Gliomas are the most common type of primary central nervous system tumors and are often aggressive with a poor prognosis. In this study, a new murine brain tumor model, ALTS1C1was established to investigate the alteration of tumor microenvironments after radiation therapy (RT). This new brain tumor model is derived from SV40 large T antigen-transfected astrocytes, ALTS1C1 recapitulates several histopathological features of human high-grade glioma, such as: increased cellularity, active mitosis, prominent cellular pleomorphism, geographic necrosis, abundant infiltrating microglia/macrophages and extensive invasion of tumor cells into adjacent brain tissues. Microarray data and immunohistochemical staining indicated that ALTS1C1 tumors expressed a relatively high level of angiogenesis/vasculogenesis-associated genes and a higher microvascular density (MVD) in vivo than GL261 tumors. To further define the role of angiogenesis/vasculogenesis-associated gene SDF-1 on tumor growth and the responses to RT, lentiviral shRNA particles were used to down-regulate SDF-1 expression in ALTS1C1 cells. SDF-knock down (SDFkd) ALTS1C1 cells formed tumors more slowly than parental ALTS1C1 cells. In contrast to the wild type tumors, they had well-defined regular borders, lacked infiltration tracts, and exhibited a lower MVD and more hypoxic areas. A single dose of irradiation decreased tumor microvasculature network and led to the development of avascular hypoxia associated with the aggregation of tumor-associated macrophages (TAMs) in both ectopic and orthotopic models, a response that was diminished in SDFkd tumors. This study not only provides a new insight into the role of SDF-1 in brain tumor invasion and into the relationship between TAMs and hypoxia, but also provides a new pre-clinical brain tumor model to design new treatment options for invasive cases.

1. Akesson, A., B. Julin, and A. Wolk. 2008. Long-term dietary cadmium intake and postmenopausal endometrial cancer incidence: a population-based prospective cohort study. Cancer Res 68:6435-6441.
2. Raizer, J. J. 2005. HER1/EGFR tyrosine kinase inhibitors for the treatment of glioblastoma multiforme. J Neurooncol 74:77-86.
3. Ohgaki, H., and P. Kleihues. 2005. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64:479-489.
4. Louis, D. N., H. Ohgaki, O. D. Wiestler, W. K. Cavenee, P. C. Burger, A. Jouvet, B. W. Scheithauer, and P. Kleihues. 2007. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97-109.
5. Mott, R. T., K. C. Turner, D. D. Bigner, and R. E. McLendon. 2008. Utility of EGFR and PTEN numerical aberrations in the evaluation of diffusely infiltrating astrocytomas. Laboratory investigation. J Neurosurg 108:330-335.
6. de Vries, N. A., J. H. Beijnen, and O. van Tellingen. 2009. High-grade glioma mouse models and their applicability for preclinical testing. Cancer Treat Rev 35:714-723.
7. Holland, E. C. 2001. Gliomagenesis: genetic alterations and mouse models. Nat Rev Genet 2:120-129.
8. Hu, X., and E. C. Holland. 2005. Applications of mouse glioma models in preclinical trials. Mutat Res 576:54-65.
9. Sullivan, C. S., and J. M. Pipas. 2002. T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis. Microbiol Mol Biol Rev 66:179-202.
10. Stacey, G., and C. MacDonald. 2001. Immortalisation of primary cells. Cell Biol Toxicol 17:231-246.
11. Newcomb, E. W., Y. Lukyanov, N. Kawashima, M. Alonso-Basanta, S. C. Wang, M. Liu, M. Jure-Kunkel, D. Zagzag, S. Demaria, and S. C. Formenti. Radiotherapy enhances antitumor effect of anti-CD137 therapy in a mouse Glioma model. Radiat Res 173:426-432.
12. Chiang, C. S., W. H. McBride, and H. R. Withers. 1993. Radiation-induced astrocytic and microglial responses in mouse brain. Radiother Oncol 29:60-68.
13. Chiang, C. S., J. H. Hong, A. Stalder, J. R. Sun, H. R. Withers, and W. H. McBride. 1997. Delayed molecular responses to brain irradiation. Int J Radiat Biol 72:45-53.
14. Campanella, M., C. Sciorati, G. Tarozzo, and M. Beltramo. 2002. Flow cytometric analysis of inflammatory cells in ischemic rat brain. Stroke 33:586-592.
15. Wang, T. H., Y. S. Lee, E. S. Chen, W. H. Kong, L. K. Chen, D. W. Hsueh, M. L. Wei, and H. S. Wang. 2004. Establishment of cDNA microarray analysis at the Genomic Medicine Research Core Laboratory (GMRCL) of Chang Gung Memorial Hospital. Chang Gung Med J 27:243-260.
16. Weiner, N. E., R. B. Pyles, C. L. Chalk, M. G. Balko, M. A. Miller, C. A. Dyer, R. E. Warnick, and L. M. Parysek. 1999. A syngeneic mouse glioma model for study of glioblastoma therapy. J Neuropathol Exp Neurol 58:54-60.
17. Tascos, N. A., J. Parr, and N. K. Gonatas. 1982. Immunocytochemical study of the glial fibrillary acidic protein in human neoplasms of the central nervous system. Hum Pathol 13:454-458.
18. Ohgaki, H., and P. Kleihues. 2009. Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci 100:2235-2241.
19. Wei, Q., L. Clarke, D. K. Scheidenhelm, B. Qian, A. Tong, N. Sabha, Z. Karim, N. A. Bock, R. Reti, R. Swoboda, E. Purev, J. F. Lavoie, M. L. Bajenaru, P. Shannon, D. Herlyn, D. Kaplan, R. M. Henkelman, D. H. Gutmann, and A. Guha. 2006. High-grade glioma formation results from postnatal pten loss or mutant epidermal growth factor receptor expression in a transgenic mouse glioma model. Cancer Res 66:7429-7437.
20. Szatmari, T., K. Lumniczky, S. Desaknai, S. Trajcevski, E. J. Hidvegi, H. Hamada, and G. Safrany. 2006. Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy. Cancer Sci 97:546-553.
21. Ausman, J. I., W. R. Shapiro, and D. P. Rall. 1970. Studies on the chemotherapy of experimental brain tumors: development of an experimental model. Cancer Res 30:2394-2400.
22. Parsons, D. W., S. Jones, X. Zhang, J. C. Lin, R. J. Leary, P. Angenendt, P. Mankoo, H. Carter, I. M. Siu, G. L. Gallia, A. Olivi, R. McLendon, B. A. Rasheed, S. Keir, T. Nikolskaya, Y. Nikolsky, D. A. Busam, H. Tekleab, L. A. Diaz, Jr., J. Hartigan, D. R. Smith, R. L. Strausberg, S. K. Marie, S. M. Shinjo, H. Yan, G. J. Riggins, D. D. Bigner, R. Karchin, N. Papadopoulos, G. Parmigiani, B. Vogelstein, V. E. Velculescu, and K. W. Kinzler. 2008. An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807-1812.
23. Raychaudhuri, B., P. Rayman, J. Ireland, J. Ko, B. Rini, E. C. Borden, J. Garcia, M. A. Vogelbaum, and J. Finke. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol 13:591-599.
24. Tashiro, K., H. Tada, R. Heilker, M. Shirozu, T. Nakano, and T. Honjo. 1993. Signal sequence trap: a cloning strategy for secreted proteins and type I membrane proteins. Science 261:600-603.
25. Thelen, M. 2001. Dancing to the tune of chemokines. Nat Immunol 2:129-134.
26. Zhou, Y., P. H. Larsen, C. Hao, and V. W. Yong. 2002. CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J Biol Chem 277:49481-49487.
27. Barbero, S., R. Bonavia, A. Bajetto, C. Porcile, P. Pirani, J. L. Ravetti, G. L. Zona, R. Spaziante, T. Florio, and G. Schettini. 2003. Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res 63:1969-1974.
28. Bajetto, A., F. Barbieri, A. Dorcaratto, S. Barbero, A. Daga, C. Porcile, J. L. Ravetti, G. Zona, R. Spaziante, G. Corte, G. Schettini, and T. Florio. 2006. Expression of CXC chemokine receptors 1-5 and their ligands in human glioma tissues: role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochem Int 49:423-432.
29. Zlotnik, A. 2004. Chemokines in neoplastic progression. Semin Cancer Biol 14:181-185.
30. Kucia, M., K. Jankowski, R. Reca, M. Wysoczynski, L. Bandura, D. J. Allendorf, J. Zhang, J. Ratajczak, and M. Z. Ratajczak. 2004. CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol 35:233-245.
31. Salvucci, O., L. Yao, S. Villalba, A. Sajewicz, S. Pittaluga, and G. Tosato. 2002. Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1. Blood 99:2703-2711.
32. Sung, B., S. Jhurani, K. S. Ahn, Y. Mastuo, T. Yi, S. Guha, M. Liu, and B. B. Aggarwal. 2008. Zerumbone down-regulates chemokine receptor CXCR4 expression leading to inhibition of CXCL12-induced invasion of breast and pancreatic tumor cells. Cancer Res 68:8938-8944.
33. Balkwill, F. 2003. Chemokine biology in cancer. Semin Immunol 15:49-55.
34. Dewan, M. Z., S. Ahmed, Y. Iwasaki, K. Ohba, M. Toi, and N. Yamamoto. 2006. Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer. Biomed Pharmacother 60:273-276.
35. Luker, K. E., and G. D. Luker. 2006. Functions of CXCL12 and CXCR4 in breast cancer. Cancer Lett 238:30-41.
36. Liang, Z., H. Wu, S. Reddy, A. Zhu, S. Wang, D. Blevins, Y. Yoon, Y. Zhang, and H. Shim. 2007. Blockade of invasion and metastasis of breast cancer cells via targeting CXCR4 with an artificial microRNA. Biochem Biophys Res Commun 363:542-546.
37. Orimo, A., P. B. Gupta, D. C. Sgroi, F. Arenzana-Seisdedos, T. Delaunay, R. Naeem, V. J. Carey, A. L. Richardson, and R. A. Weinberg. 2005. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335-348.
38. Zheng, H., G. Fu, T. Dai, and H. Huang. 2007. Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1alpha/CXCR4 via PI3K/Akt/eNOS signal transduction pathway. J Cardiovasc Pharmacol 50:274-280.
39. Flynn, G., S. Maru, J. Loughlin, I. A. Romero, and D. Male. 2003. Regulation of chemokine receptor expression in human microglia and astrocytes. J Neuroimmunol 136:84-93.
40. Li, M., and R. M. Ransohoff. 2008. Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol 84:116-131.
41. Bajetto, A., R. Bonavia, S. Barbero, T. Florio, and G. Schettini. 2001. Chemokines and their receptors in the central nervous system. Front Neuroendocrinol 22:147-184.
42. McCandless, E. E., L. Piccio, B. M. Woerner, R. E. Schmidt, J. B. Rubin, A. H. Cross, and R. S. Klein. 2008. Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis. Am J Pathol 172:799-808.
43. Mantovani, A., A. Sica, S. Sozzani, P. Allavena, A. Vecchi, and M. Locati. 2004. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677-686.
44. Salmaggi, A., M. Gelati, B. Pollo, S. Frigerio, M. Eoli, A. Silvani, G. Broggi, E. Ciusani, D. Croci, A. Boiardi, and M. De Rossi. 2004. CXCL12 in malignant glial tumors: a possible role in angiogenesis and cross-talk between endothelial and tumoral cells. J Neurooncol 67:305-317.
45. Aghi, M., K. S. Cohen, R. J. Klein, D. T. Scadden, and E. A. Chiocca. 2006. Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res 66:9054-9064.
46. Komatani, H., Y. Sugita, F. Arakawa, K. Ohshima, and M. Shigemori. 2009. Expression of CXCL12 on pseudopalisading cells and proliferating microvessels in glioblastomas: an accelerated growth factor in glioblastomas. Int J Oncol 34:665-672.
47. Hendrix, M. J., E. A. Seftor, D. A. Kirschmann, and R. E. Seftor. 2000. Molecular biology of breast cancer metastasis. Molecular expression of vascular markers by aggressive breast cancer cells. Breast Cancer Res 2:417-422.
48. Liotta, L. A., and E. C. Kohn. 2001. The microenvironment of the tumour-host interface. Nature 411:375-379.
49. Radisky, D., C. Hagios, and M. J. Bissell. 2001. Tumors are unique organs defined by abnormal signaling and context. Seminars in cancer biology 11:87-95.
50. Folkman, J. 1971. Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182-1186.
51. Ahmad, M., N. R. Khurana, and J. E. Jaberi. 2007. Ionizing radiation decreases capillary-like structure formation by endothelial cells in vitro. Microvasc Res 73:14-19.
52. Tsai, J. H., S. Makonnen, M. Feldman, C. M. Sehgal, A. Maity, and W. M. Lee. 2005. Ionizing radiation inhibits tumor neovascularization by inducing ineffective angiogenesis. Cancer Biol Ther 4:1395-1400.
53. Chen, F. H., C. S. Chiang, C. C. Wang, C. S. Tsai, S. M. Jung, C. C. Lee, W. H. McBride, and J. H. Hong. 2009. Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors. Clin Cancer Res 15:1721-1729.
54. Chen, F. H., C. S. Chiang, C. C. Wang, S. Y. Fu, C. S. Tsai, S. M. Jung, C. J. Wen, C. C. Lee, and J. H. Hong. Vasculatures in tumors growing from preirradiated tissues: formed by vasculogenesis and resistant to radiation and antiangiogenic therapy. Int J Radiat Oncol Biol Phys 80:1512-1521.
55. Mantovani, A., S. Sozzani, M. Locati, P. Allavena, and A. Sica. 2002. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23:549-555.
56. Dirkx, A. E., M. G. Oude Egbrink, J. Wagstaff, and A. W. Griffioen. 2006. Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol 80:1183-1196.
57. Murdoch, C., and C. E. Lewis. 2005. Macrophage migration and gene expression in response to tumor hypoxia. Int J Cancer 117:701-708.
58. Lewis, C., and C. Murdoch. 2005. Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies. Am J Pathol 167:627-635.
59. Carmeliet, P., and R. K. Jain. 2000. Angiogenesis in cancer and other diseases. Nature 407:249-257.
60. Lewis, J. S., R. J. Landers, J. C. Underwood, A. L. Harris, and C. E. Lewis. 2000. Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. The Journal of pathology 192:150-158.
61. Pollard, J. W. 2004. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71-78.
62. Milas, L., H. Ito, N. Hunter, S. Jones, and L. J. Peters. 1986. Retardation of tumor growth in mice caused by radiation-induced injury of tumor bed stroma: dependency on tumor type. Cancer research 46:723-727.
63. Leitao, M. M., Jr., and D. S. Chi. 2002. Recurrent cervical cancer. Curr Treat Options Oncol 3:105-111.
64. Kao, J., M. C. Garofalo, M. T. Milano, S. J. Chmura, J. R. Citron, and D. J. Haraf. 2003. Reirradiation of recurrent and second primary head and neck malignancies: a comprehensive review. Cancer Treat Rev 29:21-30.
65. Ito, H., T. Barkley, Jr., L. J. Peters, and L. Milas. 1985. Modification of tumor response to cyclophosphamide and irradiation by preirradiation of the tumor bed: prolonged growth delay but reduced curability. International journal of radiation oncology, biology, physics 11:547-553.
66. Milas, L., H. Hirata, N. Hunter, and L. J. Peters. 1988. Effect of radiation-induced injury of tumor bed stroma on metastatic spread of murine sarcomas and carcinomas. Cancer research 48:2116-2120.
67. Vicini, F. A., L. Kestin, R. Huang, and A. Martinez. 2003. Does local recurrence affect the rate of distant metastases and survival in patients with early-stage breast carcinoma treated with breast-conserving therapy? Cancer 97:910-919.
68. Milas, L. 1990. Tumor bed effect in murine tumors: relationship to tumor take and tumor macrophage content. Radiat Res 123:232-236.
69. Jirtle, R., J. H. Rankin, and K. H. Clifton. 1978. Effect of x-irradiation of tumour bed on tumour blood flow and vascular response to drugs. Br J Cancer 37:1033-1038.
70. Tsai, C. S., F. H. Chen, C. C. Wang, H. L. Huang, S. M. Jung, C. J. Wu, C. C. Lee, W. H. McBride, C. S. Chiang, and J. H. Hong. 2007. Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. Int J Radiat Oncol Biol Phys 68:499-507.
71. Milas, L., N. Hunter, and L. J. Peters. 1989. Tumor bed effect-induced reduction of tumor radiocurability through the increase in hypoxic cell fraction. Int J Radiat Oncol Biol Phys 16:139-142.
72. Monnier, Y., P. Farmer, G. Bieler, N. Imaizumi, T. Sengstag, G. C. Alghisi, J. C. Stehle, L. Ciarloni, S. Andrejevic-Blant, R. Moeckli, R. O. Mirimanoff, S. L. Goodman, M. Delorenzi, and C. Ruegg. 2008. CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma. Cancer Res 68:7323-7331.
73. Zagzag, D., D. C. Miller, L. Chiriboga, H. Yee, and E. W. Newcomb. 2003. Green fluorescent protein immunohistochemistry as a novel experimental tool for the detection of glioma cell invasion in vivo. Brain Pathol 13:34-37.
74. Benito, R., R. Gil-Benso, V. Quilis, M. Perez, M. Gregori-Romero, P. Roldan, J. Gonzalez-Darder, M. Cerda-Nicolas, and C. Lopez-Gines. Primary glioblastomas with and without EGFR amplification: relationship to genetic alterations and clinicopathological features. Neuropathology 30:392-400.
75. Lee, S. H., J. H. Kim, C. H. Rhee, Y. S. Kang, J. H. Lee, S. I. Hong, and K. S. Choi. 1995. Loss of heterozygosity on chromosome 10, 13q(Rb), 17p, and p53 gene mutations in human brain gliomas. J Korean Med Sci 10:442-448.
76. Newcomb, E. W., and D. Zagzag. 2009. The Murine GL261 Glioma Experimental Model to Assess Novel Brain Tumor Treatments. In CNS Cancer, Cancer Drug Discovery and Development. E. G. Van Meir, ed. Humana Press. 227 - 241.
77. Moskovits, N., A. Kalinkovich, J. Bar, T. Lapidot, and M. Oren. 2006. p53 Attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts. Cancer Res 66:10671-10676.
78. Addadi, Y., N. Moskovits, D. Granot, G. Lozano, Y. Carmi, R. N. Apte, M. Neeman, and M. Oren. 2010. p53 Status in Stromal Fibroblasts Modulates Tumor Growth in an SDF1-Dependent Manner. Cancer Res 70:9650-9658.
79. Hu, B., P. Guo, Q. Fang, H. Q. Tao, D. Wang, M. Nagane, H. J. Huang, Y. Gunji, R. Nishikawa, K. Alitalo, W. K. Cavenee, and S. Y. Cheng. 2003. Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proceedings of the National Academy of Sciences of the United States of America 100:8904-8909.
80. Weiss, W. A., M. Israel, C. Cobbs, E. Holland, C. D. James, D. N. Louis, C. Marks, A. I. McClatchey, T. Roberts, T. Van Dyke, C. Wetmore, I. M. Chiu, M. Giovannini, A. Guha, R. J. Higgins, S. Marino, I. Radovanovic, K. Reilly, and K. Aldape. 2002. Neuropathology of genetically engineered mice: consensus report and recommendations from an international forum. Oncogene 21:7453-7463.
81. Fidler, I. J. 1990. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 50:6130-6138.
82. Fidler, I. J., C. Wilmanns, A. Staroselsky, R. Radinsky, Z. Dong, and D. Fan. 1994. Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev 13:209-222.
83. Foster, B. A., J. R. Gingrich, E. D. Kwon, C. Madias, and N. M. Greenberg. 1997. Characterization of prostatic epithelial cell lines derived from transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Cancer Res 57:3325-3330.
84. Qian, B. Z., and J. W. Pollard. 2010. Macrophage diversity enhances tumor progression and metastasis. Cell 141:39-51.
85. Lewis, C. E., and J. W. Pollard. 2006. Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605-612.
86. Bingle, L., N. J. Brown, and C. E. Lewis. 2002. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 196:254-265.
87. Mantovani, A., W. J. Ming, C. Balotta, B. Abdeljalil, and B. Bottazzi. 1986. Origin and regulatin of tumor-associated macrophages: the role of tumor-derived chemotactic facotr. Biochim Biophys. Acta 865:59- 67.
88. Chiang, C. S., F. H. Chen, J. H. Hong, P. S. Jiang, H. L. Huang, C. C. Wang, and W. H. McBride. 2008. Functional phenotype of macrophages depends on assay procedures. Int Immunol 20:215-222.
89. Stout, R. D., C. Jiang, B. Matta, I. Tietzel, S. K. Watkins, and J. Suttles. 2005. Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. J Immunol 175:342-349.
90. Watters, J. J., J. M. Schartner, and B. Badie. 2005. Microglia function in brain tumors. Journal of Neuroscience Research 81:447-455.
91. Komohara, Y., K. Ohnishi, J. Kuratsu, and M. Takeya. 2008. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 216:15-24.
92. Strik, H. M., M. H. Deininger, B. Frank, H. J. Schluesener, and R. Meyermann. 2001. Galectin-3: cellular distribution and correlation with WHO-grade in human gliomas. J Neurooncol 53:13-20.
93. Watters, J. J., J. M. Schartner, and B. Badie. 2005. Microglia function in brain tumors. J Neurosci Res 81:447-455.
94. Utsugi, T., A. J. Schroit, J. Connor, C. D. Bucana, and I. J. Fidler. 1991. Elevated expression of phosphatidylserine in the outer membrane leaflet of human tumor cells and recognition by activated human blood monocytes. Cancer Res 51:3062-3066.
95. Chan, W. Y., S. Kohsaka, and P. Rezaie. 2007. The origin and cell lineage of microglia: new concepts. Brain Res Rev 53:344-354.
96. Davoust, N., C. Vuaillat, G. Androdias, and S. Nataf. 2008. From bone marrow to microglia: barriers and avenues. Trends Immunol 29:227-234.
97. Zhang, M., and Y. Olsson. 1995. Reactions of astrocytes and microglial cells around hematogenous metastases of the human brain. Expression of endothelin-like immunoreactivity in reactive astrocytes and activation of microglial cells. J Neurol Sci 134:26-32.
98. Ransohoff, R. M., and V. H. Perry. 2009. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119-145.
99. Kioi, M., H. Vogel, G. Schultz, R. M. Hoffman, G. R. Harsh, and J. M. Brown. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 120:694-705.
100. Kozin, S. V., W. S. Kamoun, Y. Huang, M. R. Dawson, R. K. Jain, and D. G. Duda. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res 70:5679-5685.
101. Heissig, B., K. Hattori, S. Dias, M. Friedrich, B. Ferris, N. R. Hackett, R. G. Crystal, P. Besmer, D. Lyden, M. A. Moore, Z. Werb, and S. Rafii. 2002. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109:625-637.
102. Urbich, C., C. Heeschen, A. Aicher, K. Sasaki, T. Bruhl, M. R. Farhadi, P. Vajkoczy, W. K. Hofmann, C. Peters, L. A. Pennacchio, N. D. Abolmaali, E. Chavakis, T. Reinheckel, A. M. Zeiher, and S. Dimmeler. 2005. Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nat Med 11:206-213.
103. Kollet, O., A. Dar, S. Shivtiel, A. Kalinkovich, K. Lapid, Y. Sztainberg, M. Tesio, R. M. Samstein, P. Goichberg, A. Spiegel, A. Elson, and T. Lapidot. 2006. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 12:657-664.
104. Aiuti, A., I. J. Webb, C. Bleul, T. Springer, and J. C. Gutierrez-Ramos. 1997. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 185:111-120.
105. Pusic, I., and J. F. DiPersio. 2010. Update on clinical experience with AMD3100, an SDF-1/CXCL12-CXCR4 inhibitor, in mobilization of hematopoietic stem and progenitor cells. Curr Opin Hematol 17:319-326.
106. Kioi, M., H. Vogel, G. Schultz, R. M. Hoffman, G. R. Harsh, and J. M. Brown. 2010. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 120:694-705.
107. Rempel, S. A., S. Dudas, S. Ge, and J. A. Gutierrez. 2000. 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 6:102-111.
108. Salcedo, R., and J. J. Oppenheim. 2003. Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 10:359-370.
109. Kenig, S., M. B. Alonso, M. M. Mueller, and T. T. Lah. 2010. Glioblastoma and endothelial cells cross-talk, mediated by SDF-1, enhances tumour invasion and endothelial proliferation by increasing expression of cathepsins B, S, and MMP-9. Cancer Lett 289:53-61.
110. Rehman, A. O., and C. Y. Wang. 2009. CXCL12/SDF-1 alpha activates NF-kappaB and promotes oral cancer invasion through the Carma3/Bcl10/Malt1 complex. Int J Oral Sci 1:105-118.
111. Ceradini, D. J., A. R. Kulkarni, M. J. Callaghan, O. M. Tepper, N. Bastidas, M. E. Kleinman, J. M. Capla, R. D. Galiano, J. P. Levine, and G. C. Gurtner. 2004. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858-864.
112. Wang, Y., H. Haider, N. Ahmad, D. Zhang, and M. Ashraf. 2006. Evidence for ischemia induced host-derived bone marrow cell mobilization into cardiac allografts. J Mol Cell Cardiol 41:478-487.
113. Jin, D. K., K. Shido, H. G. Kopp, I. Petit, S. V. Shmelkov, L. M. Young, A. T. Hooper, H. Amano, S. T. Avecilla, B. Heissig, K. Hattori, F. Zhang, D. J. Hicklin, Y. Wu, Z. Zhu, A. Dunn, H. Salari, Z. Werb, N. R. Hackett, R. G. Crystal, D. Lyden, and S. Rafii. 2006. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med 12:557-567.
114. Grunewald, M., I. Avraham, Y. Dor, E. Bachar-Lustig, A. Itin, S. Jung, S. Chimenti, L. Landsman, R. Abramovitch, and E. Keshet. 2006. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175-189.
115. Fang, H. Y., R. Hughes, C. Murdoch, S. B. Coffelt, S. K. Biswas, A. L. Harris, R. S. Johnson, H. Z. Imityaz, M. C. Simon, E. Fredlund, F. R. Greten, J. Rius, and C. E. Lewis. 2009. Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 114:844-859.
116. Yin, Q., P. Jin, X. Liu, H. Wei, X. Lin, C. Chi, Y. Liu, C. Sun, and Y. Wei. 2011. SDF-1alpha inhibits hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells through PI3K/Akt and ERK1/2 signaling pathways. Mol Biol Rep 38:9-16.
117. De Clercq, E. 2005. Potential clinical applications of the CXCR4 antagonist bicyclam AMD3100. Mini Rev Med Chem 5:805-824.
118. Tsutsumi, H., T. Tanaka, N. Ohashi, H. Masuno, H. Tamamura, K. Hiramatsu, T. Araki, S. Ueda, S. Oishi, and N. Fujii. 2007. Therapeutic potential of the chemokine receptor CXCR4 antagonists as multifunctional agents. Biopolymers 88:279-289.
119. Zagzag, D., Y. Lukyanov, L. Lan, M. A. Ali, M. Esencay, O. Mendez, H. Yee, E. B. Voura, and E. W. Newcomb. 2006. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 86:1221-1232.
120. Ping, Y. F., X. H. Yao, J. Y. Jiang, L. T. Zhao, S. C. Yu, T. Jiang, M. C. Lin, J. H. Chen, B. Wang, R. Zhang, Y. H. Cui, C. Qian, J. M. Wang, and X. W. Bian. The chemokine CXCL12 and its receptor CXCR4 promote glioma stem cell-mediated VEGF production and tumour angiogenesis via PI3K/AKT signalling. J Pathol.
121. Cali, C., and P. Bezzi. 2010. CXCR4-mediated glutamate exocytosis from astrocytes. J Neuroimmunol 224:13-21.
122. Solinas, G., S. Schiarea, M. Liguori, M. Fabbri, S. Pesce, L. Zammataro, F. Pasqualini, M. Nebuloni, C. Chiabrando, A. Mantovani, and P. Allavena. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J Immunol 185:642-652.
123. Leek, R. D., C. E. Lewis, R. Whitehouse, M. Greenall, J. Clarke, and A. L. Harris. 1996. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625-4629.
124. Mantovani, A., P. Allavena, and A. Sica. 2004. Tumour-associated macrophages as a prototypic type II polarised phagocyte population: role in tumour progression. Eur J Cancer 40:1660-1667.
125. Allavena, P., M. Signorelli, M. Chieppa, E. Erba, G. Bianchi, F. Marchesi, C. O. Olimpio, C. Bonardi, A. Garbi, A. Lissoni, F. de Braud, J. Jimeno, and M. D'Incalci. 2005. Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res 65:2964-2971.
126. Kim, I. H., M. J. Lemmon, and J. M. Brown. 1993. The influence of irradiation of the tumor bed on tumor hypoxia: measurements by radiation response, oxygen electrodes, and nitroimidazole binding. Radiat Res 135:411-417.
127. Rubin, J. B., A. L. Kung, R. S. Klein, J. A. Chan, Y. Sun, K. Schmidt, M. W. Kieran, A. D. Luster, and R. A. Segal. 2003. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A 100:13513-13518.
128. Ohno, S., Y. Ohno, N. Suzuki, T. Kamei, K. Koike, H. Inagawa, C. Kohchi, G. Soma, and M. Inoue. 2004. Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer. Anticancer Res 24:3335-3342.
129. Heissig, B., S. Rafii, H. Akiyama, Y. Ohki, Y. Sato, T. Rafael, Z. Zhu, D. J. Hicklin, K. Okumura, H. Ogawa, Z. Werb, and K. Hattori. 2005. Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. J Exp Med 202:739-750.
130. Madlambayan, G. J., J. M. Butler, K. Hosaka, M. Jorgensen, D. Fu, S. M. Guthrie, A. K. Shenoy, A. Brank, K. J. Russell, J. Otero, D. W. Siemann, E. W. Scott, and C. R. Cogle. 2009. Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger. Blood 114:4310-4319.
131. Bailey, A. S., H. Willenbring, S. Jiang, D. A. Anderson, D. A. Schroeder, M. H. Wong, M. Grompe, and W. H. Fleming. 2006. Myeloid lineage progenitors give rise to vascular endothelium. Proc Natl Acad Sci U S A 103:13156-13161.
132. Ahn, G. O., and J. M. Brown. 2008. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13:193-205.
133. De Falco, E., D. Porcelli, A. R. Torella, S. Straino, M. G. Iachininoto, A. Orlandi, S. Truffa, P. Biglioli, M. Napolitano, M. C. Capogrossi, and M. Pesce. 2004. SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood 104:3472-3482.
134. Ohki, Y., B. Heissig, Y. Sato, H. Akiyama, Z. Zhu, D. J. Hicklin, K. Shimada, H. Ogawa, H. Daida, K. Hattori, and A. Ohsaka. 2005. Granulocyte colony-stimulating factor promotes neovascularization by releasing vascular endothelial growth factor from neutrophils. FASEB J 19:2005-2007.
135. Korbling, M., J. M. Reuben, H. Gao, B. N. Lee, D. M. Harris, D. Cogdell, S. A. Giralt, I. F. Khouri, R. M. Saliba, R. E. Champlin, W. Zhang, and Z. Estrov. 2006. Recombinant human granulocyte-colony-stimulating factor-mobilized and apheresis-collected endothelial progenitor cells: a novel blood cell component for therapeutic vasculogenesis. Transfusion 46:1795-1802.
136. Misao, Y., G. Takemura, M. Arai, T. Ohno, H. Onogi, T. Takahashi, S. Minatoguchi, T. Fujiwara, and H. Fujiwara. 2006. Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF. Cardiovasc Res 71:455-465.