Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice.

Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1-dependent stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4. Pharmacologic inhibition of HIF-1 or of the SDF-1/CXCR4 interaction prevented the influx of BMDCs, primarily CD11b+ myelomonocytes, and the postirradiation development of functional tumor vasculature, resulting in abrogation of tumor regrowth. Similar results were found using neutralizing antibodies against CXCR4. Our data therefore suggest a novel approach for the treatment of GBM: in addition to radiotherapy, the vasculogenesis pathway needs to be blocked, and this can be accomplished using the clinically approved drug AMD3100, a small molecule inhibitor of SDF-1/CXCR4 interactions.

[1]  A. Sica,et al.  A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood "resident" monocytes, and embryonic macrophages suggests common functions and developmental relationships. , 2009, Blood.

[2]  Masahiro Inoue,et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. , 2009, Cancer cell.

[3]  J. Erler,et al.  Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. , 2009, Cancer cell.

[4]  M. Celeste Simon,et al.  The impact of O2 availability on human cancer , 2008, Nature Reviews Cancer.

[5]  Wolfhard Semmler,et al.  Vessel fractions in tumor xenografts depicted by flow- or contrast-sensitive three-dimensional high-frequency Doppler ultrasound respond differently to antiangiogenic treatment. , 2008, Cancer research.

[6]  D. Hanahan,et al.  Modes of resistance to anti-angiogenic therapy , 2008, Nature Reviews Cancer.

[7]  G. Ahn,et al.  Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. , 2008, Cancer cell.

[8]  S. Vandenberg,et al.  HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. , 2008, Cancer cell.

[9]  G. Fuh,et al.  Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells , 2007, Nature Biotechnology.

[10]  David J. Chen,et al.  Influence of tumor cell and stroma sensitivity on tumor response to radiation. , 2007, Cancer research.

[11]  D. Scadden,et al.  Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. , 2006, Cancer research.

[12]  H. Haider,et al.  Evidence for ischemia induced host-derived bone marrow cell mobilization into cardiac allografts. , 2006, Journal of molecular and cellular cardiology.

[13]  M. Wong,et al.  Myeloid lineage progenitors give rise to vascular endothelium , 2006, Proceedings of the National Academy of Sciences.

[14]  Fan Zhang,et al.  Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes , 2006, Nature Medicine.

[15]  J. Pollard,et al.  Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis , 2006, Cell.

[16]  Rinat Abramovitch,et al.  VEGF-Induced Adult Neovascularization: Recruitment, Retention, and Role of Accessory Cells , 2006, Cell.

[17]  D. Link,et al.  G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism. , 2005, Blood.

[18]  Luigi Naldini,et al.  Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. , 2005, Cancer cell.

[19]  Z. Werb,et al.  PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival , 2005, Nature Cell Biology.

[20]  Masahiro Hiraoka,et al.  Optical Imaging of Tumor Hypoxia and Evaluation of Efficacy of a Hypoxia-Targeting Drug in Living Animals , 2005, Molecular imaging.

[21]  P. Workman,et al.  Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors. , 2005, Cancer research.

[22]  R. Puri,et al.  Evidence That IL-13Rα2 Chain in Human Glioma Cells Is Responsible for the Antitumor Activity Mediated by Receptor-Directed Cytotoxin Therapy , 2005, Journal of immunotherapy.

[23]  Christie M. Orschell,et al.  Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist , 2005, The Journal of experimental medicine.

[24]  L. Coussens,et al.  The contribution of bone marrow-derived cells to the tumor vasculature in neuroblastoma is matrix metalloproteinase-9 dependent. , 2005, Cancer research.

[25]  E. Rofstad,et al.  The tumor bed effect: increased metastatic dissemination from hypoxia-induced up-regulation of metastasis-promoting gene products. , 2005, Cancer research.

[26]  Meng Yang,et al.  Transgenic Nude Mouse with Ubiquitous Green Fluorescent Protein Expression as a Host for Human Tumors , 2004, Cancer Research.

[27]  Maria Werner-Wasik,et al.  Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. , 2004, International journal of radiation oncology, biology, physics.

[28]  Mark A. Hall,et al.  Genetically tagging endothelial cells in vivo: bone marrow-derived cells do not contribute to tumor endothelium. , 2004, Blood.

[29]  Geoffrey C Gurtner,et al.  Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 , 2004, Nature Medicine.

[30]  M. Dewhirst,et al.  Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. , 2004, Cancer cell.

[31]  W. Gerald,et al.  Effect of angiogenesis inhibition by Id loss and the contribution of bone-marrow-derived endothelial cells in spontaneous murine tumors. , 2003, Cancer cell.

[32]  L. Naldini,et al.  Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells , 2003, Nature Medicine.

[33]  Shahin Rafii,et al.  Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration , 2003, Nature Medicine.

[34]  Zvi Fuks,et al.  Tumor Response to Radiotherapy Regulated by Endothelial Cell Apoptosis , 2003, Science.

[35]  L. Coussens,et al.  Inflammation and cancer , 2002, Nature.

[36]  S. Rafii,et al.  Recruitment of Stem and Progenitor Cells from the Bone Marrow Niche Requires MMP-9 Mediated Release of Kit-Ligand , 2002, Cell.

[37]  S. Rafii,et al.  Impaired recruitment of bone-marrow–derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth , 2001, Nature Medicine.

[38]  S. Rafii,et al.  Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. , 2001, Blood.

[39]  T. Schwartz,et al.  Molecular Interactions of Cyclam and Bicyclam Non-peptide Antagonists with the CXCR4 Chemokine Receptor* , 2001, The Journal of Biological Chemistry.

[40]  J. Adelman,et al.  ATP-dependent Activation of the Intermediate Conductance, Ca2+-activated K+ Channel, hIK1, Is Conferred by a C-terminal Domain* , 2001, The Journal of Biological Chemistry.

[41]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[42]  M. Baumann,et al.  Impact of the tumour bed effect on microenvironment, radiobiological hypoxia and the outcome of fractionated radiotherapy of human FaDu squamous-cell carcinoma growing in the nude mouse , 2001, International journal of radiation biology.

[43]  Nicholas R. English,et al.  Increased Production of Immature Myeloid Cells in Cancer Patients: A Mechanism of Immunosuppression in Cancer1 , 2001, The Journal of Immunology.

[44]  R. Ronca,et al.  Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. , 2000, Blood.

[45]  S. Shapiro,et al.  Contribution of Monocytes/Macrophages to Compensatory Neovascularization: The Drilling of Metalloelastase-Positive Tunnels in Ischemic Myocardium , 2000, Circulation research.

[46]  J. Bussink,et al.  Changes in Blood Perfusion and Hypoxia after Irradiation of a Human Squamous Cell Carcinoma Xenograft Tumor Line , 2000, Radiation research.

[47]  W. Gerald,et al.  Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts , 1999, Nature.

[48]  Haruchika Masuda,et al.  Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization , 1999, Nature Medicine.

[49]  N. Goldstein,et al.  In vitro neutralization of vascular endothelial growth factor activation of Flk-1 by a monoclonal antibody , 1994 .

[50]  J. Brown,et al.  Discrepancies between measured changes of radiobiological hypoxic fraction and oxygen tension monitoring using two assay systems. , 1994, International journal of radiation oncology, biology, physics.

[51]  H. Sandler,et al.  Malignant astrocytomas: focal tumor recurrence after focal external beam radiation therapy. , 1991, Journal of neurosurgery.

[52]  L. F. Fajardo,et al.  Effects of X irradiation on angiogenesis. , 1990, Radiation research.

[53]  S. Kuriyama,et al.  In vivo depletion of macrophages by desulfated ι-carrageenan in mice , 1989 .

[54]  Fred H. Hochberg,et al.  Assumptions in the radiotherapy of glioblastoma , 1980, Neurology.

[55]  Simon Frantz,et al.  Adverse drug reactions: A broader perspective , 2004, Nature Reviews Drug Discovery.

[56]  J. Pollard.  Tumour-educated macrophages promote tumour progression and metastasis , 2004, Nature Reviews Cancer.

[57]  M. Prados,et al.  Patterns of recurrence of glioblastoma multiforme after external irradiation followed by implant boost. , 1994, International journal of radiation oncology, biology, physics.