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A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.

Publication ,  Journal Article
Curtis, VF; Wang, H; Yang, P; McLendon, RE; Li, X; Zhou, Q-Y; Wang, X-F
Published in: PLoS One
2013

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.

Duke Scholars

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

1

Start / End Page

e54916

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Tumor Burden
  • Receptors, N-Methyl-D-Aspartate
  • Pancreatic Neoplasms
  • Neuropeptides
  • Nerve Tissue Proteins
  • Neovascularization, Pathologic
  • Myeloid Cells
  • Mice
 

Citation

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Curtis, V. F., Wang, H., Yang, P., McLendon, R. E., Li, X., Zhou, Q.-Y., & Wang, X.-F. (2013). A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer. PLoS One, 8(1), e54916. https://doi.org/10.1371/journal.pone.0054916
Curtis, Valerie F., Hui Wang, Pengyuan Yang, Roger E. McLendon, Xiaohan Li, Qun-Yong Zhou, and Xiao-Fan Wang. “A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.PLoS One 8, no. 1 (2013): e54916. https://doi.org/10.1371/journal.pone.0054916.
Curtis, Valerie F., et al. “A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.PLoS One, vol. 8, no. 1, 2013, p. e54916. Pubmed, doi:10.1371/journal.pone.0054916.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2013

Volume

8

Issue

1

Start / End Page

e54916

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Tumor Burden
  • Receptors, N-Methyl-D-Aspartate
  • Pancreatic Neoplasms
  • Neuropeptides
  • Nerve Tissue Proteins
  • Neovascularization, Pathologic
  • Myeloid Cells
  • Mice