Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs.
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.
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Qing
Q
Chen
Xiang H-F
XH
Zhang
Joan
J
Massagué
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000556:secondary*; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009360:Neoplastic Cells, Circulating / Q000276:immunology* / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D051058:Oncogene Protein v-akt; D019010:Vascular Cell Adhesion Molecule-1; D000099149:Ezrin