_:b462899060 . _:b462899061 . _:b462899038 "2"^^ . _:b462899062 . _:b462899004 . _:b462899063 . _:b462899056 . _:b462899057 . _:b462899033 "2"^^ . _:b462899058 . _:b462899007 . _:b462899059 . _:b462899068 . . _:b462899069 . _:b462899122 . _:b462899032 "2"^^ . . _:b462899070 . _:b462899006 . _:b462899071 . _:b462899064 . _:b462899065 . _:b462899035 "2"^^ . _:b462899066 . _:b462899001 . . _:b462899067 . _:b462899044 . _:b462899045 . _:b462899021 . _:b462899034 "2"^^ . _:b462899046 . _:b462899000 . _:b462899095 . _:b462899047 . _:b462899040 . _:b462899041 . _:b462899045 "2"^^ . _:b462899042 . _:b462899003 . _:b462899043 . _:b462899052 . . _:b462899053 . _:b462899044 "2"^^ . _:b462899054 . _:b462899002 . _:b462899055 . _:b462899048 . _:b462899030 . _:b462899049 . _:b462899047 "2"^^ . _:b462899104 . _:b462899050 . _:b462899013 . . _:b462899051 . _:b462899028 . _:b462899029 . _:b462899046 "2"^^ . _:b462899030 . _:b462899012 . _:b462899031 . _:b462899024 . . _:b462899025 . _:b462899041 "2"^^ . _:b462899026 . _:b462899015 . _:b462899027 . _:b462899036 . _:b462899037 . _:b462899040 "2"^^ . . _:b462899038 . _:b462899014 . _:b462899039 . _:b462899032 . . _:b462899033 . _:b462899043 "2"^^ . _:b462899034 . _:b462899009 . _:b462899035 . _:b462899012 . _:b462899013 . _:b462899042 "2"^^ . _:b462899014 . _:b462899008 . _:b462899015 . _:b462899008 . _:b462899009 . _:b462899053 "2"^^ . _:b462899010 . _:b462899011 . _:b462899011 . _:b462899055 . _:b462899020 . _:b462899021 . _:b462899052 "2"^^ . _:b462899022 . _:b462899010 . _:b462899023 . _:b462899016 . _:b462899094 . _:b462899017 . _:b462899055 "2"^^ . _:b462899018 . _:b462899021 . . _:b462899019 . _:b462899124 . _:b462899125 . _:b462899102 . _:b462898992 . _:b462899126 . _:b462899054 "2"^^ . _:b462899020 . _:b462899127 . _:b462899120 . _:b462899121 . _:b11100948 "In pre-clinical models, several investigators have reported that radiation inhibits local angiogenesis, the generation of new vessels from surrounding vessels (Udagawa et al, >>2007<<; Imaizumi et al, 2010)." . _:b462899100 . _:b462899049 "2"^^ . _:b462899122 . _:b462899023 . _:b462899123 . _:b462899048 "2"^^ . _:b462899022 . _:b462899128 . _:b462899129 . _:b462899051 "2"^^ . . _:b462899130 . _:b462899017 . _:b462899108 . _:b462899109 . _:b462899050 "2"^^ . _:b11100949 "In pre-clinical models, several investigators have reported that radiation inhibits local angiogenesis, the generation of new vessels from surrounding vessels (Udagawa et al, 2007; Imaizumi et al, >>2010<<). However, in these studies it is difficult to determine whether cells, locally or distantly, mediate tumour revascularisation after irradiation. To interrogate whether new vasculature formation relies on a different mechanism in the" . _:b462899110 . _:b462899016 . _:b462899111 . _:b462899104 . _:b462899105 . _:b462899061 "2"^^ . _:b462899106 . _:b462899019 . _:b462899107 . _:b462899116 . _:b462899117 . _:b462899060 "2"^^ . _:b11100944 "Chemotaxis of CXCR4-expressing murine muscle satellite cells towards SDF-1 has also been demonstrated, suggesting that migration of tissue-specific stem cells may be regulated by SDF-1 (Ratajczak et al, >>2003<<)." . _:b462899118 . _:b462899018 . . _:b462899119 . _:b462899112 . _:b462899113 . _:b462899024 . _:b462899063 "2"^^ . _:b462899114 . _:b462899049 . _:b462899029 . _:b462899115 . _:b462899092 . _:b462899019 . _:b462899093 . . _:b462899094 . _:b462899062 "2"^^ . _:b462899028 . _:b462899095 . _:b462899088 . _:b462899089 . _:b462899014 . _:b462899090 . . _:b462899057 "2"^^ . _:b462899031 . _:b462899091 . _:b462899100 . _:b462899101 . _:b462899056 "2"^^ . _:b462899062 . _:b462899102 . _:b462899030 . _:b11100938 . _:b462899115 . _:b462899103 . _:b462899096 . . _:b462899097 . _:b462899059 "2"^^ . _:b462899098 . _:b462899025 . _:b462899099 . _:b462899076 . _:b462899077 . _:b462899058 "2"^^ . _:b11100950 "Tumour growth is restored following irradiation if the bone marrow in the MMP-9 KO mouse is replaced with wild-type bone marrow (Ahn and Brown, >>2008<<). Thus, MMP-9 from cells in the bone marrow transplant could restore tumour vasculature (determined by CD31 immunostaining and injection of Hoechst dye) and support tumour growth at a pre-irradiated site. This illustrated that" . _:b462899078 . _:b462899024 . _:b462899079 . _:b462899072 . _:b462899073 . _:b462899069 "2"^^ . _:b462899074 . _:b462899027 . _:b462899075 . _:b462899084 . _:b462899085 . _:b462899068 "2"^^ . _:b462899086 . _:b462899026 . _:b462899087 . _:b462899083 . _:b462899080 . _:b462899081 . _:b462899071 "2"^^ . _:b11100975 "CXCR7 has also recently been shown to be co-expressed with CXCR4 on cortical interneurons and to be essential for their SDF-1-stimulated migration (Sanchez-Alcaniz et al, >>2011<<). CD11b+ cells in the irradiated tumour may also help recruit ECs into the tumour or help reorganise the tumour extracellular matrix via MMP-9 to mediate revascularisation. Thus, the restoration of the tumour vasculature following" . _:b462899082 . _:b462899037 . _:b462899083 . _:b462899018 . _:b11100941 . _:b462899070 "2"^^ . _:b462899036 . _:b462899065 "2"^^ . _:b462899039 . _:b462899086 . _:b11100943 . _:b462899064 "2"^^ . _:b462899038 . _:b462898984 . . _:b462899067 "2"^^ . _:b462899033 . . _:b462899066 "2"^^ . _:b462899032 . . _:b462899090 . _:b462899077 "2"^^ . _:b11100935 "As recurrences outside the radiation field were observed after a longer follow-up time, different mechanisms may be responsible for in-field and out-of-field recurrences (Minniti et al, >>2010<<). Blocking tumour revascularisation after irradiation by inhibiting vasculogenesis would be the most relevant method to prevent recurrences of GBM in the radiation field and this strategy would benefit the majority of patients with GBM." . _:b462899035 . _:b462899076 "2"^^ . _:b462899034 . . . _:b462899079 "2"^^ . _:b462899045 . _:b462899008 . _:b462899036 . . _:b462899078 "2"^^ . _:b462899044 . . . _:b11100952 . _:b462899073 "2"^^ . _:b462899047 . . _:b462899072 "2"^^ . _:b11100955 . _:b462899046 . _:b462899121 . _:b462899112 . . _:b462899075 "2"^^ . _:b462899041 . . _:b462898995 . _:b462899074 "2"^^ . _:b462899040 . . _:b462899085 "2"^^ . _:b462899043 . . _:b11100952 "We and others who have measured tumour ECs after irradiation do not see this rapid apoptosis (Kioi et al, >>2010<<; Kozin et al, 2010)." . _:b462899084 "2"^^ . _:b462899042 . _:b462899087 "2"^^ . _:b462899053 . _:b462899037 . . _:b11100971 "Other investigators have shown using either orthotopic aortic allografting (Hillebrands et al, 2002) or a parabiotic mouse system combined with reverse bone marrow transplantation (Aicher et al, >>2007<<) that non-bone marrow-derived circulating ECs or EPCs from the liver and small intestine home to sites of active angiogenesis." . _:b462899039 . _:b462899086 "2"^^ . _:b462899052 . _:b11100945 "the role of sdf-1/cxcr4 in restoring functional vasculature in irradiated gbms" . _:b462899081 "2"^^ . _:b462899055 . _:b462899080 "2"^^ . _:b462899054 . . _:b462899083 "2"^^ . _:b462899033 . _:b462899049 . _:b462899082 "2"^^ . _:b462899048 . . _:b462899093 "2"^^ . _:b462899051 . _:b11100973 . _:b462899092 "2"^^ . _:b462899050 . _:b462899095 "2"^^ . _:b462899061 . _:b462899094 "2"^^ . _:b462899060 . _:b11100956 . _:b462899089 "2"^^ . _:b462899063 . . _:b462899088 "2"^^ . _:b462899062 . . _:b462899091 "2"^^ . _:b462899057 . _:b462899090 "2"^^ . _:b462899056 . . _:b462899101 "2"^^ . _:b462899059 . _:b462899107 . _:b462899100 "2"^^ . _:b462899058 . _:b462899029 . _:b462899011 . _:b462899103 "2"^^ . _:b462899069 . _:b11100937 "The interaction between the CXCR4 receptor and its ligand, SDF-1\u03B1, has been shown to mediate tumour metastasis (Muller et al, >>2001<<; Sun et al, 2005). Overexpression of CXCR4 has been detected in a variety of human malignancies, including breast, pancreatic, prostate cancer, and GBM." . . _:b462899102 "2"^^ . _:b462899068 . _:b11100969 . _:b462899097 "2"^^ . _:b462899071 . _:b462899096 "2"^^ . _:b462899070 . . _:b462898988 . _:b462899099 "2"^^ . _:b462899065 . _:b11100976 . . _:b462899098 "2"^^ . _:b462899064 . _:b462899003 . . _:b462899109 "2"^^ . _:b462899067 . _:b11100954 . _:b462899108 "2"^^ . _:b462899066 . _:b462898990 . _:b11100953 "We and others who have measured tumour ECs after irradiation do not see this rapid apoptosis (Kioi et al, 2010; Kozin et al, >>2010<<). Rather, we observe that ECs disappear slowly after irradiation over several days, consistent with a mitotically linked death." . _:b11100934 . _:b462899111 "2"^^ . _:b462899077 . . _:b462899006 . _:b462899110 "2"^^ . _:b462899076 . _:b462899105 "2"^^ . _:b462899041 . _:b462899079 . _:b462899012 . . _:b462899119 . . _:b462899104 "2"^^ . _:b462899078 . _:b462899107 "2"^^ . _:b462899073 . _:b462899073 . _:b462899042 . _:b462899106 "2"^^ . _:b462899072 . . _:b462899117 "2"^^ . _:b462899075 . _:b11100947 . _:b11100944 . _:b11100966 "From such studies, we and others concluded that the ECs in the tumour do not arise from cells in the bone marrow (Ahn and Brown, >>2008<<; Kioi et al, 2010; Kozin et al, 2010)." . . _:b11100961 "We and others have shown that SDF-1 levels are increased in irradiated tumours (Kioi et al, >>2010<<; Kozin et al, 2010) and in the plasma following local tumour irradiation of intracranial GBM (unpublished data)." . _:b462899116 "2"^^ . _:b462899074 . _:b462899109 . _:b462899045 . _:b462899119 "2"^^ . _:b462899085 . _:b462899118 "2"^^ . _:b462899084 . _:b462899004 . . _:b462899113 "2"^^ . _:b462899087 . _:b462899112 "2"^^ . _:b462899086 . _:b11100971 . _:b11100966 . . _:b11100939 "Muller et al (>>2001<<) demonstrated that CXCR4 is expressed in primary breast cancer cells and that SDF-1 was highly expressed in the most common sites of metastasis, including the lymph nodes, lungs, liver, and bone." . _:b462899077 . _:b462899115 "2"^^ . _:b462899081 . _:b462899028 . _:b462899114 "2"^^ . _:b462899080 . _:b462899125 "2"^^ . _:b462899083 . . . _:b462899124 "2"^^ . _:b462899082 . _:b462899113 . _:b462899127 "2"^^ . _:b462899093 . . _:b462899057 . . _:b462899126 "2"^^ . _:b462899026 . _:b462899092 . . _:b462899121 "2"^^ . _:b462899095 . . _:b462898985 . _:b462899120 "2"^^ . _:b462899094 . _:b462899123 "2"^^ . _:b462899089 . . _:b462899122 "2"^^ . . . _:b462899088 . _:b462899099 . . _:b462899091 . . _:b462899090 . _:b11100973 "The stimulus for this colonisation by ECs is likely to be SDF-1 via its receptor CXCR4 (Orimo et al, 2005) and/or its receptor CXCR7, which is highly expressed in tumour-associated blood vessels including those in GBM (Miao et al, >>2007<<; Liu et al, 2010). CXCR7 has also recently been shown to be co-expressed with CXCR4 on cortical interneurons and to be essential for their SDF-1-stimulated migration (Sanchez-Alcaniz et al, 2011)." . _:b462899101 . _:b462898996 . _:b11100961 . _:b11100938 "The interaction between the CXCR4 receptor and its ligand, SDF-1\u03B1, has been shown to mediate tumour metastasis (Muller et al, 2001; Sun et al, >>2005<<). Overexpression of CXCR4 has been detected in a variety of human malignancies, including breast, pancreatic, prostate cancer, and GBM." . _:b462899100 . _:b462899129 "2"^^ . _:b11100960 . _:b462899103 . . _:b462899076 . _:b462899128 "2"^^ . _:b462899102 . _:b462899032 . _:b11100950 . _:b462899097 . . _:b462899130 "2"^^ . _:b462899096 . . . _:b462899099 . _:b11100958 "the literature showing that the recruitment and retention of proangiogenic hematopoietic cells to sites of ischaemic tissue damage or to tumours is mediated by the interaction of the SDF-1 with CXCR4 (Ceradini et al, 2004; Aghi et al, >>2006<<; Jin et al, 2006). Stromal cell-derived factor-1 functions as a hypoxia-inducible gene through the action of the transcription factor hypoxia inducible factor-1 (HIF-1)." . _:b11100967 . _:b462899098 . _:b462899023 . _:b462899109 . _:b462898998 . _:b462899108 . . _:b462899088 . _:b462899111 . . . _:b462899110 . _:b462899105 . _:b11100962 . . _:b11100942 . . . _:b462899104 . _:b11100963 . _:b462899107 . _:b462899051 . _:b462899106 . . . _:b11100965 . _:b462899117 . _:b11100946 . _:b462899116 . . _:b462899060 . _:b462899119 . _:b462899118 . _:b11100933 . _:b462899113 . _:b462899010 . _:b462899112 . _:b462899040 . . _:b462899115 . _:b11100968 . _:b11100946 "As most of the recurrences occur within the radiation field (Minniti et al, >>2010<<; McDonald et al, 2010), any method of improving local control of the primary tumour by radiotherapy would improve the curability of patients with GBM." . . _:b11100936 "the sdf-1/cxcr4 pathway in tumour metastasis and tissue injury" . _:b11100936 . _:b462899114 . _:b462899125 . . _:b11100945 . _:b462899124 . _:b462899038 . _:b462899127 . _:b462899096 . . _:b462899126 . . _:b11100959 . _:b462899121 . _:b462899120 . . _:b11100935 . _:b462899123 . _:b462899015 . _:b11100940 "When the CXCR4/SDF-1 interaction was blocked with a neutralising anti-CXCR4 antibody using an in vivo xenotransplant model, metastatic load was significantly reduced (Muller et al, >>2001<<). These data support the role of the SDF-1/CXCR4 pathway in the formation of metastasis for some tumours." . _:b462899122 . _:b11100942 "The SDF-1/CXCR4 pathway is also involved in tissue repair (Kollet et al, 2003; Ratajczak et al, >>2003<<). Kollet et al (2003) showed that CCl4-mediated liver injury led to an increase in the recruitment of human CD34+ progenitor cells by SDF-1 to the injured liver in NOD/SCID mice, suggesting that SDF-1 may direct haematopoietic progenitor" . _:b11100957 "by data in the literature showing that the recruitment and retention of proangiogenic hematopoietic cells to sites of ischaemic tissue damage or to tumours is mediated by the interaction of the SDF-1 with CXCR4 (Ceradini et al, >>2004<<; Aghi et al, 2006; Jin et al, 2006). Stromal cell-derived factor-1 functions as a hypoxia-inducible gene through the action of the transcription factor hypoxia inducible factor-1 (HIF-1)." . . _:b462899118 . _:b462898997 . . . . _:b462899013 . _:b462899070 . _:b462899129 . . _:b462899111 . _:b462899128 . _:b11100953 . _:b462899130 . . _:b11100933 . . _:b11100941 "The SDF-1/CXCR4 pathway is also involved in tissue repair (Kollet et al, >>2003<<; Ratajczak et al, 2003)." . . _:b11100934 . . . _:b11100935 . _:b462899084 . . . . _:b462899020 . _:b462899071 . _:b11100970 "Other investigators have shown using either orthotopic aortic allografting (Hillebrands et al, >>2002<<) or a parabiotic mouse system combined with reverse bone marrow transplantation (Aicher et al, 2007) that non-bone marrow-derived circulating ECs or EPCs from the liver and small intestine home to sites of active angiogenesis." . . _:b462899035 . _:b11100940 . _:b11100972 "The stimulus for this colonisation by ECs is likely to be SDF-1 via its receptor CXCR4 (Orimo et al, >>2005<<) and/or its receptor CXCR7, which is highly expressed in tumour-associated blood vessels including those in GBM (Miao et al, 2007; Liu et al, 2010)." . . _:b11100941 . _:b11100942 . . _:b11100943 . _:b11100936 . _:b462898986 . _:b11100937 . _:b11100938 . _:b462899002 . _:b462899078 . _:b11100939 . _:b11100951 "is important to note that our finding that radiation prevents local angiogenesis is not the same as the proposal of Fuks and Kolesnick that radiation produces a rapid apoptosis of tumour ECs and vascular shutdown (Garcia-Barros et al, >>2003<<). We and others who have measured tumour ECs after irradiation do not see this rapid apoptosis (Kioi et al, 2010; Kozin et al, 2010)." . _:b11100948 . . _:b462899108 . _:b11100972 . _:b11100949 . . _:b11100950 . . . _:b462899031 . _:b11100951 . . _:b11100944 . _:b462899046 . _:b462899072 . _:b11100945 . _:b462899120 . _:b11100946 . . _:b462899098 . _:b11100947 . _:b11100956 . _:b11100957 . _:b462899130 . . _:b11100958 . . . _:b462899068 . _:b11100959 . . _:b462899124 . _:b11100955 "Moreover, these inhibitors abrogated or delayed the recurrence of the tumours following irradiation (Kioi et al, >>2010<<). Potentiation of the anticancer drug BCNU by AMD3100 has also been shown with the intracranially implanted U87 human glioblastoma, though the mechanism for this may have involved abrogation of the survival function of the SDF-1/CXCR4" . _:b11100952 . . _:b462899047 . _:b462899043 . _:b11100953 . _:b462899093 . _:b11100954 . _:b462899127 . . _:b11100955 . _:b462898987 . "PMC0" . _:b11100964 . _:b462899129 . _:b462899059 . _:b11100965 . _:b462899089 . _:b11100951 . _:b11100966 . _:b11100967 . _:b11100960 . "10.1038%2Fbjc.2011.169" . _:b462899067 . _:b11100961 . _:b462899069 . _:b11100962 . _:b11100963 . _:b11100972 . _:b11100974 . _:b462899080 . _:b462899116 . _:b11100973 . _:b11100974 . _:b462899079 . _:b11100963 _:b11100968 . _:b11100963 _:b11100969 . _:b11100963 _:b11100970 . . _:b11100975 . _:b11100963 _:b11100971 . _:b11100963 _:b11100972 . _:b462899085 . _:b11100960 "Consistent with this, the HIF-1 inhibitor NSC 134754 prevents both the radiation-induced tumour accumulation of CD11b+ monocytes/macrophages and prevents tumour recurrence (Kioi et al, >>2010<<). We and others have shown that SDF-1 levels are increased in irradiated tumours (Kioi et al, 2010; Kozin et al, 2010) and in the plasma following local tumour irradiation of intracranial GBM (unpublished data). A model showing the" . _:b11100963 _:b11100973 . _:b11100963 _:b11100974 . _:b11100963 _:b11100975 . _:b11100968 . _:b462899016 . _:b462899103 . _:b11100969 . _:b11100963 _:b11100964 . _:b462898991 . _:b11100963 _:b11100965 . _:b11100963 _:b11100966 . _:b11100963 _:b11100967 . _:b11100970 . . _:b11100971 . . _:b11100963 _:b11100976 . . _:b11100976 . . _:b462899097 . _:b462899101 . _:b462899125 . . . _:b462899126 . _:b11100958 . _:b11100945 _:b11100960 . _:b11100970 . . _:b11100945 _:b11100961 . _:b11100945 _:b11100962 . _:b11100975 . _:b462899007 . _:b11100949 . . . _:b11100954 "Neutralising the antibodies against CD11b+ monocytes/macrophages given after irradiation markedly enhances the antitumour effect of radiation in human tumour xenografted mice (Ahn et al, >>2010<<). We observe that these monocytes also express CXCR4 on their surface. Inhibition of the interaction of SDF-1 and CXCR4 using the CXCR4 inhibitor, AMD3100, or antibodies against CXCR4 prevented the radiation-induced increase of CD11b+" . _:b11100976 "Other groups have explored alternative hypotheses by which tumours establish and/or maintain their vasculature, including endothelial differentiation of GBM stem-like cells (Ricci-Vitiani et al, >>2010<<). However, markers used to define ECs can be expressed by normal stem cells and cancer stem cells, and it does not necessarily indicate that GBM stem cells possess plasticity towards an EC fate. A subset of GBM stem cells may acquire" . . . _:b462899027 . _:b462899053 . . . _:b462899052 . _:b462899058 . . . _:b11100957 . _:b11100945 _:b11100946 . _:b11100945 _:b11100947 . _:b11100945 _:b11100948 . _:b11100945 _:b11100949 . _:b11100945 _:b11100950 . _:b11100945 _:b11100951 . . _:b11100945 _:b11100952 . _:b11100945 _:b11100953 . _:b11100945 _:b11100954 . . _:b462899092 . _:b11100945 _:b11100955 . . _:b11100945 _:b11100956 . . _:b462899110 . _:b11100945 _:b11100957 . _:b462899066 . _:b11100956 "by AMD3100 has also been shown with the intracranially implanted U87 human glioblastoma, though the mechanism for this may have involved abrogation of the survival function of the SDF-1/CXCR4 pathway in the tumour cells (Redjal et al, >>2006<<) rather than prevention of revascularisation after irradiation." . _:b11100945 _:b11100958 . _:b11100945 _:b11100959 . _:b462898993 . . . . _:b462899044 . _:b11100936 _:b11100940 . _:b11100936 _:b11100941 . _:b462899128 . . _:b11100936 _:b11100942 . _:b11100936 _:b11100943 . _:b11100936 _:b11100937 . _:b11100936 _:b11100938 . _:b11100936 _:b11100939 . . . _:b11100936 _:b11100944 . _:b11100969 "For instance, Purhonen et al (>>2008<<) have shown using a parabiotic mouse system (two mice joined so as to have a common blood supply) that VEGFR-2+ bone marrow cells did not incorporate into the tumour endothelium." . _:b462898989 . _:b462899081 . . _:b462899000 . . _:b462899114 . _:b11100967 "From such studies, we and others concluded that the ECs in the tumour do not arise from cells in the bone marrow (Ahn and Brown, 2008; Kioi et al, >>2010<<; Kozin et al, 2010)." . _:b462899009 . _:b11100934 "We have shown by immunohistochemistry that the levels of CD11b+ monocytes/macrophages are higher in GBM recurrences than in the same tumours prior to therapy (Kioi et al, >>2010<<). Whether or not these cells mediate revascularisation of human GBM after irradiation is not yet known. However, understanding the pathway involved in local recurrence of GBM after radiotherapy holds much clinical potential for preventing" . . . _:b11100933 _:b11100934 . . _:b11100933 _:b11100935 . . . . _:b11100943 "Kollet et al (>>2003<<) showed that CCl4-mediated liver injury led to an increase in the recruitment of human CD34+ progenitor cells by SDF-1 to the injured liver in NOD/SCID mice, suggesting that SDF-1 may direct haematopoietic progenitor cells to sites of" . . . . . . . . . _:b462899065 . _:b11100948 . . _:b11100963 "restoration of tumour blood vessels after irradiation" . _:b462899117 . _:b462899064 . . _:b11100933 "clinical data" . _:b462899105 . _:b462899056 . _:b11100937 . . . _:b462899063 . _:b11100939 . . _:b462898989 "4"^^ . _:b11100940 . _:b462899087 . _:b462898988 "5"^^ . _:b462898991 "4"^^ . _:b462898990 "4"^^ . _:b462899017 . . . _:b462899123 . _:b462898987 "5"^^ . _:b462898985 "6"^^ . _:b462898984 "11"^^ . . _:b462898986 "5"^^ . _:b462898994 . _:b462898997 "3"^^ . _:b462898996 "3"^^ . _:b11100959 "that the recruitment and retention of proangiogenic hematopoietic cells to sites of ischaemic tissue damage or to tumours is mediated by the interaction of the SDF-1 with CXCR4 (Ceradini et al, 2004; Aghi et al, 2006; Jin et al, >>2006<<). Stromal cell-derived factor-1 functions as a hypoxia-inducible gene through the action of the transcription factor hypoxia inducible factor-1 (HIF-1)." . . _:b462898999 "3"^^ . . . _:b11100964 "in our studies (15\u201320\u2009Gy) or at TCD50 doses (doses that control 50% of the tumours) typical for transplanted tumours (40\u2013100\u2009Gy), and particularly in SCID mice in which all the stromal cells are highly radiosensitive (Budach et al, >>1993<<)." . _:b462898998 "3"^^ . _:b462899025 . _:b462898993 "4"^^ . _:b462899074 . _:b462898992 "4"^^ . . . _:b11100974 "for this colonisation by ECs is likely to be SDF-1 via its receptor CXCR4 (Orimo et al, 2005) and/or its receptor CXCR7, which is highly expressed in tumour-associated blood vessels including those in GBM (Miao et al, 2007; Liu et al, >>2010<<). CXCR7 has also recently been shown to be co-expressed with CXCR4 on cortical interneurons and to be essential for their SDF-1-stimulated migration (Sanchez-Alcaniz et al, 2011)." . _:b462898995 "3"^^ . . . _:b462898994 "4"^^ . . . _:b462899005 "3"^^ . _:b462899075 . . _:b462899004 "3"^^ . _:b462899007 "3"^^ . _:b462899006 "3"^^ . . _:b462899001 "3"^^ . _:b462899001 . . _:b462899000 "3"^^ . _:b462899003 "3"^^ . _:b462899082 . _:b462899002 "3"^^ . _:b462899013 "3"^^ . _:b11100947 "As most of the recurrences occur within the radiation field (Minniti et al, 2010; McDonald et al, >>2010<<), any method of improving local control of the primary tumour by radiotherapy would improve the curability of patients with GBM." . _:b462899012 "3"^^ . . _:b462899048 . _:b462899015 "2"^^ . . _:b462899054 . _:b462899106 . _:b462899034 . _:b462899014 "3"^^ . _:b462899009 "3"^^ . . _:b462899008 "3"^^ . . . _:b462899022 . . _:b462899005 . _:b462899011 "3"^^ . . . _:b462899010 "3"^^ . _:b462899021 "2"^^ . . _:b462899020 "2"^^ . _:b462899023 "2"^^ . _:b462898989 . _:b462898996 . _:b462898997 . _:b462899022 "2"^^ . _:b462898998 . _:b462898999 . _:b462898988 . . _:b462898992 . . _:b462898993 . _:b462899017 "2"^^ . . _:b462898994 . _:b462898995 . _:b462898991 . _:b462899004 . _:b462899005 . _:b462899091 . _:b462899016 "2"^^ . _:b462899006 . _:b462899007 . _:b462898990 . _:b462899000 . _:b11100968 "From such studies, we and others concluded that the ECs in the tumour do not arise from cells in the bone marrow (Ahn and Brown, 2008; Kioi et al, 2010; Kozin et al, >>2010<<). To our knowledge, the so-called bone marrow-derived \u2018endothelial progenitor cells\u2019 have not been shown directly to form tumour vasculature. For instance, Purhonen et al (2008) have shown using a parabiotic mouse system (two mice joined" . _:b462899001 . _:b462899019 "2"^^ . _:b462899002 . _:b462899003 . _:b462898985 . _:b462899018 "2"^^ . . _:b462898984 . _:b462899029 "2"^^ . . _:b462898987 . _:b462898988 . _:b462898989 . _:b11100962 "We and others have shown that SDF-1 levels are increased in irradiated tumours (Kioi et al, 2010; Kozin et al, >>2010<<) and in the plasma following local tumour irradiation of intracranial GBM (unpublished data)." . _:b462899028 "2"^^ . _:b11100964 . _:b462898990 . _:b462898991 . _:b462898986 . _:b462898984 . _:b462898985 . _:b462899031 "2"^^ . _:b462898986 . _:b462898987 . _:b462898997 . . _:b462899030 "2"^^ . _:b462898996 . _:b462899025 "2"^^ . _:b462898999 . _:b462899050 . _:b462899024 "2"^^ . _:b462898998 . _:b11100965 "CD11b+ cells from an irradiated tumour share many of the same properties as ECs and have been shown to interact with newly forming tumour blood vessels (De Palma et al, >>2005<<). Whether or not there exists EPCs in the BM that directly give rise to tumour endothelium has been a source of controversy and confusion in the literature. To address whether cells in the bone marrow directly give rise to the components" . _:b462899027 "2"^^ . _:b462898993 . . _:b462899026 "2"^^ . _:b462898992 . . _:b462899037 "2"^^ . _:b462899061 . _:b462898995 . _:b462898999 . _:b462899036 "2"^^ . _:b462898994 . _:b462899039 "2"^^ . _:b462899005 .