Infiltration of macrophages (red, left) into tumors is blocked when tumors are treated with anti–IL-8 antibody (right).

A protein previously hailed as a tumor suppressor has a sinister agenda, according to Rolny et al. (page 1155). Although this false savior, semaphorin 3B (SEMA3B), tells tumor cells to stop growing, it then sends them on their way to grow elsewhere.

Semaphorins were initially identified as extracellular navigation signals for growing axons. Some of them are now known to enhance tumor progression by increasing the growth of blood vessels that feed the tumor. SEMA3B, however, is thought to be a tumor suppressor because it also inhibits tumor cell proliferation.

Rolny et al. now find that this suppression comes at a potentially fatal price. Most tumor suppressors are either absent or expressed at low levels in cancerous tissues. But the group found high levels of SEMA3B in many cancer cell lines and in metastatic tumors from patients. Although SEMA3B inhibited the proliferation of these tumor cells in vitro, the poor prognosis of these patients suggested that SEMA3B signaling might have detrimental effects in vivo.

To test this hypothesis, the authors engineered human tumor cells in which SEMA3B expression was controlled by a drug-inducible promoter and injected these cells into the skin of immune cell-depleted mice. Drug-treated mice had smaller skin tumors but developed secondary lung tumors, suggesting that SEMA3B induced metastasis.

The authors found that SEMA3B inhibited growth and simultaneously triggered metastasis by activating the signaling kinase p38. p38 then activated a cell cycle inhibitor and induced tumor cells to secrete IL-8, a cytokine known to induce leukocyte chemotaxis. The IL-8–secreting tumors were full of infiltrating macrophages, which are thought to spur metastasis by producing soluble factors such as VEGF. Blocking the release of IL-8 in response to SEMA3B, the group found, blocked the metastasis of these tumors.