Research Briefs: May 2014

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Click on a research brief to learn more about the leading-edge research being conducted at Jefferson:

 


Can Vitamin A Turn Back the Clock on Breast Cancer?

A derivative of vitamin A, known as retinoic acid, found abundantly in sweet potato and carrots, helps turn precancer cells back to normal healthy breast cells, according to research published this month in the International Journal of Oncology. The research could help explain why some clinical studies have been unable to see a benefit of vitamin A on cancer: the vitamin doesn’t appear to change the course of full-blown cancer, only precancerous cells, and only works at a very narrow dose.

Using a model of breast cancer progression composed of four types of cells, each one representing a different stage of breast cancer: normal, precancerous, cancerous and a fully aggressive model, Sandra V. Fernandez, PhD, assistant research professor of Medical Oncology at Jefferson, and colleagues, exposed the cells to different concentrations of retinoic acid – one of the chemicals that the body converts vitamin A into. Not only did the precancerous cells begin to look more like normal cells in terms of their shape, they also changed their genetic signature (based on 443 genes) back to that of normal cells.

Interestingly, the cells that were considered fully cancerous did not respond at all to retinoic acid, suggesting that there may be a small window of opportunity for retinoic acid to be helpful in preventing cancer progression. In addition, the researchers showed that only one concentration of retinoic acid (about one micro Molar) produced the anticancer effects. Lower concentrations gave no change, and higher concentrations produced a smaller effect. “It will be interesting to see if these results can be applied to patients.”


Radiation Therapy and Cancer Vaccines: Timing Is Everything

Radiation therapy fights cancer in more ways than one. Not only does it force cancer cells to self-destruct, but several studies demonstrate that it also activates the immune system to attack tumor cells. This activation can be used to boost current immunotherapies, such as antitumor vaccines, to produce better clinical results. What’s less clear, however, is exactly how to combine the two therapies to get the best bang for the therapeutic buck.

To address this question, Jefferson researchers tested an experimental colon cancer vaccine in combination with radiation therapy in mice with colorectal cancer. In research published online in the International Journal of Radiation Oncology, they showed that the vaccine was most effective when tumors were irradiated first and then vaccinated a week later.

“Prior to these experiments, we didn’t appreciate the impact that sequencing of these treatments had on their combined ability to generate immune and clinical responses,” says Thomas Jefferson University radiation oncologist Matthew Witek MD, first author of the study. “Remarkably, immune activation and tumor regression only occurred when radiation was given prior to vaccination.”

When mice received either treatment alone, the researchers noticed only a modest reduction in tumor size. However, when radiation was given first, the investigators saw a six-fold increase in cancer-fighting immune cells, and impressively, complete remission of the majority of tumors.

“In a patient population that will undergo radiation therapy as standard treatment, these results provide a roadmap to amplifying the effects of immunotherapies like the one we’re developing for colon cancer,” says lead researcher Adam Snook, PhD, an instructor in the Department of Pharmacology and Experimental Therapeutics.


Why Alcoholism Saps Muscle Strength

Muscle weakness is a common symptom of both longtime alcoholics and patients with mitochondrial disease. Now researchers have found a common link: mitochondria that are unable to self-repair. The results were published online in The Journal of Cell Biology. The link to self-repair provides researchers both a new way to diagnose mitochondrial disease and a new drug target.

Mitochondria – organelles that have been called powerhouses for energy needed by muscle, brain and every other cell in the body – repair their broken components by fusing with other mitochondria and exchanging their contents. Damaged parts are segregated for recycling and replaced with properly functioning proteins donated from healthy mitochondria. However, when these powerhouses are damaged, muscle cells don’t have enough fuel to pump powerfully.

The research team, led by Gyorgy Hajnoczky, MD, PhD, director of the Jefferson MitoCare Center and professor in the Department of Pathology, Anatomy and Cell Biology, showed that the gene for the mitochondrial fusion protein, called mitofusin (Mfn1), was most important in helping repair skeletal muscle cells.

When the researchers fed rats a regular alcohol diet, they saw muscle cells produce about 50 percent less Mfn1, while other fusion proteins were unchanged, greatly decreasing mitochondrial fusion. When Mfn1 was restored, so was the mitochondrial fusion. They also saw that this decrease was linked to muscle fatigue in rats.

“That alcohol can have a specific effect on this one gene involved in mitochondrial fusion suggests that other environmental factors may also specifically alter mitochondrial fusion and repair,” says Dr. Hajnoczky.

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