In advanced cancer, anti-tumor therapies often work only partially or not at all, and tumors progress following treatment. Scientists have now linked a treatment-induced growth factor to the cancer’s future spread.

A team at Vanderbilt-Ingram Cancer Center team reports in the May issue of Journal of Clinical Investigation that radiation and chemotherapy increase circulating levels of the growth factor TGF-beta, circulating cancer cells, and tumor metastases in mice implanted with metastatic breast cancer.

Radiation therapy and the chemotherapeutic agents doxorubicin (Adriamycin) and docetaxel (Taxotere) all increased TGF-beta levels and accelerated metastasis, an effect that was blocked by neutralizing antibodies directed against TGF-beta.

Blocking TGF-beta in the model prevented tumor metastases, suggesting that drugs designed to block TGF-beta may be clinically useful in combination with primary therapies.

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

TGF-beta (TGF-β) is a peptide that controls regulates cell proliferation, angiogenesis, metastasis, and immune suppression. “Dysregulation of the TGFbeta pathway in tumor cells often leads to resistance to the anti-proliferative effects of TGFbeta while supporting other cellular processes that promote tumor invasiveness.” (Gaspar NJ. Mol Pharmacol. 2007 Mar 30 full text free online).

Carlos Arteaga, M.D., who led the Vanderbilt study, had previously sstimulating 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 (Adriamycin) and docetaxe (Taxotere) all increased TGF-beta levels and accelerated metastasis, an effect that the scientists found they could block by directing neutralizing antibodies against TGF-beta. Similar results 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.

In the tests that Vanderbilt is running on breast cancer patients. Arteaga said, “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.”

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 study appears in reports in the May issue of the Journal of Clinical Investigation.

Carlos Arteaga, M.D., in the lab with Marta Guix, M.D., center, and Swati Biswas, Ph.D. (photo by Susan Urmy)

Carlos L. Arteaga, M.D. is Vice Chancellor’s Chair in Breast Cancer Research, Director of Specialized Program of Research Excellence in Breast Cancer, Professor of Medicine at Vanderbilt-Ingram Cancer Center, which is the only National Cancer Institute-designated Comprehensive Cancer Center in Tennessee and one of only 39 to earn this distinction nationwide.

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.