Cancer Cell
Volume 20, Issue 4, 18 October 2011, Pages 538-549
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Article
Macrophage Binding to Receptor VCAM-1 Transmits Survival Signals in Breast Cancer Cells that Invade the Lungs

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Summary

Aberrant expression of vascular cell adhesion molecule-1 (VCAM-1) in breast cancer cells is associated with lung relapse, but the role of VCAM-1 as a mediator of metastasis has remained unknown. We report that VCAM-1 provides a survival advantage to breast cancer cells that infiltrate leukocyte-rich microenvironments such as the lungs. VCAM-1 tethers metastasis-associated macrophages to cancer cells via counter-receptor α4-integrins. Clustering of cell surface VCAM-1, acting through Ezrin, triggers Akt activation and protects cancer cells from proapoptotic cytokines such as TRAIL. This prosurvival function of VCAM-1 can be blocked by antibodies against α4-integrins. Thus, newly disseminated cancer cells expressing VCAM-1 can thrive in leukocyte-rich microenvironments through juxtacrine activation of a VCAM-1–Ezrin-PI3K/Akt survival pathway.

Highlights

► Breast cancer cells expressing VCAM-1 have a survival advantage in the lungs ► Macrophage binding to VCAM-1 on cancer cells triggers Akt survival signal via Ezrin ► VCAM-1 primes cancer cells for residence in leukocyte-rich microenvironments ► Blocking the VCAM-1-α4-integrin interaction enhances cancer cell death

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