February 8, 2008

Immune system helps cancer protein switch teams: study

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Li Yang, Ph.D., right, and Hal Moses, M.D., are studying the dual identity of TGF-beta. (photo by Dana Johnson)

Immune system helps cancer protein switch teams: study

Transforming growth factor-beta (TGF-beta) is a fickle protein.

While it suppresses cell division and inhibits tumor growth in the early stages of cancer, it can also promote tumor cell growth and metastasis in later stages. However, the reasons behind this switch in function are not clear.

A team of Vanderbilt-Ingram Cancer Center researchers, led by Li Yang, Ph.D., and Hal Moses, M.D., has found a clue to the seemingly contradictory biological actions of TGF-beta. In the Jan. 23 issue of Cancer Cell, they report a critical role for the body's own immune cells in causing TGF-beta's change of heart.

“TGF-beta signaling has been known to work both as a tumor suppressor and tumor promoter. But nobody knows how it switches from suppressor to promoter,” said Yang, a research assistant professor of Cancer Biology.

Moses, the director of the Frances Williams Preston Laboratories, and his lab first discovered this multifunctional role for TGF-beta in 1981. Since then, researchers around the world — including several Vanderbilt investigators — have set out to understand the molecule's dual role.

Much more than just a biological curiosity, this dual identity of TGF-beta presents a serious clinical challenge. Treatments designed to inhibit TGF-beta signaling, including neutralizing antibodies and small molecule inhibitors, are currently being developed and tested.

“We may treat a cancer patient with TGF-beta neutralizing antibodies in the hopes that the patient will benefit from that treatment,” said Yang. “But the worry is: what if you treat the patient when TGF-beta signaling is acting as a tumor suppressor? Then you are killing a 'good guy,' and that promotes tumor progression.”

In 2004, Yang and colleagues found that a specific type of host immune cells, called myeloid immune suppressor cells (MISCs), infiltrates into tumors and promotes the growth of new tumor blood vessels. Yang began to suspect that such host factors might be involved in TGF-beta's switch from tumor suppressor to promoter.

Yang and colleagues decided to further examine the role of these cells in a mouse model of breast cancer.

In these mice, the investigators deleted the gene encoding a receptor for TGF-beta, and found that the tumors of these mice contained a significantly higher number of MISCs than tumors from mice with a functional TGF-beta receptor. The MISCs were found mainly at the invasive front of tumors.

“They go where the tumors are invading into the normal tissues,” Yang explained. “These cells also produce TGF-beta and matrix metalloproteinases, (enzymes) known to be important modulators of tumor metastasis.”

Yang's team also found that the increased recruitment of these immune cells to tumors with deleted TGF-beta signaling resulted from an increased production of a signaling molecule (chemokine) by the tumor cells. Blocking the interaction between this chemokine, called CXCL5, and its receptor inhibited the recruitment of MISCs suggesting that “cytokine cues in the microenvironment are very important for recruitment of those cells.”

“Another chemokine signaling system, SDF-1/CXCR4, was also responsible for the recruitment of MISCs” said Yang. “Targeting these chemokine/receptor interactions inhibits MISC recruitment and tumor metastasis. So we concluded that the switch from suppressor to promoter involves the recruitment of those cells into the tumor microenvironment.”

Since MISCs are known to circulate in peripheral blood, Yang predicts that it may be possible to develop a blood test for these cells that could indicate whether TGF-beta inhibitor treatments would benefit the patient.

“TGF-beta inhibitors would be better and more efficient for patients that have the cells in their blood. When they don't have these cells in their blood, TGF-beta inhibitor treatment may actually cause a worse outcome,” she said.

Another potential application of these findings would be to develop therapies that inhibit the production and recruitment of MISCs, which would improve the host immune system's ability to “fight” the tumor and inhibit tumor metastasis at the same time.

This would have the effect of “killing two birds with one stone,” Yang said.