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dc.contributor.advisor Wang, Xiao-Fan en_US
dc.contributor.author Curtis, VF
dc.contributor.author Wang, H
dc.contributor.author Yang, P
dc.contributor.author McLendon, RE
dc.contributor.author Li, X
dc.contributor.author Zhou, QY
dc.contributor.author Wang, XF
dc.coverage.spatial United States
dc.date.accessioned 2012-01-10T15:58:21Z
dc.date.issued 2013
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/23372791
dc.identifier PONE-D-11-11749
dc.identifier.citation PLoS One, 2013, 8 (1), pp. e54916 - ?
dc.identifier.uri http://hdl.handle.net/10161/4982
dc.description Dissertation en_US
dc.description.abstract Infiltration of myeloid cells in the tumor microenvironment is often associated with enhanced angiogenesis and tumor progression, resulting in poor prognosis in many types of cancer. The polypeptide chemokine PK2 (Bv8, PROK2) has been shown to regulate myeloid cell mobilization from the bone marrow, leading to activation of the angiogenic process, as well as accumulation of macrophages and neutrophils in the tumor site. Neutralizing antibodies against PK2 were shown to display potent anti-tumor efficacy, illustrating the potential of PK2-antagonists as therapeutic agents for the treatment of cancer. In this study we demonstrate the anti-tumor activity of a small molecule PK2 antagonist, PKRA7, in the context of glioblastoma and pancreatic cancer xenograft tumor models. For the highly vascularized glioblastoma, PKRA7 was associated with decreased blood vessel density and increased necrotic areas in the tumor mass. Consistent with the anti-angiogenic activity of PKRA7 in vivo, this compound effectively reduced PK2-induced microvascular endothelial cell branching in vitro. For the poorly vascularized pancreatic cancer, the primary anti-tumor effect of PKRA7 appears to be mediated by the blockage of myeloid cell migration/infiltration. At the molecular level, PKRA7 inhibits PK2-induced expression of certain pro-migratory chemokines and chemokine receptors in macrophages. Combining PKRA7 treatment with standard chemotherapeutic agents resulted in enhanced effects in xenograft models for both types of tumor. Taken together, our results indicate that the anti-tumor activity of PKRA7 can be mediated by two distinct mechanisms that are relevant to the pathological features of the specific type of cancer. This small molecule PK2 antagonist holds the promise to be further developed as an effective agent for combinational cancer therapy.
dc.format.extent e54916 - ?
dc.language eng
dc.relation.ispartof PLoS One
dc.relation.isversionof 10.1371/journal.pone.0054916
dc.subject Animals
dc.subject Antineoplastic Agents
dc.subject Carrier Proteins
dc.subject Cell Line, Tumor
dc.subject Cell Movement
dc.subject Cell Transformation, Neoplastic
dc.subject Endothelial Cells
dc.subject Gastrointestinal Hormones
dc.subject Glioma
dc.subject Humans
dc.subject Macrophages
dc.subject Mice
dc.subject Myeloid Cells
dc.subject Neovascularization, Pathologic
dc.subject Nerve Tissue Proteins
dc.subject Neuropeptides
dc.subject Pancreatic Neoplasms
dc.subject Receptors, N-Methyl-D-Aspartate
dc.subject Tumor Burden
dc.subject Tumor Microenvironment
dc.subject Xenograft Model Antitumor Assays
dc.title A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.
dc.type Journal Article
dc.department Molecular Cancer Biology en_US
duke.embargo.months 24 en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/23372791
pubs.issue 1
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Pharmacology & Cancer Biology
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments
pubs.organisational-group /Duke/School of Medicine/Clinical Science Departments/Pathology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published
pubs.volume 8
dc.identifier.eissn 1932-6203

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