A Small-molecule Antagonist of CXCR4 Inhibits Intracranial Growth of Primary Brain Tumors

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 Nov 5

PMID 14595012

Citations 267

Authors

Joshua B Rubin

Andrew L Kung

Robyn S Klein

Jennifer A Chan

Yanping Sun

Karl Schmidt

Mark W Kieran

Andrew D Luster

Rosalind A Segal

Affiliations

Soon will be listed here.

Abstract

The vast majority of brain tumors in adults exhibit glial characteristics. Brain tumors in children are diverse: Many have neuronal characteristics, whereas others have glial features. Here we show that activation of the Gi protein-coupled receptor CXCR4 is critical for the growth of both malignant neuronal and glial tumors. Systemic administration of CXCR4 antagonist AMD 3100 inhibits growth of intracranial glioblastoma and medulloblastoma xenografts by increasing apoptosis and decreasing the proliferation of tumor cells. This reflects the ability of AMD 3100 to reduce the activation of extracellular signal-regulated kinases 1 and 2 and Akt, all of which are pathways downstream of CXCR4 that promote survival, proliferation, and migration. These studies (i) demonstrate that CXCR4 is critical to the progression of diverse brain malignances and (ii) provide a scientific rationale for clinical evaluation of AMD 3100 in treating both adults and children with malignant brain tumors.

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References

Goodrich L, Milenkovic L, Higgins K, Scott M . Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997; 277(5329):1109-13. DOI: 10.1126/science.277.5329.1109. View

Klein R, Rubin J, Gibson H, DeHaan E, Segal R, Luster A . SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development. 2001; 128(11):1971-81. DOI: 10.1242/dev.128.11.1971. View

Kijima T, Maulik G, Ma P, Tibaldi E, Turner R, Rollins B . Regulation of cellular proliferation, cytoskeletal function, and signal transduction through CXCR4 and c-Kit in small cell lung cancer cells. Cancer Res. 2002; 62(21):6304-11. View

Lee T, Avraham H, Lee S, Avraham S . Vascular endothelial growth factor modulates neutrophil transendothelial migration via up-regulation of interleukin-8 in human brain microvascular endothelial cells. J Biol Chem. 2002; 277(12):10445-51. DOI: 10.1074/jbc.M107348200. View

Pomeroy S, Tamayo P, Gaasenbeek M, Sturla L, Angelo M, McLaughlin M . Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature. 2002; 415(6870):436-42. DOI: 10.1038/415436a. View

Zhao Q, Kho A, Kenney A, Kohane I, Rowitch D . Identification of genes expressed with temporal-spatial restriction to developing cerebellar neuron precursors by a functional genomic approach. Proc Natl Acad Sci U S A. 2002; 99(8):5704-9. PMC: 122835. DOI: 10.1073/pnas.082092399. View

Luster A . Chemokines--chemotactic cytokines that mediate inflammation. N Engl J Med. 1998; 338(7):436-45. DOI: 10.1056/NEJM199802123380706. View

Sehgal A, Keener C, Boynton A, Warrick J, Murphy G . CXCR-4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells. J Surg Oncol. 1998; 69(2):99-104. DOI: 10.1002/(sici)1096-9098(199810)69:2<99::aid-jso10>3.0.co;2-m. View

Ma Q, Jones D, Borghesani P, Segal R, Nagasawa T, Kishimoto T . Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A. 1998; 95(16):9448-53. PMC: 21358. DOI: 10.1073/pnas.95.16.9448. View

10.

Payne A, Cornelius L . The role of chemokines in melanoma tumor growth and metastasis. J Invest Dermatol. 2002; 118(6):915-22. DOI: 10.1046/j.1523-1747.2002.01725.x. View

11.

Rehemtulla A, Stegman L, Cardozo S, Gupta S, Hall D, Contag C . Rapid and quantitative assessment of cancer treatment response using in vivo bioluminescence imaging. Neoplasia. 2001; 2(6):491-5. PMC: 1508085. DOI: 10.1038/sj.neo.7900121. View

12.

Zhou Y, Larsen P, Hao C, Yong V . CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J Biol Chem. 2002; 277(51):49481-7. DOI: 10.1074/jbc.M206222200. View

13.

Rempel S, Dudas S, Ge S, Gutierrez J . Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res. 2000; 6(1):102-11. View

14.

Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz I . A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. J Immunol. 2001; 167(8):4747-57. DOI: 10.4049/jimmunol.167.8.4747. View

15.

Helbig G, Christopherson 2nd K, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller K . NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003; 278(24):21631-8. DOI: 10.1074/jbc.M300609200. View

16.

Sun Y, Zhou J, Stayner C, Munasinghe J, Shen X, Beier D . Magnetic resonance imaging assessment of a murine model of recessive polycystic kidney disease. Comp Med. 2002; 52(5):433-8. View

17.

Schrader A, Lechner O, Templin M, Dittmar K, Machtens S, Mengel M . CXCR4/CXCL12 expression and signalling in kidney cancer. Br J Cancer. 2002; 86(8):1250-6. PMC: 2375348. DOI: 10.1038/sj.bjc.6600221. View

18.

Zhu Y, Yu T, Zhang X, Nagasawa T, Wu J, Rao Y . Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nat Neurosci. 2002; 5(8):719-20. PMC: 2072873. DOI: 10.1038/nn881. View

19.

Klein R, Williams K, Westmoreland S, Force T, Lackner A, Luster A . Chemokine receptor expression and signaling in macaque and human fetal neurons and astrocytes: implications for the neuropathogenesis of AIDS. J Immunol. 1999; 163(3):1636-46. View

20.

Hatse S, Princen K, Bridger G, De Clercq E, Schols D . Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS Lett. 2002; 527(1-3):255-62. DOI: 10.1016/s0014-5793(02)03143-5. View