CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma.
CD44 attenuates activation of the hippo signaling pathway and is a prime therapeutic target for glioblastoma.
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DOI：
10.1158/0008-5472.can-09-2505
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Xu Y;Stamenkovic I;Yu Q
多形性胶质母细胞瘤（GBM）是最具侵袭性的脑肿瘤，由于其对化疗和放疗的抵抗力，目前无法治愈。因此，迫切需要鉴定其靶向可以消除 GBM 细胞和/或使胶质母细胞瘤细胞对细胞毒性药物敏感的分子。 CD44 是一种主要的细胞表面透明质酸受体和癌症干细胞标记物，与多种癌症类型的进展有关。然而，介导其促肿瘤作用的主要下游信号通路以及 CD44 在 GBM 进展和 GBM 化学反应中的作用尚未确定。在这里，我们发现 CD44 在 GBM 中上调，并且 CD44 的缺失会阻止 GBM 生长并使 GBM 细胞对体内细胞毒性药物敏感。与这一观察结果一致，CD44 拮抗剂可有效抑制临床前小鼠模型中的神经胶质瘤生长。我们提供了第一个证据，证明 CD44 在哺乳动物 Hippo 信号通路的上游发挥作用，并且 CD44 通过减弱 Hippo 信号通路的激活来促进肿瘤细胞对活性氧和细胞毒性剂诱导的应激的抵抗。总之，我们的结果确定 CD44 是 GBM 的主要治疗靶点，建立了 CD44 拮抗剂的有效抗神经胶质瘤功效，揭示了一种新的 CD44 信号通路，并提供了第一个机制解释：CD44 的上调如何可能构成导致癌细胞对不同来源的应激产生抵抗的关键事件。最后，我们的结果为 CD44 的功能性抑制增强化疗和放疗疗效的观察结果提供了合理的解释。
Glioblastoma multiforme (GBM) is the most aggressive brain tumor that, by virtue of its resistance to chemo- and radiotherapy, is currently incurable. Identification of molecules whose targeting may eliminate GBM cells and/or sensitize glioblastoma cells to cytotoxic drugs is therefore urgently needed. CD44 is a major cell surface hyaluronan receptor and cancer stem cell marker that has been implicated in the progression of a variety of cancer types. However, the major downstream signaling pathways that mediate its pro-tumor effects and the role of CD44 in the progression and GBM chemoresponse of GBM have not been established. Here we show that CD44 is up-regulated in GBM and that its depletion blocks GBM growth and sensitizes GBM cells to cytotoxic drugs in vivo. Consistent with this observation, CD44 antagonists potently inhibit glioma growth in preclinical mouse models. We provide the first evidence that CD44 functions upstream of the mammalian Hippo signaling pathway and that CD44 promotes tumor cell resistance to reactive oxygen species- and cytotoxic agent-induced stress by attenuating activation of the Hippo signaling pathway. Together, our results identify CD44 as a prime therapeutic target for GBM, establish potent anti-glioma efficacy of CD44 antagonists, uncover a novel CD44 signaling pathway, and provide a first mechanistic explanation as to how up-regulation of CD44 may constitute a key event in leading to cancer cell resistance to stresses of different origins. Finally, our results provide a rational explanation for the observation that functional inhibition of CD44 augments the efficacy of chemo- and radiation therapy.