Targeting Enablers to Prevent Relapse

Many cells in a tumor are not actually cancer cells. A mix of extracellular matrix, endothelial cells and microvasculature collectively known as the stroma can make up 90 percent of a tumor. A study by scientists at the University of Cambridge reported that taking out one type of stromal cells can unmask an immune response to tumors. The reason appears to be that tumor fibroblasts express fibroblast activating protein, or FAP, which is present in much lower levels in noncancerous fibroblasts. In animal studies, killing FAP-expressing cells allowed the mice to mount an immune response to lung cancer cells. The authors of a related Perspective noted that because targeting FAP should help the immune system get a handle on very small tumors, the approach "may help eliminate clinically undetectable cancer cells that have already metastasized before excision of the primary tumor, a common cause of relapse." The work was published in the Nov. 5, 2010, issue of Science.

Impeding Progress for the Good of Humanity

HIV infection is nearly 100 percent fatal – 99.67 percent, to be exact. About 1 in 300 individuals is an "elite controller" who can stave off AIDS after HIV infection without the use of medications. Scientists have been mining the genome of such elite controllers, trying to find secrets of their success that could be translated into therapies for less resilient individuals. In the Nov. 5, 2010, issue of Science, an international consortium of researchers reported that they have identified more than 300 variants distinguishing elite controllers from progressers. All 300 pointed to the region of chromosome 6 that contains HLA genes, which are major immune system genes. More detailed studies identified six amino acids, five of which lined the groove where the HLA peptide binds to the virus. The findings suggested that the exact binding of virus to HLA affects the T-cell response and is critical for controlling the virus.

Kidney Risk Gene Branches Out

Another genomics study, by scientists from Emory University, has identified a risk gene for autism, schizophrenia and other neurodevelopmental disorders that is already known to some of their clinician colleagues. The same genetic area, a region on the short/long arm of chromosome 17, contains a risk gene for renal cysts and diabetes syndrome. People with the deletion still had only about a 1 in 1,000 chance of having autism or schizophrenia: 24 patients out of more than 23,000 that the scientists tested. Still, with the deletion not showing up in even one of more than 50,000 control samples, that means someone with the deletion was more than 13 times as likely to be affected as controls. The deleted region contains 15 genes, but in their work, the scientists zeroed in on the protein HNF1B, which has been associated with renal cysts and diabetes syndrome previously. The research was published in the Nov. 4, 2010, issue of the American Journal of Human Genetics.

New Approaches to Gynecologic Cancers

Researchers at the University of California, Los Angeles have reported that a biomarker that can help diagnose ovarian cancer might also prove useful therapeutically. Apolipoprotein A-I (apoA-I), the major component of HDL "good" cholesterol, appears to be protective against development of the disease. Transgenics expressing high levels of apoA-1 were protected against the development of ovarian cancer, and had an extended life span if they did develop the disease. The study was published Nov. 1,2010, in the Proceedings of the National Academy of Sciences. An 18-amino acid mimetic was also effective and would be much easier to administer than the full-length apoA-I, which is more than 10 times as long. Mice that were given the shorter mimetic by injection had about 60 percent less cancer than controls. The peptide was also protective when administered orally. The authors hope to complete an early stage clinical trial with the peptide within two years. A separate study, published in the November 2010 edition of PloS One by scientists from St. Michael's Hospital at the University of Toronto, showed that tranilast, which is an approved asthma and eczema drug in parts of Asia, but not in North America, killed breast cancer cells. In the U.S., tranilast is in clinical development for the treatment of arthritis and gout by San Mateo, Calif.-based Nuon Therapeutics Inc.

Biomarker for Ectopic Pregnancies

Researchers from the University of Edinburgh reported this week that they may have identified a diagnostic biomarker for ectopic pregnancy. An ectopic pregnancy – a rogue embryo implanting itself outside the uterus, most often in the fallopian tubes – is a leading cause of pregnancy-related first trimester deaths. Such deaths are rare in the developed world, but much more common in developing countries, most often because the ectopic pregnancy is not diagnosed until it is too late. The University of Edinburgh researchers have identified a biomarker that could aid such diagnosis: placental growth factor, a key molecule in the formation of blood vessels. Placental growth factor was lower in serum samples of women with ectopic pregnancies than in women with regular, intrauterine pregnancies. The authors hope their findings, which were accepted for publication in the January 2011 Journal of Clinical Endocrinology & Metabolism and are now available online, can "have a significant impact on reducing emotional distress and unnecessary deaths."

Killing Two Birds with One Receptor Antagonist

Especially for alcoholics, alcohol and nicotine are two great tastes that taste great together: 60 percent to 80 percent of heavy drinkers are also smokers, and even for social drinkers, a smoking relapse can easily be set off by a night at the bar. Researchers at the University of California, San Francisco, and Pfizer Inc. now describe two compounds – CP-601932 and PF-4575180 – that may be an antidote to both smoking and drinking. The compounds target a subtype of nicotinic acetylcholine receptor that has been implicated in both smoking and heavy drinking by genetic studies. Blocking the receptors reduced alcohol drinking in an animal study; importantly, it did not reduce the drinking of sugary beverages, which suggests it does not act via general effects on the reward system. The authors published their findings in the Nov. 3, 2010, issue of Neuropsychopharmacology.

Getting the Immune System Worked Up

The immune system, whatever else one might say about it, does not suffer from attention deficit hyperactivity disorder. Quite the contrary. Faced with a sheer endless menu of protein parts it could respond to on foreign invaders, it will usually pick a very few to respond to – a phenomenon known as immunodominance. Researchers from Johns Hopkins University have identified a simple and rapid way to identify the epitopes that get the immune system going. Their cell-free antigen processing system, which basically consists of selected Major Histocompatibility Class II proteins to bind to antigens and cathepsins to break large antigens up into the smaller epitopes that are actually bound, is able to identify immunodominant epitopes – which are often the most promising targets for vaccines and drugs – within three weeks. The authors said their system provides new basic insight into antigen processing and can "reduce cost and increase effectiveness in determining immunodominant epitopes of antigens from infectious agents, autoimmune antigens and cancer." The findings were published in the Oct. 31, 2010, online edition of Nature Medicine.

Liver Problems, Insulin Resistance

Scientists from Kanazawa University Graduate School of Medical Science in Japan reported that the liver may be a bigger player in insulin resistance than has been suspected. In analogy with adipokines – cytokines secreted by fat tissue, some of whom contribute to insulin resistance – the scientists have described a class of secretory factors they termed hepatokines, proteins secreted by the liver that contribute to insulin resistance and Type II diabetes. In the November 2010 issue of Cell Metabolism, they described in more detail that one such hepatokine, selenoprotein P (SeP), is present at higher levels in liver cells and the blood of Type II diabetics. Administering SeP to normal mice increased insulin resistance and blood sugar levels. Blocked SeP in the livers of diabetic and obese mice had the opposite effect on insulin sensitivity as well as blood sugar levels. The findings suggested SeP could be a target for fighting insulin resistance and Type II diabetes.

Adipokines Aren't All Bad, Though . . .

Adipokines themselves, meanwhile, were also in the science news recently. A team from Sanford-Burnham Medical Research Institute described how adiponectin, a major adipokine, exerts cardioprotective effects. Somewhat counter intuitively, adiponectin protects against stress-induced heart disease. The reason is that it is secreted by healthy fat. In a study published in the Nov. 1, 2010, issue of the Journal of Clinical Investigation, the researchers reported that adiponectin protects the heart by binding to T-cadherin, which sets off a signaling cascade that activates the AMP kinase, which regulates energy use in the cell.

. . . And Neither is Helicobacter Pylori

As a causative agent of both stomach ulcers and gastric cancers, and possibly pancreatic cancer as well, Helicobacter pylori infection is something most people would just as soon do without. But research by scientists from the University of Michigan suggested that H. pylori infection may have upsides as well. In their work, published in the Oct. 25, 2010, online edition issue of Inflammatory Bowel Diseases, researchers showed that infection with H. pylori protected mice from developing inflammatory bowel disease in response to salmonella infection a month later. The study may explain why H. pylori infection is so common, with almost half of the global population being infected. Though many people think of salmonella as a modern scourge, on the rise due to factory farming, it was more frequent still before the advent of clean water and food refrigeration and safety systems.

– Anette Breindl, Science Editor