Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
Cancer Res. 2010 Mar 15;70(6):2455-64. doi: 10.1158/0008-5472.CAN-09-2505. Epub 2010 Mar 2.
Glioblastoma multiforme (GBM) is the most aggressive brain tumor that, by virtue of its resistance to chemotherapy 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 protumor effects and the role of CD44 in the progression and chemoresponse of GBM have not been established. Here we show that CD44 is upregulated 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-induced 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 antiglioma efficacy of CD44 antagonists, uncover a novel CD44 signaling pathway, and provide a first mechanistic explanation as to how upregulation 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 chemotherapy and radiation therapy.
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耐药性，目前无法治愈。因此，迫切需要鉴定出可以靶向某些分子，从而消除 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志物，它与多种癌症类型的进展有关。然而，介导其促进肿瘤作用的主要下游信号通路以及 CD44 在 GBM 进展和化疗反应中的作用尚未确定。在这里，我们表明 CD44 在 GBM 中上调，其耗竭可阻止 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 拮抗剂在临床前小鼠模型中强烈抑制神经胶质瘤的生长。我们提供了第一个证据，表明 CD44 在上游作用于哺乳动物 Hippo 信号通路，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诱导和细胞毒性剂诱导的应激的抵抗。总之，我们的研究结果将 CD44 确定为 GBM 的主要治疗靶标，确立了 CD44 拮抗剂的强大抗神经胶质瘤功效，揭示了一种新的 CD44 信号通路，并首次解释了 CD44 的上调如何构成导致癌细胞抵抗不同来源应激的关键事件。最后，我们的研究结果为功能抑制 CD44 增强化疗和放疗疗效的观察结果提供了合理的解释。
