Hypoxia-induced Lysyl Oxidase is a Critical Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic Niche

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2008 Dec 30

PMID 19111879

Citations 643

Authors

Janine T Erler

Kevin L Bennewith

Thomas R Cox

Georgina Lang

Demelza Bird

Albert Koong

Quynh-Thu Le

Amato J Giaccia

Affiliations

Soon will be listed here.

Abstract

Tumor cell metastasis is facilitated by "premetastatic niches" formed in destination organs by invading bone marrow-derived cells (BMDCs). Lysyl oxidase (LOX) is critical for premetastatic niche formation. LOX secreted by hypoxic breast tumor cells accumulates at premetastatic sites, crosslinks collagen IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells adhere to crosslinked collagen IV and produce matrix metalloproteinase-2, which cleaves collagen, enhancing the invasion and recruitment of BMDCs and metastasizing tumor cells. LOX inhibition prevents CD11b+ cell recruitment and metastatic growth. CD11b+ cells and LOX also colocalize in biopsies of human metastases. Our findings demonstrate a critical role for LOX in premetastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease.

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References

Kagan H, Li W . Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem. 2003; 88(4):660-72. DOI: 10.1002/jcb.10413. View

Ahn G, Brown J . Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell. 2008; 13(3):193-205. PMC: 2967441. DOI: 10.1016/j.ccr.2007.11.032. View

Cameron J, Skubitz A, Furcht L . Type IV collagen and corneal epithelial adhesion and migration. Effects of type IV collagen fragments and synthetic peptides on rabbit corneal epithelial cell adhesion and migration in vitro. Invest Ophthalmol Vis Sci. 1991; 32(10):2766-73. View

Du R, Lu K, Petritsch C, Liu P, Ganss R, Passegue E . HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008; 13(3):206-20. PMC: 2643426. DOI: 10.1016/j.ccr.2008.01.034. View

Condeelis J, Pollard J . Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006; 124(2):263-6. DOI: 10.1016/j.cell.2006.01.007. View

Kent M, Light N, Bailey A . Evidence for glucose-mediated covalent cross-linking of collagen after glycosylation in vitro. Biochem J. 1985; 225(3):745-52. PMC: 1144652. DOI: 10.1042/bj2250745. View

Erler J, Bennewith K, Nicolau M, Dornhofer N, Kong C, Le Q . Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 2006; 440(7088):1222-6. DOI: 10.1038/nature04695. View

Caniggia I, Mostachfi H, Winter J, Gassmann M, Lye S, Kuliszewski M . Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). J Clin Invest. 2000; 105(5):577-87. PMC: 289179. DOI: 10.1172/JCI8316. View

Yang L, Huang J, Ren X, Gorska A, Chytil A, Aakre M . Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell. 2008; 13(1):23-35. PMC: 2245859. DOI: 10.1016/j.ccr.2007.12.004. View

10.

Kusmartsev S, Eruslanov E, Kubler H, Tseng T, Sakai Y, Su Z . Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. J Immunol. 2008; 181(1):346-53. DOI: 10.4049/jimmunol.181.1.346. View

11.

Koivunen E, Arap W, Valtanen H, Rainisalo A, Medina O, Heikkila P . Tumor targeting with a selective gelatinase inhibitor. Nat Biotechnol. 1999; 17(8):768-74. DOI: 10.1038/11703. View

12.

Maki J, Rasanen J, Tikkanen H, Sormunen R, Makikallio K, Kivirikko K . Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. Circulation. 2002; 106(19):2503-9. DOI: 10.1161/01.cir.0000038109.84500.1e. View

13.

Lazarus H, Cruikshank W, Narasimhan N, Kagan H, Center D . Induction of human monocyte motility by lysyl oxidase. Matrix Biol. 1995; 14(9):727-31. DOI: 10.1016/s0945-053x(05)80015-0. View

14.

Liu C, Yu S, Kappes J, Wang J, Grizzle W, Zinn K . Expansion of spleen myeloid suppressor cells represses NK cell cytotoxicity in tumor-bearing host. Blood. 2007; 109(10):4336-42. PMC: 1885503. DOI: 10.1182/blood-2006-09-046201. View

15.

Kirschmann D, Seftor E, Fong S, Nieva D, Sullivan C, Edwards E . A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res. 2002; 62(15):4478-83. View

16.

Fogelgren B, Polgar N, Szauter K, Ujfaludi Z, Laczko R, Fong K . Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation. J Biol Chem. 2005; 280(26):24690-7. DOI: 10.1074/jbc.M412979200. View

17.

Kaplan R, Riba R, Zacharoulis S, Bramley A, Vincent L, Costa C . VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005; 438(7069):820-7. PMC: 2945882. DOI: 10.1038/nature04186. View

18.

Yang L, DeBusk L, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y . Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004; 6(4):409-21. DOI: 10.1016/j.ccr.2004.08.031. View

19.

Coussens L, Werb Z . Inflammation and cancer. Nature. 2002; 420(6917):860-7. PMC: 2803035. DOI: 10.1038/nature01322. View

20.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T . Cancer statistics, 2008. CA Cancer J Clin. 2008; 58(2):71-96. DOI: 10.3322/CA.2007.0010. View