Press Release for Nature Medicine:
December 2002

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TUMOR VACCINE TARGETS NEW BLOOD VESSELS

Researchers have engineered an oral vaccine that counteracts cancer in mice by choking the blood supply to tumors. The DNA-based vaccine, developed by Ralph Reisfeld at the Scripps Research Institute in La Jolla, California, and colleagues is described in the December issue of Nature Medicine.

Tumors need a blood supply to survive once they get more than a couple millimeters in size. This fact has propelled a great deal of interest in the design of treatments that prevent infusion of blood vessels into tumors. Such an approach also has the advantage of being potentially effective against a wide range of tumor types. In this study, the investigators targeted a protein produced in new blood vessels, called vascular endothelial growth factor receptor 2 or FLK-1. To target FLK-1, the authors engineered DNA encoding the FLK-1 protein into a non-infectious strain of the bacterium S. typhimurium, and administered this live vaccine into mice. Animals treated with the FLK-1 vaccine showed reduced vessel growth and were able to fend off tumors in models of three different types of cancer. The vaccine induced no ill effects by several measures, including fertility. But the mice did have a slight delay in wound healing, consistent with the involvement of new vessel growth in this process.

Many current approaches to shutting off tumor blood supply rely on specific inhibitors that often require constant administration at relatively high doses. The FLK-1 vaccine, in contrast, protected mice even 10 months after their last dose. Moreover, DNA vaccines based on other proteins are already being tested in clinical trials. Whether a FLK-1 vaccine could work in humans remains to be seen, but could be particularly effective in combination with treatments that promote cell death or affect other aspects of tumorigenesis. Such a vaccine has the greatest potential in preventing or delaying the onset of recurrent malignancies, especially in cases of minimal residual disease after other treatments.

UNCOVERING WHY SICKLE-CELL ANEMIA IS PAINFUL

Sickle cell anemia is a chronic, painful disease in which the red blood cells, normally disc-shaped, become crescent shaped due to the inheritance of an abnormal type of hemoglobin called hemoglobin S. As a result of inheriting this mutation, the red blood cells function abnormally and break down, releasing large amounts of hemoglobin directly into the blood stream. The link between freely circulating hemoglobin and the pain associated with sickle cell anemia is now clear from a recent report in the 11 November online version of Nature Medicine.

Mark Gladwin and colleagues at the National Institutes of Health have discovered that the chronic release of hemoglobin into the blood stream overwhelms the systems in place to remove it. This excess cell-free hemoglobin reacts with the gas nitric oxide 1,000 times more rapidly than it would if the hemoglobin was in a red blood cell. Nitric oxide has an important role in regulating blood flow responses, and when unavailable (due to excess removal by the freely circulating hemoglobin) can cause vessels to constrict unnecessarily.

Using nitric oxide inhalation therapy and a set of highly sensitive assays, the authors illustrate that nitric oxide scavenging by the cell-free hemoglobin plays a major role in sickle cell pain crisis. They also show that the increase in cell-free hemoglobin results in an increase a soluble vascular cell adhesion molecule, which in turn increases the breakdown of more red blood cells, thus initiating a vicious cycle. Taken together these observations illustrate the heretofore-unknown role of cell-free hemoglobin in the sickle cell pain crisis and dispel a common misconception that cell-free hemoglobin has no role in regulating the cardiovascular system. In addition to the impact that this work will have on sickle cell research, it has the potential to further our understanding of the reasons behind a number of other diseases in which red blood cell breakdown is an underlying feature.

STREP THROAT OR TOXIC SHOCK? GENES MATTER IN RESPONSE TO STREP A

Group A streptococci have earned the popular name 'flesh-eating bacteria' for their role in an often fatal infection of soft tissues, necrotizing fasciitis. But the same type of bacteria can also cause only mild illness, such as strep throat. Why do some people walk away unscathed from Strep A infection while others succumb to horrible disease? In the December issue of Nature Medicine, Malak Kotb at the Veterans Affairs Medical Center in Memphis and colleagues begin to answer the question. They had an inkling that a particular set of genes might have something to do with susceptibility to infection. These genes, called HLA-II genes, encode proteins on the cell surface of immune cells. It's known that these proteins can bind to certain toxins secreted by Strep A.

The authors examined the HLA-II genes from 279 individuals afflicted with severe infection - either necrotizing fasciitis or streptococcal toxic shock syndrome - and compared them to the HLA-II genes of 256 healthy individuals. Certain HLA-II gene variants were present more often in individuals with severe infection, while other variants were present more frequently in healthy individuals. The authors also found that immune cells with either predisposing or protective HLA-II gene variants differed in their response to bacterial toxins. There are numerous previous reports of association between HLA variants and diseases such as multiple sclerosis, arthritis, and type 1 diabetes. This study, however, delves into the mechanism, and also presents an opportunity for further study in mice - mice can be engineered to express human HLA genes, and are also susceptible to infection by group A streptococci.