A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.
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.
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, United States of America.
Valerie F
VF
Curtis
Hui
H
Wang
Pengyuan
P
Yang
Roger E
RE
McLendon
Xiaohan
X
Li
Qun-Yong
QY
Zhou
Xiao-Fan
XF
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000037:antagonists & inhibitors*; D005910:Glioma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009479:Neuropeptides / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D005768:Gastrointestinal Hormones; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C423608:PROK2 protein, human; D016194:Receptors, N-Methyl-D-Aspartate