Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity
Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity
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DOI：
10.1101/gad.193565.112
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发表时间：
2012-06-01
影响因子：
10.5
通讯作者：
Rich, Jeremy N.
中科院分区：
文献类型：
--
作者：
Kim, Youngmi;Kim, Eunhee;Rich, Jeremy N.
生长因子介导的增殖和自我更新维持组织特异性干细胞，但在癌症中经常失调。正如基因工程模型所证明的那样，血小板源性生长因子 (PDGF) 配体和受体 (PDGFR) 在神经胶质瘤中通常过度表达并引发肿瘤。虽然 PDGFR α 改变告知原神经胶质母细胞瘤 (GBM) 亚型的肿瘤间异质性，但我们探讨了 PDGFR 在肿瘤内 GBM 异质性中的作用。我们发现PDGFR α仅在GBM的一个子集中表达，而PDGFR β更常见于肿瘤中表达，但优先由自我更新的致瘤GBM干细胞（GSC）表达。 PDGFR β（但不是 PDGFR α）的遗传或药理学靶向减弱了 GSC 的自我更新、存活、肿瘤生长和侵袭。 PDGFR β 抑制减少了癌症干细胞信号传导节点 STAT3 的激活，而持续活跃的 STAT3 则挽救了 PDGFR β 靶向导致的 GSC 自我更新丧失。计算机生存分析表明，PDGFRB 提示预后不良，而 PDGFRA 是积极的预后因素。我们的结果可以解释基于抗 PDGFR 的方法的混合临床反应，并表明需要将癌症模型作为器官系统整合到癌症疗法的开发中。
Growth factor-mediated proliferation and self-renewal maintain tissue-specific stem cells and are frequently dysregulated in cancers. Platelet-derived growth factor (PDGF) ligands and receptors (PDGFRs) are commonly overexpressed in gliomas and initiate tumors, as proven in genetically engineered models. While PDGFR alpha alterations inform intertumoral heterogeneity toward a proneural glioblastoma (GBM) subtype, we interrogated the role of PDGFRs in intratumoral GBM heterogeneity. We found that PDGFR alpha is expressed only in a subset of GBMs, while PDGFR beta is more commonly expressed in tumors but is preferentially expressed by self-renewing tumorigenic GBM stem cells (GSCs). Genetic or pharmacological targeting of PDGFR beta (but not PDGFR alpha) attenuated GSC self-renewal, survival, tumor growth, and invasion. PDGFR beta inhibition decreased activation of the cancer stem cell signaling node STAT3, while constitutively active STAT3 rescued the loss of GSC self-renewal caused by PDGFR beta targeting. In silico survival analysis demonstrated that PDGFRB informed poor prognosis, while PDGFRA was a positive prognostic factor. Our results may explain mixed clinical responses of anti-PDGFR-based approaches and suggest the need for integration of models of cancer as an organ system into development of cancer therapies.