Modified Tetracycline May Help Prevent Cancer Recurrence

Building on previous research, University of Iowa scientists have discovered that a drug already being tested as an anti-cancer agent could potentially be used in conjunction with other cancer therapies to reduce the likelihood of cancer recurrence by targeting the tumor microenvironment.

UI scientists in the laboratory of Mary Hendrix, Ph.D., the Kate Daum Research Professor and head of anatomy and cell biology, previously discovered that aggressive tumor cells can modify their local environment and can induce less aggressive tumor cells encountering this modified environment to become more aggressive. This suggested that in addition to treating tumor cells, changes to the surrounding tissue caused by an aggressive tumor should also be treated to reduce the likelihood of recurrence.

In a study, which appears in the November issue of the journal Molecular Cancer Therapeutics, the UI researchers demonstrate that a chemically modified tetracycline called COL-3 is able to prevent the altered cellular environment from inducing less aggressive cancer cells to behave more aggressively.

In their earlier studies, the UI team discovered that aggressive melanoma cells produce a molecule called laminin 5 gamma 2 chain and deposit it into their local environment. Enzymes known as matrix metalloproteinases (MMPs) breakdown the laminin molecules and the resulting fragments act as signaling molecules. Less aggressive melanoma cells respond to these signaling fragments and become more aggressive. The fragments of laminin laid down in the environment by the aggressive tumor cells persist in the environment long after the aggressive cells have gone and affect the less aggressive tumor cells that move into the altered environment.

"Standard cancer treatments aim to remove or destroy aggressive cancer cells," said Richard Seftor, Ph.D., lead author of the study and a UI research scientist in Hendrix's lab. "However, we also need to be concerned by the environment left behind by the aggressive cells. We may also need to block these environmental cues."

Chemically modified tetracyclines such as COL-3, are a group of drugs derived from the antibiotic tetracycline that, due to the chemical modification, no longer act as antibiotics. These drugs are powerful inhibitors of MMP enzymes. The research team found that COL-3, blocks the breakdown of laminin to the signaling fragment. It also prevents less aggressive cells from making the laminin molecule in the first place. Additionally, the drug inhibits a process known as vasculogenic mimicry in aggressive melanoma cells. This process is a hallmark of aggressive cancers.

The study results suggest that COL-3 and other drugs like it could be useful in blocking molecular cues residing in tissue surrounding a tumor, and they could be used in conjunction with therapies aimed at destroying aggressive tumor cells.

The study also found that COL-3 was able to reduce the expression of genes associated with vasculogenic mimicry. These results raise the possibility that this drug may be able to suppress this process in aggressive tumor cells, which might reduce the aggressive nature of certain cancer cells.

"These studies provide clear evidence of a successful strategic approach in modifying the tumor microenvironment that may have profound implications in the long term management of cancer," said Hendrix, who also is deputy director of the Holden Comprehensive Cancer Center at UI.

In addition to Hendrix and Seftor, UI researchers involved in the study included Elisabeth Seftor, senior research specialist, and Dawn Kirschmann, Ph.D., assistant research scientist. The study was funded by grants from the National Cancer Institute.

The Holden Comprehensive Cancer Center is Iowa's only National Cancer Institute-designated comprehensive cancer center. NCI-designated comprehensive cancer centers are recognized as the leaders in developing new approaches to cancer prevention and cancer care, conducting leading edge research and educating the public about cancer. Visit the center online at http://www.uihealthcare.com/depts/cancercenter.