May 4, 2007

Moses reveals ‘Jekyll and Hyde’ of cancer

Featured Image

Vanderbilt’s Harold Moses, M.D., delivers last week’s Discovery Lecture. (photo by Susan Urmy)

Moses reveals ‘Jekyll and Hyde’ of cancer

When Harold Moses, M.D., and his colleagues at the Mayo Clinic first described and purified a “transforming growth factor” in the early 1980s, they had no idea what they were about to unleash.

Today, TGF-beta “is in every part of cancer biology,” said Suresh Mohla, Ph.D., chief of the Tumor Biology and Metastasis Branch at the National Cancer Institute.

Moses, director emeritus of the Vanderbilt-Ingram Cancer Center, described his research April 27 during his Vanderbilt Discovery Lecture.

In introducing the lecture, Mohla said Moses, his longtime friend and colleague, has been “at the leading edge of science all his life.”

Yet “he remains extremely modest, gracious and one of the most unpretentious mentors,” Mohla continued. “At meetings, he's known for giving more attention to young scientists.”

That certainly was the case last week, when Moses took time to credit the research contributions of his younger Vanderbilt colleagues, including Neil Bhowmick, Ph.D., Hideaki Ijichi, M.D., Ph.D., and Yi Lang, M.D.

The TGF-beta field is still young, said Moses, who joined the Vanderbilt faculty in 1985, but today there are glimmers of hope that it will substantially impact the diagnosis and treatment of cancer.

Once considered to be primarily an inhibitor of cell growth, and thus a tumor suppressor, TGF-beta and its “superfamily” are now known to encompass dozens of ligands, receptors and signaling molecules that under some circumstances can stimulate cell growth and aid metastasis – the spread of cancer cells to other parts of the body.

“It's fair to conclude that the TGF-beta inhibitory pathway is impaired in a majority of human cancers,” said Moses, the Hortense B. Ingram Professor of Molecular Oncology.

TGF-beta is also involved in the tumor's ability to grow new blood vessels (angiogenesis) and to avoid detection and attack by the body's immune system (immunosuppression). Thus it can be considered “the molecular Jekyll and Hyde of cancer,” as the title of a recent review by Moses and Vanderbilt graduate student Brian Bierie in Nature Reviews Cancer suggested.

Efforts are now under way to develop therapeutic agents that can block TGF-beta's immunosuppressant activity at various points along its signaling cascade.

For example, Moses and his colleagues including Carlos Arteaga, M.D., reported last month in the Journal of Clinical Investigation that inhibition of TGF-beta with neutralizing antibodies prevented radiation-induced acceleration of metastatic breast cancer progression in mice.

The researchers concluded that circulating TGF-beta “may represent a marker of tumors destined to progress rapidly after therapy,” and that when this biomarker is detected, patients may benefit from a TGF-beta inhibitor given with their primary therapy.