Heterogeneity and Pliability of Tumor-educated Macrophages
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Series/Report no.:2008 Edward F. Hayes Graduate Research Forum. 22nd
Cancerous tumors survive, in part, by learning to manipulate the cells around them. Many tumors stimulate one type of white blood cell, the macrophage, to adopt behaviors that facilitate tumor growth and metastasis. Our recent data suggest that these pernicious behaviors elicited by tumor education may 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 similar 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 macrophage precursors—blood monocytes. Our data suggest that particular groups of infiltrating monocytes may respond to tumor education in ways that promote tumor progression, while other monocyte-macrophage populations 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 (new blood vessel growth in support of increasing tumor size) to behaviors that inhibited blood vessel and tumor growth. This change is marked by the expression of the soluble VEGF receptor, which inhibits the 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.
Professional Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
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