VCAM-1 Promotes Osteolytic Expansion of Indolent Bone Micrometastasis of Breast Cancer by Engaging α4β1-positive Osteoclast Progenitors

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2011 Dec 6

PMID 22137794

Citations 290

Authors

Xin Lu

Euphemia Mu

Yong Wei

Sabine Riethdorf

Qifeng Yang

Min Yuan

Jun Yan

Yuling Hua

Benjamin J Tiede

Xuemin Lu

Bruce G Haffty

Klaus Pantel

Joan Massague

Yibin Kang

Affiliations

Soon will be listed here.

Abstract

Breast cancer patients often develop locoregional or distant recurrence years after mastectomy. Understanding the mechanism of metastatic recurrence after dormancy is crucial for improving the cure rate for breast cancer. Here, we characterize a bone metastasis dormancy model to show that aberrant expression of vascular cell adhesion molecule 1 (VCAM-1), in part dependent on the activity of the NF-κB pathway, promotes the transition from indolent micrometastasis to overt metastasis. By interacting with the cognate receptor integrin α4β1, VCAM-1 recruits monocytic osteoclast progenitors and elevates local osteoclast activity. Antibodies against VCAM-1 and integrin α4 effectively inhibit bone metastasis progression and preserve bone structure. These findings establish VCAM-1 as a promising target for the prevention and inhibition of metastatic recurrence in bone.

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References

Carter R, Wicks I . Vascular cell adhesion molecule 1 (CD106): a multifaceted regulator of joint inflammation. Arthritis Rheum. 2001; 44(5):985-94. DOI: 10.1002/1529-0131(200105)44:5<985::AID-ANR176>3.0.CO;2-P. View

Goss P, Chambers A . Does tumour dormancy offer a therapeutic target?. Nat Rev Cancer. 2010; 10(12):871-7. DOI: 10.1038/nrc2933. View

Zhang X, Wang Q, Gerald W, Hudis C, Norton L, Smid M . Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell. 2009; 16(1):67-78. PMC: 2749247. DOI: 10.1016/j.ccr.2009.05.017. View

Hu G, Chong R, Yang Q, Wei Y, Blanco M, Li F . MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell. 2008; 15(1):9-20. PMC: 2676231. DOI: 10.1016/j.ccr.2008.11.013. View

Lurquin C, De Smet C, Brasseur F, Muscatelli F, Martelange V, De Plaen E . Two members of the human MAGEB gene family located in Xp21.3 are expressed in tumors of various histological origins. Genomics. 1998; 46(3):397-408. DOI: 10.1006/geno.1997.5052. View

Springer T . Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994; 76(2):301-14. DOI: 10.1016/0092-8674(94)90337-9. View

Naumov G, MacDonald I, Weinmeister P, Kerkvliet N, Nadkarni K, Wilson S . Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res. 2002; 62(7):2162-8. View

Iademarco M, McQuillan J, Rosen G, Dean D . Characterization of the promoter for vascular cell adhesion molecule-1 (VCAM-1). J Biol Chem. 1992; 267(23):16323-9. View

Gurtner G, Davis V, Li H, McCoy M, Sharpe A, Cybulsky M . Targeted disruption of the murine VCAM1 gene: essential role of VCAM-1 in chorioallantoic fusion and placentation. Genes Dev. 1995; 9(1):1-14. DOI: 10.1101/gad.9.1.1. View

10.

Li Z, Schem C, Shi Y, Medina D, Zhang M . Increased COX2 expression enhances tumor-induced osteoclastic lesions in breast cancer bone metastasis. Clin Exp Metastasis. 2007; 25(4):389-400. DOI: 10.1007/s10585-007-9117-3. View

11.

Lu X, Kang Y . Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants. Proc Natl Acad Sci U S A. 2009; 106(23):9385-90. PMC: 2695061. DOI: 10.1073/pnas.0900108106. View

12.

Aguirre-Ghiso J . Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007; 7(11):834-46. PMC: 2519109. DOI: 10.1038/nrc2256. View

13.

Park B, Zhang H, Zeng Q, Dai J, Keller E, Giordano T . NF-kappaB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat Med. 2006; 13(1):62-9. DOI: 10.1038/nm1519. View

14.

Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert W, Goldbrunner R, Herms J . Real-time imaging reveals the single steps of brain metastasis formation. Nat Med. 2009; 16(1):116-22. DOI: 10.1038/nm.2072. View

15.

Lin K, Lu D, Hung C, Peng S, Huang L, Jie C . Ectopic expression of vascular cell adhesion molecule-1 as a new mechanism for tumor immune evasion. Cancer Res. 2007; 67(4):1832-41. PMC: 3172051. DOI: 10.1158/0008-5472.CAN-06-3014. View

16.

Chen Q, Zhang X, Massague J . Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. Cancer Cell. 2011; 20(4):538-49. PMC: 3293160. DOI: 10.1016/j.ccr.2011.08.025. View

17.

Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U . Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science. 1995; 267(5203):1485-8. DOI: 10.1126/science.7878466. View

18.

Minn A, Gupta G, Siegel P, Bos P, Shu W, Giri D . Genes that mediate breast cancer metastasis to lung. Nature. 2005; 436(7050):518-24. PMC: 1283098. DOI: 10.1038/nature03799. View

19.

Gao D, Nolan D, Mellick A, Bambino K, McDonnell K, Mittal V . Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science. 2008; 319(5860):195-8. DOI: 10.1126/science.1150224. View

20.

Klein C . Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009; 9(4):302-12. DOI: 10.1038/nrc2627. View