A Glycolytic Mechanism Regulating an Angiogenic Switch in
Jianhua Wang, Jincheng Wang, Jinlu Dai, et al.
Cancer Res 2007;67:149-159.
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A Glycolytic Mechanism Regulating an Angiogenic
Switch in Prostate Cancer
Jianhua Wang, Jincheng Wang, Jinlu Dai, Younghun Jung, Chuen-Long Wei, 1
Yu Wang, Aaron M. Havens, Phillip J. Hogg, Evan T. Keller, Kenneth J. Pienta, 2
Jacques E. Nor, Cun-Yu Wang, and Russell S. Taichman
Department of Periodontics and Oral Medicine, 2Department of Cariology, Restorative Sciences, and Endodontics, and 3Division of Prosthodontics, Department of Biologic and Materials Sciences, University of Michigan School of Dentistry; 4Department of Urology and 5Division of Internal Medicine and Urology, University of Michigan School of Medicine, Ann Arbor, Michigan and 6Center for Vascular Research, University of New South Wales, Sydney, New South Wales, Australia
Xq13; ref. 7). In the nucleus, PGK1 influences DNA replication and repair. Surprisingly, PGK1 is secreted extracellularly by tumors, where it acts as a disulfide reductase capable of cleaving plasminogen to generate the vascular inhibitor angiostatin (8–13). Overexpression of PGK1 is therefore likely to restrict tumor growth by limiting angiogenesis. Thus, a delicate equilibrium may be established between the hypoxic response needed to generate
proangiogenic factors and events essential for anaerobic metabolism (e.g., PGK1) for tumors to grow. The challenge is to regulate PGK1 secretion.
Our previous work has focused on the role that chemokine axis of CXCL12 and its receptor CXCR4 plays in metastatic prostate cancer (14–16). We observed that CXCR4 expression is related to increasing tumor grade (14) and that CXCL12 signaling through CXCR4 triggers the adhesion of prostate cancers to bone marrow endothelial cells, possibly by activating avh3 integrins (17) and CD164 (18). Most critically, antibody to CXCR4 significantly reduces the number of prostate cancer bone metastasis in an in vivo model of metastasis (15). Further work has shown that CXCR4 signaling disrupts the delicate equilibrium between proangiogenic and
antiangiogenic signals in prostate cancer disease (16).
In the present investigation, we found that CXCR4 signaling
regulates PGK1 expression, which regulates angiogenesis by
generating angiostatin and by reducing the secretion of the
proangiogenic cytokines VEGF and IL-8. At sites of high CXCL12 production, however (bone, lymph node, and liver), PGK1 secretion is inhibited by the CXCL12/CXCR4 axis. Thus, CXCL12 signaling through CXCR4 generates an ‘angiogenic switch’ necessary for metastatic growth. Together, these data further show that CXCL12/ CXCR4 chemokine axis and PGK1 represent at least one of the
critical events necessary for...
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