A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.
Date
2011
Author
Advisors
Wang, Xiao-Fan
Blobe, Gerard
Kirsch, David
Mathey-Prevot, Bernard
Yan, Hai
Repository Usage Stats
519
views
views
1,203
downloads
downloads
Abstract
In many cancer types, infiltration of bone marrow-derived myeloid cells in the tumor
microenvironment is often associated with enhanced angiogenesis and tumor progression,
resulting in poor prognosis. The polypeptide chemokine PK2 (Bv8) regulates myeloid
cell mobilization from the bone marrow, leading to activation of angiogenesis as well
as accumulation of macrophages and neutrophils in the tumor site. Neutralizing antibodies
against PK2 display potent anti-tumor efficacy, illustrating the potential of PK2-antagonists
as therapeutic agents for the treatment of cancer. However, antibody-based therapies
can be too large to treat certain diseases and too expensive to manufacture while
small molecule therapeutics are not prohibitive in these ways. In this study, we demonstrate
the anti-tumor activity of a small molecule PK2 antagonist, PKRA7, in the contexts
of glioblastoma and pancreatic cancer xenograft tumor models. In the highly vascularized
glioblastoma, PKRA7 decreased blood vessel density while increasing 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 is mediated by the blockage of myeloid cell migration and infiltration. At
the molecular level, PKRA7 inhibits PK2-induced expression of several pro-migratory
chemokines and chemokine receptors in macrophages. Combining PKRA7 treatment with
standard chemotherapeutic agents resulted in enhanced effects in xenograft models
for both glioblastoma and pancreatic tumors. Taken together, our results indicate
that the anti-tumor activity of PKRA7 can be mediated by 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.
Type
DissertationDepartment
Molecular Cancer BiologySubject
AnimalsAntineoplastic Agents
Carrier Proteins
Cell Line, Tumor
Cell Movement
Cell Transformation, Neoplastic
Endothelial Cells
Gastrointestinal Hormones
Glioma
Humans
Macrophages
Mice
Myeloid Cells
Neovascularization, Pathologic
Nerve Tissue Proteins
Neuropeptides
Pancreatic Neoplasms
Receptors, N-Methyl-D-Aspartate
Tumor Burden
Tumor Microenvironment
Xenograft Model Antitumor Assays
Permalink
https://hdl.handle.net/10161/4982Citation
Curtis, Valerie Forbes (2011). A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis
in glioma and blocking myeloid cell infiltration in pancreatic cancer. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/4982.Collections
More Info
Show full item record
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.
Rights for Collection: Duke Dissertations
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info