A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.
A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.
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DOI：
10.1371/journal.pone.0054916
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang XF
中科院分区：
文献类型：
--
作者：
Curtis VF;Wang H;Yang P;McLendon RE;Li X;Zhou QY;Wang XF
骨髓细胞在肿瘤微环境中的浸润通常与增强的血管生成和肿瘤进展相关，导致许多类型癌症的预后不良。多肽趋化因子PK 2（Bv 8，PROK 2）已显示调节骨髓细胞从骨髓的动员，导致血管生成过程的激活，以及巨噬细胞和嗜中性粒细胞在肿瘤部位的积累。针对PK 2的中和抗体显示出有效的抗肿瘤功效，说明PK 2拮抗剂作为治疗癌症的治疗剂的潜力。在这项研究中，我们证明了小分子PK 2拮抗剂PKRA 7在胶质母细胞瘤和胰腺癌异种移植肿瘤模型中的抗肿瘤活性。对于高度血管化的胶质母细胞瘤，PKRA 7与肿瘤块中血管密度降低和坏死面积增加相关。与PKRA 7在体内的抗血管生成活性一致，该化合物在体外有效地减少PK 2诱导的微血管内皮细胞分支。对于血管化不良的胰腺癌，PKRA 7的主要抗肿瘤作用似乎是通过阻断骨髓细胞迁移/浸润介导的。在分子水平上，PKRA 7抑制巨噬细胞中某些促迁移趋化因子和趋化因子受体的PK 2诱导的表达。将PKRA 7治疗与标准化疗剂组合导致两种类型肿瘤的异种移植模型中的增强作用。总之，我们的结果表明PKRA 7的抗肿瘤活性可以通过与特定类型癌症的病理特征相关的两种不同机制介导。这种小分子PK 2拮抗剂有望进一步开发为联合癌症治疗的有效药物。
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.
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影响因子：
3
作者：
Korc, Murray
通讯作者：
Korc, Murray
影响因子：
7.3
作者：
Martucci, C;Franchi, S;Sacerdote, P
通讯作者：
Sacerdote, P
影响因子：
50.3
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
通讯作者：
Hanahan, D
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4.8
作者：
Lin, DCH;Bullock, CM;Zhou, QY
通讯作者：
Zhou, QY
影响因子：
9.9
作者：
Norden, A. D.;Young, G. S.;Wen, P. Y.
通讯作者：
Wen, P. Y.