PDF(Pubmed)
Abstract：
Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that are derived from Schwann cell lineage around peripheral nerves. As in many other cancer types, cancer stem cells (CSCs) have been identified in MPNSTs, and they are considered the cause of treatment resistance, recurrence, and metastasis. As an element defining the cancer stemness of MPNSTs, we previously reported a molecular mechanism by which exogenous adrenaline activates a core cancer stemness factor, YAP/TAZ, through β2 adrenoceptor (ADRB2). In this study, we found that MPNST cells express catecholamine synthases and that these enzymes are essential for maintaining cancer stemness, such as the ability to self-renew and maintain an undifferentiated state. Through gene knockdown and inhibition of these enzymes, we confirmed that catecholamines are indeed synthesized in MPNST cells. The results confirmed that catecholamine synthase knockdown in MPNST cells reduces the activity of YAP/TAZ. These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST.
摘要：
恶性外周神经鞘瘤(MPNSTs)是来源于外周神经周围的施万细胞谱系的恶性肿瘤。和许多其他类型的癌症一样，已经在MPNSTs中鉴定出癌症干细胞(CSC)，它们被认为是治疗抵抗的原因，复发,和转移。作为定义MPNSTs癌症干性的要素，我们先前报道了外源性肾上腺素激活核心癌症干性因子的分子机制，YAP/TAZ,通过β2肾上腺素受体（ADRB2）。在这项研究中,我们发现MPNST细胞表达儿茶酚胺合酶，这些酶对维持癌症的干性至关重要，例如自我更新和保持未分化状态的能力。通过基因敲低和抑制这些酶，我们证实儿茶酚胺确实在MPNST细胞中合成。结果证实MPNST细胞中儿茶酚胺合酶敲低降低了YAP/TAZ的活性。这些数据表明，从头合成的肾上腺素激活YAP/TAZ的机制，以及外源性肾上腺素，可能存在于MPNST细胞癌性的维持中。这种机制不仅有助于理解MPNST的病理,但也可能有助于MPNST治疗策略的发展。
