Research Reveals Growth Factor's Role in Cancer Treatment

Radiotherapy-the use of x-rays and other ionizing radiation to treat cancer-involves a deadly compromise. Bombarding a tumor with cell-killing beams inevitably affects healthy tissue in the tumor's vicinity.

Mary Helen Barcellos-Hoff, a biologist in Berkeley Lab's Life Sciences Division, has taken an important step toward reducing complications in cancer patients after radiotherapy. She has shown that ionizing radiation, such as that used in cancer treatment, activates transforming growth factor-beta (TGF-), a cell-signal molecule known for its role in scarring.

Her study provides the strongest evidence yet that the molecule is the cause of radiogenic fibrosis, a hardening of tissue that is common following radiotherapy. "We think TGF- sows the seeds that determine whether or not irradiated tissue undergoes permanent dysfunction," Barcellos-Hoff says.

More importantly, the research suggests a new way of improving radiotherapy. Blocking TGF- activation could decrease side effects, and provide the basis for more aggressive radiotherapy and better tumor control.

Typically, one-fifth of cancer patients receiving radiotherapy suffer some degree of fibrosis in the tissue surrounding a tumor. Fibrosis is the result of an overproduction of extracellular matrix (ECM), the fibrous network of molecules between cells that determines structure and regulates function of tissues. In fibrosis, tissues gradually lose their elasticity as ECM fills up the space between cells.

One of TGF-'s best understood roles in the body is coordinating the production of ECM to heal wounds. Fibrosis in some ways is like wound healing gone haywire, with TGF- converting healthy tissue to tough tissue similar to that seen in scars.

However, finding how TGF- might trigger fibrosis has been a challenge. The stumbling block has been the two-faced nature of the molecule. Most growth factors and other cell signals, such as hormones, affect surrounding tissue immediately after release. In contrast, TGF- enters the surrounding tissue in a latent form, bound to a larger carrier molecule known as latency-associated peptide, and must be activated.

To look at the effect of radiation on TGF- activation, Barcellos-Hoff created an antibody-based test that could distinguish between the two forms of the molecule. First, she obtained genetically engineered cells, provided by collaborators at UC San Francisco, that secreted either the latent or active form of the molecule. She was able to grow the cells as tumor tissue, then use the tissue to select for antibodies that would bind to one or the other form of TGF-.

By adding the antibodies to tissue, then using fluorescence to highlight the antibodies, Barcellos-Hoff could look at the distribution of the two types of TGF- in mouse mammary tissue before and after therapy-level doses of radiation. The tests showed that radiation had a dramatic effect on TGF-. Levels of the latent form, which were high in the tissue to begin with, dropped sharply within an hour of the treatment. Levels of the active form, which were nonexistent at first, increased. Active TGF- remained high for at least a week following radiation exposure.

Barcellos-Hoff found restructuring of the ECM following the treatments, suggesting that activated TGF- was already beginning to influence cells in the irradiated tissue.

Barcellos-Hoff is now examining how molecules such as antibodies could block the effects of TGF- prior to radiation treatment.