Taking Corrective Action

Cancerous tumors survive, in part, by learning to manipulate the cells around them. Many tumors stimulate nearby macrophages to adopt behaviors that facilitate tumor growth and metastasis. Our recent data suggest that these pernicious behaviors elicited by tumor education arise from discrete populations of tumor-educated macrophages. More importantly, it appears that many of these effects can be reversed.Contrary to what one might predict based on the current literature, elimination of macrophages from tumor-bearing mice using a genetically-engineered macrophage ablation model accelerated tumor growth and metastasis. This outcome appears to result from the biological effects of macrophage ablation, which include a reactive increase in levels of blood monocytes. It appears that particular groups of infiltrating monocytes respond to tumor education in ways that promote tumor progression, while others act in ways that prevent tumor growth and benefit the host.The effects of tumor education on these cells can also be reversed: When we treated mice bearing mammary tumors with intratumor GM-CSF (a natural stimulator of monocyte-macrophages), we observed a phenotype switch in the tumor-educated macrophages. GM-CSF treatment caused these cells to switch from behaviors that stimulated angiogenesis to behaviors that inhibited blood vessel and tumor growth. This change is marked by the expression of the soluble VEGF receptor, which blocks that activity of a primary angiogenic signal. Results include slower tumor growth, reduced metastasis, lower tumor oxygen levels, and fewer, more normalized blood vessels within the tumor.These data suggest new approaches to cancer therapy in which the treatment modifies the behavior of non-tumor cells, causing them to attack the tumor.