CXC chemokine receptor 4 (CXCR4) has been shown to play a critical role in chemotaxis and homing, which are key steps in cancer metastasis. There is also increasing evidence that links this receptor to angiogenesis; however, its molecular basis remains elusive. Vascular endothelial growth factor (VEGF), one of the major angiogenic factors, promotes the formation of leaky tumor vasculatures that are the hallmarks of tumor progression. Here, we investigated whether CXCR4 induces the expression of VEGF through the PI3K/Akt pathway. Our results showed that CXCR4/ CXCL12 induced Akt phosphorylation, which resulted in upregulation of VEGF at both the mRNA and protein levels. Conversely, blocking the activation of Akt signaling led to a decrease in VEGF protein levels; blocking CXCR4/CXCL12 interaction with a CXCR4 antagonist suppressed tumor angiogenesis and growth in vivo. Furthermore, VEGF mRNA levels correlated well with CXCR4 mRNA levels in patient tumor samples. In summary, our study demonstrates that the CXCR4/ CXCL12 signaling axis can induce angiogenesis and progression of tumors by increasing expression of VEGF through the activation of PI3K/Akt pathway. Our findings suggest that targeting CXCR4 could provide a potential new anti-angiogenic therapy to suppress the formation of both primary and metastatic tumors.

Generally, it has been accepted that microglia play important roles in brain inflammation. However, recently several studies suggested possible infiltration of blood neutrophils and monocytes into the brain. To understand contribution of microglia and blood inflammatory cells to brain inflammation, the behavior of microglia, neutrophils, and monocytes was investigated in LPS (lipopolysaccharide)-injected substantia nigra pars compacta, cortex, and hippocampus of normal and/or leukopenic rats using specific markers of neutrophils (myeloperoxidase, MPO), and microglia and monocytes (ionized calcium binding adaptor molecule-1, Iba-1), as well as a general marker for these inflammatory cells (CD11b). CD11b-immunopositive (CD11b 1 ) cells and Iba-1 1 cells displayed similar behavior in intact and LPSinjected brain at 6 h after the injection. Interestingly, however, CD11b1 cells and Iba-1 1 cells displayed significantly different behavior at 12 h: Iba-1 1 cells disappeared while CD11b 1 cells became round in shape. We found that CD11b/Iba-1-double positive (CD11b 1 /Iba-1 1 ) ramified microglia died within 6 h after LPS injection. The round CD11b1 cells detected at 12 h were MPO 1 . These CD11b 1 / MPO 1 cells were not found in leukopenic rats, suggestive of neutrophil infiltration. MPO 1 neutrophils expressed inducible nitric oxide synthase, interleukin-1b, cyclooxygenase-2, and monocyte chemoattractant protein-1, but died within 18 h. CD11b1 cells detected at 24 h appeared to be infiltrated monocytes, since these cells were once labeled with Iba-1 and were not found in leukopenic rats. Furthermore, transplanted monocytes were detectable in LPSinjected brain. These results suggest that at least a part of neutrophils and monocytes could have been misinterpreted as activated microglia in inflamed brain. V V C 2007 Wiley-Liss, Inc.

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Brain inflammation is a suggested risk factor for neurodegenerative disease. Interestingly, severe inflammation in the substantia nigra pars compacta (SNpc) accelerates the onset and progression of Parkinson's disease. In this study, we examined the underlying mechanisms of severe inflammation in the SNpc by comparing the inflammatory process with that in the cortex. In intact brain, the densities of CD11b 1 microglia were similar in the SNpc and cortex. However, lipopolysaccharide injection enhanced the CD11b 1 cell number in the SNpc, but not in the cortex. Previously, we reported that CD11b and myeloperoxidase (MPO) double-positive neutrophils infiltrate the SNpc following LPS injection (GLIA 55:1577-88). Notably, the MPO 1 neutrophil number increased dramatically in the SNpc, but only slightly in the cortex. The extent of neutrophil infiltration appeared to correlate with neuronal damage. We confirmed that loss of neurons in the SNpc was significantly reduced in neutropenic rats versus normal rats following LPS injection. In addition, the densities of astrocytes were much lower in the intact SNpc, compared with the cortex. Furthermore, after LPS injection, damage of endothelial cells and astrocytes, and blood-brain barrier (BBB) permeability was more pronounced in the SNpc. These results collectively suggest that excessive neutrophil infiltration and environmental factors, such as lower astrocyte density and higher BBB permeability, contribute to severe inflammation and neuronal death in the SNpc. V V C

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