New animal model offers opportunity to develop therapies for lymphedema

Stanley Rockson

For millions of cancer survivors in the United States, emerging from surgery cancer-free is the ultimate victory. But many patients who clear the hurdle of cancer trauma will subsequently face a lifetime of swelling and discomfort, caused by an untreatable buildup of fluid in their tissues.

A team at the School of Medicine has created an animal model for this complex condition, called lymphedema, taking the first steps toward understanding its behavior. Their results, published in the July 17 issue of Public Library of Science-Medicine, indicate lymphedema is characterized not just by the presence of swelling, but by a profound, accompanying inflammation. This finding suggests drug therapies could one day be used to treat this disease.

"Ten million people in the United States have lymphedema. It's heartbreaking that it goes unacknowledged or unrecognized because doctors have no treatment to offer," said Stanley Rockson, MD, associate professor of medicine (cardiovascular) and the study's senior author. "This study opens the door to the likelihood of effective therapies."

Rockson said between 15 and 30 percent of breast cancer survivors develop lymphedema from surgery-induced damage to the lymphatic system—a network of tissues and cells that make and store cells to fight infection. When surgery disrupts this circulatory system, protein-rich fluid collects in the tissue of the affected limb. This stagnant liquid bloats the tissue and impairs limb mobility, creating a cesspool for infection.

Treatments for lymphedema involve bandaging the affected area or wearing tight-fitting garments to compress the swelling. Massaging can also help improve lymphatic flow. But such measures are temporary and provide little relief. "It's like the iron lung for polio—it works, but it's certainly no way to live," Rockson said.

In this study, Rockson and his co-authors generated a mouse model to simulate human-acquired lymphedema. The model was tested using microscopic imaging and molecular-level techniques to find a molecular fingerprint or signature of the disease. Mouse tails were used for the model because of their rich lymphatic network—a simple substitute for the arm, Rockson said.

The researchers were able to trace lymphatic cell flow by injecting luciferase, the enzyme that gives fireflies their glow, into the mouse tails. Using a dynamic imaging technique, the scientists observed cell traffic slowing to a crawl in mice with lymphedema. At the molecular level, the researchers used a microarray chip to determine which of the mouse genes were active.

"Much to our delight, only 600 to 700 of the genes had changed," Rockson said, corresponding to about 1 percent of the 55,000 genes in a mouse. "This will allow us to determine whether we can treat lymphedema with a drug or compound that will revert the patient to normal behavior."

"From a patient perspective, it's exciting to see that we are moving beyond bandages and massage therapy," said Wendy Chaite, president and founder of the Lymphatic Research Foundation, a nonprofit organization based in East Hills, N.Y. "This study is a springboard for a lot of future investigations."

Rockson said the next step is developing viable therapies for humans. His team has targeted six classes of drugs for study, one of which has already been tested in mice.

"Within the next 12 to 24 months we could be at the stage of testing in human populations," Rockson said.

Other Stanford authors include undergraduates Andrew An, Smita Joshi and Ned Rockson; postdoctoral scholar Andreas Beilhack, MD; research associate Jennifer Han, MD; cardiology fellow Raymond Tabibiazar, MD; Roger Wagner, MD, PhD, instructor of cardiovascular medicine, and Soheil Dadras, MD, assistant professor of medicine (pathology). Medical students Lauren Cheung of the University of California-Irvine and Jeffrey Swanson of the University of Pennsylvania were also authors. The study was funded by the Susan G. Komen Breast Cancer Foundation and the Western States Affiliate of the American Heart Association.

Aditi Risbud is a science-writing intern in the Office of Communication & Public Affairs for the School of Medicine.