Abstract
Chemokines are 8- to 12-kDa peptides that function as chemoattractant cytokines involved in cell activation, differentiation, and trafficking. Chemokines bind to specific G-protein-coupled, seven-span transmembrane receptors on the plasma membrane of target cells. Chemokine (C-X-C motif) ligand 12 (CXCL12), an alpha-chemokine that binds to G-protein-coupled chemokine (C-X-C motif) receptor 4 (CXCR4), plays an important and unique role in the regulation of stem/progenitor-cell trafficking. As CXCR4 is expressed on several cancer cells, these CXCR4-positive cancer cells may metastasize to organs that secrete/express CXCL12. Regarding brain tumors, recent data demonstrate that glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via the CXCL12/CXCR4 pathway. In addition, CXCL12/CXCR4 have recently been shown to be expressed in primary central nervous system (PCNS) lymphomas, and a role for chemokines in the pathogenesis of PCNS lymphomas was suggested. This review focuses on current knowledge regarding the biology of the CXCL12/CXCR4 pathway in the context of understanding their potential role in malignant gliomas and PCNS lymphoma development. The CXCL12/CXCR4 interaction as a therapeutic target for malignant brain tumors is also discussed.
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References
Kucia M, Jankowski K, Reca R et al (2004) CXCR4-SDF1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol 35:233–245
Teicher BA and Fricker SP (2007) CXCL12(SDF1)/CXCR4 pathway in cancer. Clin Cancer Res 16:2927–2931
Lazarini F, Tham T N, Casanova P et al (2003) Role of the alpha-chemokine stromal cell-derived factor (SDF1) in the developing and mature central nervous system. Glia 42:139–148
Barbieri F, Bajetto A, Florio T et al (2010) Network in the development and progression of ovarian cancer: a potential novel pharmacological target. J Oncol 61:4961–4965
Singh S, Singh UP, Grizzle WE et al (2004) CXCL12-CXCR4 interactions modulate prostate cancer cell migration, metalloproteinase expression and invasion. Lab Invest 84:1666–1676
Jiang Y, Wu X-H, Shi B et al (2006) Expression of chemokine CXCL12 and its receptor CXCR4 in human epithelial ovarian cancer: an independent prognostic factor for tumor progression. Gynecol Oncol 103:226–233
Yasumoto K, Koizumi K, Kawashima A et al (2006) Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res 66:2181–2187
Zhu Y, Matsumoto T, Mikami S et al (2009) SDF1/CXCR4 signalling regulates two distinct processes of precerebellar neuronal migration and its depletion leads to abnormal pontine nuclei formation. Development 136:1919–1928
Folkins C, Shaked Y, Man S et al (2009) Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res 69:7243–7251
Smith JR, Braziel RM, Paoletti S et al (2003) Expression of B-cell-attracting chemokine 1(CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma. Blood 101:815–821
Brunn A, Montesinos-Rongen M, Strack A et al (2007) Expression pattern and cellular sources of chemokines in primary central nervous system lymphoma. Acta Neuropathathol 114:271–276
Smith JR, Falkenhagen KM, Coupland SE et al (2007) Malignant B cells from patients with primary central nervous system lymphoma express stromal cell-derived factor-1. Am J Clin Pathol 127:633–641
Jahnke K, Coupland SE, Na IK et al (2005) Expression of the chemokine receptors CXCR4, CXCR5, and CCR7 in primary central nervous system lymphoma. Blood 106:384–385
Fischer L, Korfel A, Pfeiffer S et al (2007) CXCL13 and CXCL12 in central nervous system lymphoma patient. Clin Cancer Res 15:5968–5973
Scotton CJ, Wilson JL, Scott K et al (2002) Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res 61:4961–4965
Uchida D, Onoue T, Tomizuka Y et al (2007) Involvement of autocrine stromal cell-derived factor-1/CXCR4 system on the distant metastasis of human oral squamous cell carcinoma. Cancer Res 5:685–694
Yang SX, Chen JH, Jiang XF et al (2005) Activation of chemokine receptor CXCR4 in malignant glioma cells promotes the production of vascular endothelial growth factor. Biochem Biophys Res Commun 335:523–528
Liang Z, Brooks J, Willard M et al (2007) CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem Biophys Res Commun 359:716–722
Reddy K, Zhou Z, Jia SF et al (2008) Stromal cell-derived factor-1 stimulates vasculogenesis and enhances Ewing’s sarcoma tumor growth in the absence of vascular endothelial growth factor. Int J Cancer 123:831–837
Matsuo Y, Ochi N, Sawai H et al (2009) CXCL8/IL-8 and CXCL12/SDF-1 alpha co-operatively promote invasiveness and angiogenesis in pancreatic cancer. Int J Cancer 124:853–861
Salmaggi A, Gelati M, Pollo B, et al (2004) CXCL12 in malignant glial tumors: a possible role in angiogenesis and cross-talk between endothelial and tumoral cells. J Neurooncol 67:305–317
Maderna E, Salmaggi A, Calatozzolo C et al (2007) Nestin, PDGFRbeta, CXCL12, and VEGF in glioma patients: different profiles of (pro-angiogenic) molecule expression are related with tumor grade and may provide prognostic information. Cancer Biol Ther 6:1018–1024
Oh JW, Olman M, Benveniste EN (2009) CXCL12-mediated induction of plasminogen activator inhibitor-1 expression in human CXCR4 positive astroglioma cells. Biol Pharm Bull 32:573–577
Bartolomé RA, Ferreiro S, Miquilena-Colina ME et al (2009) The chemokine receptor CXCR4 and the metalloproteinase MT1-MMP are mutually required during melanoma metastasis to lungs. Am J Pathol 174:602–612
Tan C-T, Chu C-Y, Lu Y-C et al (2008) CXCL12/CXCR4 promote laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP13-dependent invasion via the ERK1/2/AP-1 pathway. Carcinogenesis 29:1519–1527
Zhang J, Sarkar S, Yong VW (2005) The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. Carcinogenesis 26:2069–2077
Sugita Y, Nakamura Y, Yamamoto M et al (2005) Expression of tubulin beta II in neuroepithelial tumors: reflection of architectural changes in the developing human brain. Acta Neuropathol 110:127–134
Ma YH, Mentlein R, Knerlich F et al (2008) Expression of stem cell markers in human astrocytomas of different WHO grades. J Neurooncol 86:31–45
Ehtesham M, Mapara KY, Stevenson CB et al (2009) CXCR4 mediates the proliferation of glioblastoma progenitor cells. Cancer Lett 274:305–312
Komatani H, Sugita Y, Arakawa F et al (2009) Expression of CXCL12 on pseudopalisading cells and proliferating microvessels in glioblastomas: an accelerated growth factor in glioblastomas. Int J Oncol 34:665–672
Kleihues P, Burger PC, Aldape KD et al (2006) glioblastoma. In: Pathology and genetics of tumours of the nervous system, Louis DN, Ohgaki H, Wiestler OD and Cavenee WK (eds) International agency for research on cancer, Lyon, pp 33–52
Brat DJ and Van Meir EG (2004) Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest 84:397–405
Rempel SA, Dudas S, Ge S et al (2000) Identification and localization of cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6:102–111
Zagzag D, Lukyanov Y, Lan Li et al (2006) Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 86:1221–1232
Zagzag D, Esencay M, Mendez O et al (2008) Hypoxia- and vascular endothelial growth factor-induced stromal cell-derived factor-1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Schere’s structures. Am J Pathol 173:545–560
Rubin JB, Kung AL, Klein RS et al (2003) A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 100:13513–13518
Redjal N, Chan JA, Segal RA et al (2006) CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas. Clin Cancer Res 12:6765–6771
Kioi M, Vogel H, Schultz G et al (2010) Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 120:694–705
Yang L, Jackson E, Woerner BM et al (2007) Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Cancer Res 67:651–658
Ping YF, Yao XH, Chen JH et al (2007) The anti-cancer compound Nordy inhibits CXCR4-mediated production of IL-8 and VEGF by malignant human glioma cells. J Neurooncol 84:21–29
Burger JA and Bürkle A (2007) The CXCR4 chemokine receptor in acute and chronic leukaemia: a marrow homing receptor and potential therapeutic target. Br J Haematol 137:288–296
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This study was partly supported by a grant from the Ishibashi Foundation for the Promotion of Science.
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Terasaki, M., Sugita, Y., Arakawa, F. et al. CXCL12/CXCR4 signaling in malignant brain tumors: a potential pharmacological therapeutic target. Brain Tumor Pathol 28, 89–97 (2011). https://doi.org/10.1007/s10014-010-0013-1
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DOI: https://doi.org/10.1007/s10014-010-0013-1