, researchers say.
For instance, some women who discover they have the BRCA gene mutation, which puts them at higher risk for breast cancer, choose to tell their children about it before the children are old enough to understand the significance or deal with it, a new study found.
“Parents with the BRCA mutation are discussing their genetic test results with their offspring often many years before the offspring would need to do anything,” said study author Dr. Angela Bradbury, director of the Fox Chase Cancer Center’s Family Risk Assessment Program, in Philadelphia.
According to Bradbury, more than half of parents she surveyed told their children about genetic test results. Some parents reported that their children didn’t seem to understand the significance of the information, and some had initial negative reactions to the news.
“A lot of genetic information is being shared within families and there hasn’t been a lot of guidance from health-care professionals,” Bradbury said. “While this genetic risk may be shared accurately, there is risk of inaccurate sharing.”
In the study, Bradbury’s team interviewed 42 women who had the BRCA mutation. The researchers found that 55 percent of parents discussed the finding and the risk of breast cancer with at least one of their children who was under 25.
Also, most of the women didn’t avail themselves of the services of a doctor or genetic counselor in helping to tell their children, Bradbury’s group found.
Bradbury is concerned that sharing genetic information with young children can create anxiety. “The children could be overly concerned about their own risk at a time when there is nothing that they need to do,” she said.
But, she added, “it may be possible that sharing may be good for children in adapting to this information.”
The findings are published in the Aug. 20 issue of the Journal of Clinical Oncology.
The lack of definitive data on when — or if — to discuss genetic test results with children is a real problem, Bradbury said.
“As we move genetic testing forward for cancer or other illnesses, we have to consider the context of the whole family and focus our counseling to the whole family, and not just the person who comes in for testing,” Bradbury said. “We should learn more about how and when we should talk to children about this, so that we can promote healthy behaviors without causing too much anxiety for the offspring.”
Barbara Brenner, executive director of Breast Cancer Action, agreed that the psychological component of genetic testing needs more attention.
“This is the tip of a very scary iceberg,” Brenner said. “We don’t know the psychological consequences [of BRCA testing], not only to the person who has the test, but to her family members.”
Brenner thinks guidelines to help parents deal with this information are needed. So is help from doctors and genetic counselors in counseling family members, especially children, she added.
LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth), supported by the National Institutes of Health. This study will follow the girls prospectively in order to evaluate epidemiologic and epigenetic pathways of childhood exposures in relation to pubertal development, age at menarche, breast tissue characteristics, biomarkers of exposure, genomic DNA methylation, and the psychosocial impact of increased breast cancer susceptibility in 6-13 YO girls. http://legacygirlsstudy.org/
3. Bradbury AR, Patrick-Miller L, Egleston BL, Schwartz LA, Sands CB, Shorter R, Moore CW, Tuchman L, Rauch P, Malhotra S et al: Knowledge and perceptions of familial and genetic risks for breast cancer risk in adolescent girls. Breast cancer research and treatment 2012, 136(3):749-757.
4. Bradbury AR, Patrick-Miller L, Egleston BL, Olopade OI, Daly MB, Moore CW, Sands CB, Schmidheiser H, Kondamudi PK, Feigon M et al: When parents disclose BRCA1/2 test results: their communication and perceptions of offspring response. Cancer 2012, 118(13):3417-3425.
Nitric oxide (NO) is a lipophilic, highly diffusible and short-lived molecule that acts as a physiological messenger and has been known to regulate a variety of important physiological responses including vasodilation, respiration, cell migration, immune response and apoptosis. Jordi Muntané et al
NO is synthesized by the Nitric Oxide synthase (NOS) enzyme and the enzyme is encoded in three different forms in mammals: neuronal NOS (nNOS or NOS-1), inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3). The three isoforms, although similar in structure and catalytic function, differ in the way their activity and synthesis in controlled inside a cell. NOS-2, for example is induced in response to inflammatory stimuli, while NOS-1 and NOS-3 are constitutively expressed.
Regulation by Nitric oxide
NO is a versatile signaling molecule and the net effect of NO on gene regulation is variable and ranges from activation to inhibition of transcription.
The intracellular localization is relevant for the activity of NOS. Infact, NOSs are subject to specific targeting to subcellular compartments (plasma membrane, Golgi, cytosol, nucleus and mitochondria) and that this trafficking is crucial for NO production and specific post-translational modifications of target proteins.
Role of Nitric oxide in Cancer
One in four cases of cancer worldwide are a result of chronic inflammation. An inflammatory response causes high levels of activated macrophages. Macrophage activation, in turn, leads to the induction of iNOS gene that results in the generation of large amount of NO. The expression of iNOS induced by inflammatory stimuli coupled with the constitutive expression of nNOS and eNOS may contribute to increased cancer risk. NO can have varied roles in the tumor environment influencing DNA repair, cell cycle, and apoptosis. It can result in antagonistic actions including DNA damage and protection from cytotoxicity, inhibiting and stimulation cell proliferation, and being both anti-apoptotic and pro-apoptotic. Genotoxicity due to high levels of NO could be through direct modification of DNA (nitrosative deamination of nucleic acid bases, transition and/or transversion of nucleic acids, alkylation and DNA strand breakage) and inhibition of DNA repair enzymes (such as alkyltransferase and DNA ligase) through direct or indirect mechanisms. The Multiple actions of NO are probably the result of its chemical (post-translational modifications) and biological heterogeneity (cellular production, consumption and responses). Post-translational modifications of proteins by nitration, nitrosation, phosphorylation, acetylation or polyADP-ribosylation could lead to an increase in the cancer risk. This process can drive carcinogenesis by altering targets and pathways that are crucial for cancer progression much faster than would otherwise occur in healthy tissue.
NO can have several effects even within the tumor microenvironment where it could originate from several cell types including cancer cells, host cells, tumor endothelial cells. Tumor-derived NO could have several functional roles. It can affect cancer progression by augmenting cancer cell proliferation and invasiveness. Infact, it has been proposed that NO promotes tumor growth by regulating blood flow and maintaining the vasodilated tumor microenvironment.NO can stimulate angiogenesis and can also promote metastasis by increasing vascular permeability and upregulating matrix metalloproteinases (MMPs). MMPs have been associated with several functions including cell proliferation, migration, adhesion, differentiation, angiogenesis and so on. Recently, it was reported that metastatic tumor-released NO might impair the immune system, which enables them to escape the immunosurveillance mechanism of cells. Molecular regulation of tumour angiogenesis by nitric oxide.
S-nitrosylation and Cancer
The most prominent and recognized NO reaction with thiols groups of cysteineresidues is called S-nitrosylation or S-nitrosation, which leads to the formation of more stable nitrosothiols. High concentrations of intracellular NO can result in high concentrations of S-nitrosylated proteins and dysregulated S-nitrosylation has been implicated in cancer. Oxidative and nitrosative stress is sensed and closely associated with transcriptional regulation of multiple target genes.
Following are a few proteins that are modified via NO and modification of these proteins, in turn, has been known to play direct or indirect roles in cancer.
NO mediated aberrant proteins in Cancer
Bcl2
Bcl-2 is an important anti-apoptotic protein. It works by inhibiting mitochondrial Cytochrome C that is released in response to apoptotic stimuli. In a variety of tumors, Bcl-2 has been shown to be upregulated, and it has additionally been implicated with cancer chemo-resistance through dysregulation of apoptosis. NO exposure causes S-nitrosylation at the two cysteine residues – Cys158 and Cys229 that prevents ubiquitin-proteasomal pathway mediated degradation of the protein. Once prevented from degradation, the protein attenuates its anti-apoptotic effects in cancer progression. The S-nitrosylation based modification of Bcl-2 has been observed to be relevant in drug treatment studies (for eg. Cisplatin). Thus, the impairment of S-nitrosylated Bcl-2 proteins might serve as an effective therapeutic target to decrease cancer-drug resistance.
p53
p53 has been well documented as a tumor suppressor protein and acts as a major player in response to DNA damage and other genomic alterations within the cell. The activation of p53 can lead to cell cycle arrest and DNA repair, however, in case of irrepairable DNA damage, p53 can lead to apoptosis. Nuclear p53 accumulation has been related to NO-mediated anti-tumoral properties. High concentration of NO has been found to cause conformational changes in p53 resulting in biological dysfunction.. In RAW264.7, a murine macrophage cell line, NO donors induce p53 accumulation and apoptosis through JNK-1/2.
HIF-1a
Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor that is predominantly active under hypoxic conditions because the HIF-1a subunit is rapidly degraded in normoxic conditions by proteasomal degradation. It regulates the transciption of several genes including those involved in angiogenesis, cell cycle, cell metabolism, and apoptosis. Hypoxic conditions within the tumor can lead to overexpression of HIF-1a. Similar to hypoxia-mediated stress, nitrosative stress can stabilize HIF-1a. NO derivatives have also been shown to participate in hypoxia signaling. Resistance to radiotherapy has been traced back to NO-mediated HIF-1a in solid tumors in some cases.
PTEN
Phosphatase and tensin homolog deleted on chromosome ten (PTEN), is again a tumor suppressor protein. It is a phosphatase and has been implicated in many human cancers. PTEN is a crucial negative regulator of PI3K/Akt signaling pathway. Over-activation of PI3K/Akt mediated signaling pathway is known to play a major role in tumorigenesis and angiogenesis. S-nitrosylation of PTEN, that could be a result of NO stress, inhibits PTEN. Inhibition of PTEN phosphatase activity, in turn, leads to promotion of angiogenesis.
C-Src
C-src belongs to the Src family of protein tyrosine kinases and has been implicated in the promotion of cancer cell invasion and metastasis. It was demonstrated that S-nitrosylation of c-Src at cysteine 498 enhanced its kinase activity, thus, resulting in the enhancement of cancer cell invasion and metastasis.
Jaiswal M, et al. Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol. 2001 Sep;281(3):G626-34. http://www.ncbi.nlm.nih.gov/pubmed/11518674
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