Tumors Stopped From Spreading In Mice

The team led by Carlos Arteaga, M.D., reports in the May issue of the Journal of Clinical Investigation that radiation and chemotherapy increase circulating levels of the growth factor TGF-beta, circulating cancer cells, and tumor metastases in a mouse model of metastatic breast cancer.

Blocking TGF-beta in the model prevented tumor metastases, suggesting that TGF-beta inhibitors may be clinically useful in combination with primary therapies. Arteaga and colleagues had previously shown that a brief induction of TGF-beta in a transgenic mouse model of breast cancer dramatically accelerated metastasis.

Then they came across a few clinical studies showing that radiation and chemotherapy increase TGF-beta in patients or in experimental tumors.

"We wondered then if TGF-beta induced by anti-cancer therapies can serve as a survival signal for tumor cells, thus allowing them to withstand therapy and later recur," said Arteaga, professor of Medicine and Cancer Biology and director of the Vanderbilt-Ingram Breast Cancer Program.

This appears to be the case, he said. Radiation therapy and the chemotherapeutic agents doxorubicin and docetaxel all increased TGF-beta levels and accelerated metastasis, an effect that was blocked by neutralizing antibodies directed against TGF-beta.

Similar results not reported in this paper have been observed with small molecule inhibitors of the TGF-beta type I receptor kinase. "We speculate, based on these observations, that this will occur in some patients," Arteaga said.

Patients who have treatment-induced increases in TGF-beta may not respond as well to the anti-cancer therapy as those who do not, and this is a testable hypothesis, he added.

The team is currently assessing TGF-beta levels in the serum of patients with breast cancer who are being treated with neoadjuvant chemotherapy to shrink the tumor prior to surgery.

"We'll be looking to see in what proportion of patients the serum and tumor TGF-beta goes up, and whether the increase correlates with the inability of the therapy to eliminate the cancer in the breast," Arteaga said.

Increased circulating and/or tumor TGF-beta in response to treatment may be a marker of tumors destined to progress rapidly after therapy, he said. Patients with such tumors might benefit from the addition of TGF-beta inhibitors to the primary therapy. Several TGF-beta inhibitors are currently in early stage clinical trials, some of which are being conducted at Vanderbilt.

"It probably isn't just TGF-beta that is having this effect," Arteaga said. "There are other growth factors and cytokines that have been reported to increase in response to radiation, chemotherapy and surgery, and some of these could also be tumor survival and prometastatic signals. "TGF-beta may be just the tip of the iceberg."

The research was supported by multiple grants from the National Institutes of Health, including a Breast Cancer Specialized Program of Research Excellence (SPORE) directed by Arteaga. The work also received support from the pharmaceutical company Aventis.

Authors contributing to the work included Swati Biswas, Ph.D., Marta Guix, M.D., Cammie Rinehart, Teresa Dugger, Anna Chytil, Harold Moses, M.D., and Michael Freeman, Ph.D.