Macrophage Binding to Receptor VCAM-1 Transmits Survival Signals in Breast Cancer Cells That Invade the Lungs

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2011 Oct 22

PMID 22014578

Citations 317

Authors

Qing Chen

Xiang H-F Zhang

Joan Massague

Affiliations

Soon will be listed here.

Abstract

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.

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References

Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H . Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004; 6(1):17-32. DOI: 10.1016/j.ccr.2004.06.010. View

Fidler I . The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer. 2003; 3(6):453-8. DOI: 10.1038/nrc1098. View

Collins B, Deak M, Arthur J, Armit L, Alessi D . In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation. EMBO J. 2003; 22(16):4202-11. PMC: 175797. DOI: 10.1093/emboj/cdg407. View

Lipscomb M, Bice D, Lyons C, Schuyler M, Wilkes D . The regulation of pulmonary immunity. Adv Immunol. 1995; 59:369-455. PMC: 7131473. DOI: 10.1016/s0065-2776(08)60634-3. View

Gocheva V, Wang H, Gadea B, Shree T, Hunter K, Garfall A . IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 2010; 24(3):241-55. PMC: 2811826. DOI: 10.1101/gad.1874010. View

Tavazoie S, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos P . Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008; 451(7175):147-52. PMC: 2782491. DOI: 10.1038/nature06487. View

Shin J, Kim J, Ryu B, Chi S, Park H . Caveolin-1 is associated with VCAM-1 dependent adhesion of gastric cancer cells to endothelial cells. Cell Physiol Biochem. 2006; 17(5-6):211-20. DOI: 10.1159/000094126. View

Wyckoff J, Wang W, Lin E, Wang Y, Pixley F, Stanley E . A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 2004; 64(19):7022-9. DOI: 10.1158/0008-5472.CAN-04-1449. View

Anan K, Mitsuyama S, Koga K, Tanabe R, Saimura M, Tanabe Y . Disparities in the survival improvement of recurrent breast cancer. Breast Cancer. 2009; 17(1):48-55. DOI: 10.1007/s12282-009-0103-2. View

10.

Padua D, Zhang X, Wang Q, Nadal C, Gerald W, Gomis R . TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell. 2008; 133(1):66-77. PMC: 2390892. DOI: 10.1016/j.cell.2008.01.046. View

11.

Sangaletti S, Di Carlo E, Gariboldi S, Miotti S, Cappetti B, Parenza M . Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. Cancer Res. 2008; 68(21):9050-9. DOI: 10.1158/0008-5472.CAN-08-1327. View

12.

Kalogeris T, Kevil C, Laroux F, Coe L, Phifer T, Alexander J . Differential monocyte adhesion and adhesion molecule expression in venous and arterial endothelial cells. Am J Physiol. 1999; 276(1):L9-L19. DOI: 10.1152/ajplung.1999.276.1.L9. View

13.

Jones D, Nakashima T, Sanchez O, Kozieradzki I, Komarova S, Sarosi I . Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006; 440(7084):692-6. DOI: 10.1038/nature04524. View

14.

Minn A, Gupta G, Padua D, Bos P, Nguyen D, Nuyten D . Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci U S A. 2007; 104(16):6740-5. PMC: 1871856. DOI: 10.1073/pnas.0701138104. View

15.

Elices M, Osborn L, Takada Y, Crouse C, Luhowskyj S, Hemler M . VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell. 1990; 60(4):577-84. DOI: 10.1016/0092-8674(90)90661-w. View

16.

Ruco L, De Laat P, Matteucci C, Bernasconi S, Sciacca F, van der Kwast T . Expression of ICAM-1 and VCAM-1 in human malignant mesothelioma. J Pathol. 1996; 179(3):266-71. DOI: 10.1002/(SICI)1096-9896(199607)179:3<266::AID-PATH592>3.0.CO;2-Y. View

17.

Wong C, Lee A, Shientag L, Yu J, Dong Y, Kao G . Apoptosis: an early event in metastatic inefficiency. Cancer Res. 2001; 61(1):333-8. View

18.

Qian B, Pollard J . Macrophage diversity enhances tumor progression and metastasis. Cell. 2010; 141(1):39-51. PMC: 4994190. DOI: 10.1016/j.cell.2010.03.014. View

19.

van Wetering S, van den Berk N, van Buul J, Mul F, Lommerse I, Mous R . VCAM-1-mediated Rac signaling controls endothelial cell-cell contacts and leukocyte transmigration. Am J Physiol Cell Physiol. 2003; 285(2):C343-52. DOI: 10.1152/ajpcell.00048.2003. View

20.

Cybulsky M, FRIES J, Williams A, Sultan P, Eddy R, Byers M . Gene structure, chromosomal location, and basis for alternative mRNA splicing of the human VCAM1 gene. Proc Natl Acad Sci U S A. 1991; 88(17):7859-63. PMC: 52403. DOI: 10.1073/pnas.88.17.7859. View