Hyaluronidase as a Therapeutic Target in Cancer: A Matter of Too Little or Too Much

Abstract

Snake bites have something in common with cancer. So do spider bites, and stings from scorpions and bees. Now, research done at the University of Miami Sylvester Comprehensive Cancer Center defines how a naturally-occurring enzyme which is present in most venom plays a crucial role in the viability and spread of many tumors - and may yield two different ways to fight the disease.

The enzyme is hyaluronidase, and it breaks down hyaluronic acid (HA), a large, complex sugar polymer present in human tissues. HA is also present in tumors, and when hyaluronidase produced by tumor cells breaks down HA the small fragments help the cancer to spread in the body.

Vinata Lokeshwar, Ph.D., associate professor of Urology and Cell Biology and Anatomy at the University of Miami Leonard M. Miller School of Medicine, previously identified a way to use both HA and hyaluronidase as prognostic tools to predict whether prostate cancer will spread and as screening tools to help diagnose bladder cancer. Now, she is investigating two ways to use hyaluronidase as a potential cancer therapy.

For 15 years there have been two schools of thought on this enzyme. Researchers in California showed that treating tumors with hyaluronidase could inhibit tumor growth. In fact, as early as 1992 studies found that adding the enzyme to chemotherapy improved tumor response in breast cancer. But beginning in 1996, Dr. Lokeshwar showed that tumor cells produce hyaluronidase. In fact, within a certain limit the higher the hyaluronidase the more aggressive the tumor. So, among researchers, there was a spirited debate over whether hyaluronidase aided or impeded tumor growth.It turns out that both sides were right.

To be technical, Dr. Lokeshwar's newest work shows that when cancer cells have between 42- and 80-milliunits of hyaluronidase activity, they actively grow and spread. Researchers tested the presence and activity of the enzyme using a high-speed chemical assay and cell and molecular assays to monitor how it affected the growth, spread or death of cells. They also measured the growth of new blood microvessels, which feed growing tumors.

The results in the lab were dramatic. Blocking hyaluronidase in bladder tumors cut tumor growth by nine- to 17-fold. Adding much more of it completely blocked the formation of tumors. "The moment we exceeded that normal threshold there was no tumor, absolutely none," said Lokeshwar. "The tumor just went away."

Block the enzyme and there isn't enough for cancer to advance - add too much and it dies. "Tumor cells are very smart," said Lokeshwar. "They produce just the right amount to take advantage of its role in angiogenesis, its role in cell growth and its role in invasion. But you can fool them by externally supplying very large amounts of hyaluronidase and then you can really control that tumor."

There are six different types of hyaluronidase in humans, but they all play the same role - breaking down hyaluronic acid. HA plays a key role in normal tissues, including lubricating the skin, eyes and connective tissue. But HA also helps regulate how cells reproduce and move and is critical to helping tumors grow new blood vessels. Since HA appears at higher-than-normal levels in cancer cells it can help tumors grow and spread - if it has just the right amount of hyaluronidase to break down the HA.

"Hyaluronidase is both a tumor promoter and a suppressor depending on the level," said Lokeshwar. "Now you have a two-edged sword. You can either use a hyaluronidase inhibitor or give large amounts of the enzyme to control local tumor growth and its spread." The results of this latest study will be published in the journal Cancer Research on September 1 in an article co-authored by Dr. Lokeshwar, her husband Balakrishna L. Lokeshwar, Ph.D., an Associate Professor of Urology, and Wolfgang Cerwinka, M.D., a resident in Urology.

The enzyme also plays a crucial role in the spread of bacterial infections and toxins - hence its presence in venom. A specific hyaluronidase, HYAL1, is the most likely to appear in high levels in breast, colon, head and neck, prostate, and bladder cancer. Dr. Lokeshwar has exploited that knowledge by developing and patenting a highly accurate, non-invasive screening test for bladder cancer, and a promising prostate cancer test, which may predict metastasis earlier than any other method. The bladder cancer test, HA-HAase, not only detects tumor recurrence earlier than visual inspection with cytoscopy, it can identify whether the tumor is low or high grade. Since bladder cancer recurs in more than half of all patients after treatment, the value of a reliable, non-invasive test is clear.

Lokwshwar's work with HYAL1 as a tool to predict cancer has earned her funding from both the Department of Defense and National Institutes of Health. A key collaborator in developing tests for bladder and prostate cancer has been Mark S. Soloway, M.D., chairman of the Department of Urology at UM. Dr. Bal Lokeshwar also helped in settling the debate whether hyaluronidase promotes or thwarts cancer and he has also been supported by both the DOD and NIH for his own work in the control of prostate cancer metastasis. Together, the Lokeshwars are one of the few husband-wife teams to have secured independent funding from the Pentagon and the NIH.

Vinata Lokeshwar also chaired the committee on tumor markers at the International Consultation on Bladder Cancer, organized last year by the World Health Organization and the Société Internationale d'Urologie. The Consultation, led by Soloway, will publish a 700-page text on bladder cancer later this year.

UM/Sylvester was founded in 1992 to provide comprehensive cancer services and today serves as the hub for cancer-related research, diagnosis, and treatment at the University of Miami Leonard M. Miller School of Medicine. UM/Sylvester handles more than 1,300 inpatient admissions annually, performs 2,900 surgical procedures, and treats 3,000 new cancer patients. All UM/Sylvester physicians are on the faculty of the Miller School of Medicine, South Florida's only academic medical center. In addition, UM/Sylvester physicians and scientists are engaged in more than 150 clinical trials and receive more than $31 million annually in research grants. UM/Sylvester at Deerfield Beach recently opened to better meet the needs of residents of Broward and Palm Beach counties. This 10,000-square-foot facility at I-95 and S.W. 10th Street offers appointments with physicians from six cancer specialties, complementary therapies from the Courtelis Center, and education and outreach events. http://www.sylvester.org.

Contact: Kelly Kaufhold; Office of Communications; University of Miami Leonard M. Miller School of Medicine; 305.243.5184; [email protected]