Major finding: VCAM-1 promotes lung metastasis by tethering breast cancer cells to lung TAMs.
Mechanism: Juxtacrine activation of a VCAM-1–Ezrin–PI3K/AKT pathway promotes survival.
Impact: Antibodies blocking the VCAM-1–α4-integrin interaction may decrease metastatic potential.
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.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at www.AACR.org/CDnews.