A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors

Rubin, Joshua B.; Kung, Andrew L.; Klein, Robyn S.; Chan, Jennifer A.; Sun, Yanping; Schmidt, Karl F.; Kieran, Mark W.; Luster, Andrew D.; Segal, Rosalind A.

doi:10.1073/pnas.2235846100

Cited by 584 publications

(541 citation statements)

References 38 publications

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“…Medulloblastoma cells are thought to arise from external granular layer cerebellar precursors derived from the rhombic lip, and these results provide an obvious developmental parallel with our studies of Slit2 inhibition of medulloblastoma cell invasion. Slit also inhibits CXCR4-induced motility in breast cancer cells and CXCR4 antagonists have been shown to inhibit medulloblastoma tumor growth in vivo (Rubin et al, 2003;Prasad et al, 2004). However, in contrast to our studies, Slit treatment alone did not influence the motility of the breast cancer cells (Prasad et al, 2004).…”

Section: Discussioncontrasting

confidence: 99%

Inhibition of medulloblastoma cell invasion by Slit

et al. 2006

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Section: Discussioncontrasting

confidence: 99%

Inhibition of medulloblastoma cell invasion by Slit

et al. 2006

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“…Moreover, tumor stromal fibroblasts, but not normal fibroblasts, elaborate SDF-1, which in turn promotes tumor growth and angiogenesis [25,26] (Table 1). Finally, SDF-1 expression by tumor vasculature has been reported in brain tumors [27,28].…”

Section: Expression Of Sdf-1 In Hypoxic Tissuesmentioning

confidence: 95%

“…Chronic treatment of AMD3100 efficiently blocks SDF-1-mediated vasculogenesis [20,21]. In tumor models, inhibition of the SDF-1-CXCR4 pathway with chronic administration of AMD3100 leads to efficient reduction of tumor growth and angiogenesis by targeting (i) proliferation of CXCR4-expressing tumor cells, (ii) diminishing recruitment of CXCR4 + angiogenic cells and (iii) promoting CXCR4-dependent metastasis [27,58,63]. In addition, CXCR4 antagonists might prevent vascular neointima formation and atherosclerosis [10].…”

Section: Modulating Sdf-1 Signals Offers Promising Therapeutic Stratementioning

confidence: 99%

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Petit

Jin

Rafii

2007

Trends in Immunology

527

382

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Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4 + BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4 + VEGFR1 + hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1-CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively.

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“…In vitro and in vivo (xenograft mouse model) studies using the CXCR4 antagonist AMD3100 supported this concept by showing an inhibition of glioblastoma growth via increased apoptosis and decreased proliferation. 83 Studies using AMD3100 have also been conducted in the EAE model. 84 Animals treated with this CXCR4 antagonist displayed worsened clinical disease and extensive demyelination, although numbers of mononuclear cells were similar in CNS tissues and in vehicle-treated mice.…”

Section: Multiple Sclerosis: a Jumble Of Chemokines And Chemokine Recmentioning

confidence: 99%

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

Savarin-Vuaillat¹,

Ransohoff²

2007

Neurotherapeutics

155

126

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Summary:Chemokines and chemokine receptors comprise a large number of molecules implicated in a wide range of physiological and pathological functions. Numerous studies have demonstrated the roles of chemokines and chemokine receptors: 1) during development, by regulating hematopoiesis, cardiogenesis, and vascular and cerebellar development; 2) during tumor biology, by controlling cell proliferation, angiogenesis, and metastasis; and 3), especially during leukocyte migration, by acting on firm adhesion, locomotion, diapedesis, and chemotaxis. This review focuses on chemokine and chemokine receptor involvement in diverse neurological diseases and their therapeutic potentials. Because of its induction or upregulation during CNS pathologies, members of the chemokine system can be used as biological markers. CXCR4 and CXCL12, by the correlation between their expression and the glioblastoma tumor progression, could be a marker to grade this type of CNS tumor. CCR1, by virtue of specific expression in A␤ plaques, may be a marker for Alzheimer pathology. Downregulation of CCL2 in cerebrospinal fluid may be a candidate to characterize multiple sclerosis (MS), but needs additional investigation. Moreover, chemokines and chemokine receptors represent interesting therapeutic targets. Using chemokine receptor antagonists, several studies provided exciting findings for potential neurological disease treatment. Chemokine receptor antagonists reduce disease severity in animal models of MS. In glioblastoma, a CXCR4 antagonist (AMD3100) showed an inhibition of tumor growth. Inhibition of chemokine receptor signaling is not the only therapeutic strategy: for example, CXCR4 -CXCL12 has anti-inflammatory properties and CX3CL1-CX3CR1 controls neurotoxicity. Thus, chemokine biology suggests several approaches for treating neurological disease.

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A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors

Cited by 584 publications

References 38 publications

Inhibition of medulloblastoma cell invasion by Slit

Inhibition of medulloblastoma cell invasion by Slit

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

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