VCAM-1 Binds Macrophages to Promote Survival of Lung Metastases

Disseminated tumor cells must receive survival signals upon infiltration of a distant organ for metastatic colonization. Based on previous work identifying vascular cell adhesion molecule-1 (VCAM-1) as part of a gene signature expressed in lung-metastatic breast cancer cells, Chen and colleagues hypothesized that VCAM-1 is required for lung metastasis. Interestingly, knockdown of VCAM-1 in breast cancer cells had no effect on lung invasion but led to a striking reduction of metastatic colonies associated with an increase in apoptotic cells. To identify the lung stromal cell types that VCAM-1–expressing cells encounter, the authors prepared single-cell suspensions from lung nodules, incubated the cells with VCAM-1, and used specific cell markers to identify and quantify interacting cells by flow cytometry. VCAM-1 bound specifically to macrophages, which expressed high levels of cell surface α4-integrin and comprised approximately 7% of the total cell population of metastatic nodules. Furthermore, binding of VCAM-1 to α4-integrin was required for the anti-apoptotic effect of VCAM-1. The authors found that VCAM-1–α4-integrin engagement specifically activated Ezrin and induced PI3K/AKT signaling to suppress apoptosis, indicating that tumor-associated macrophages (TAM) act in a juxtacrine manner to promote the survival of metastatic breast cancer cells upon lung invasion. Collectively, these data suggest that VCAM-1–expressing cancer cells have a survival advantage in leukocyte-rich organs such as the lungs, an observation that was supported by a bioinformatic analysis of breast tumors showing that a leukocyte expression signature was specifically associated with lung metastasis and high expression of VCAM-1. Because targeted therapies such as natalizumab that disrupt the interaction between endothelial VCAM-1 and leukocyte α4-integrins are already in use for such diseases as multiple sclerosis, these findings suggest that similar approaches may be effective in elimination of residual disease following primary tumor resection.

Chen Q, Zhang XH-F, Massagué J. Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell. 2011;20:538–49.

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