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Targeting endocannabinoid signaling in tumor-associated macrophages as treatment for glioblastoma multiforme

机译:靶向与肿瘤相关巨噬细胞中的内源性大麻素信号传导作为多种胶质母细胞瘤的治疗

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Glioblastoma multiforme (GBM) is the most common form of primary brain tumor and is diagnosed in approximately 15,000 people each year in the United States alone. No cure for this type of cancer exists, and the current standard of care treatments provide little benefit and are associated with debilitating side effects. Recent evidence shows that a large number of tumor-associated macrophages (TAMs) invade the GBM tumor mass and secrete factors that directly and indirectly promote tumor growth. TAMs express a panel of unique receptors that could be targeted for therapeutic benefit. One such receptor, cannabinoid receptor 2 (CB2), is a member of the endocannabinoid (eCB) signaling system, and its activation has been shown to tightly control the migration and phenotype of both macrophages and microglia. Additional receptors, also engaged by eCBs and cannabinoid-like compounds, are expressed by macrophages and microglia. These receptors also control cell migration and phenotype, but exhibit distinct pharmacological profiles and operate through a different mechanism of action. Strong evidence accumulated over the past decade indicates that membrane receptors expressed by TAMs represent novel targeting opportunities to treat GBM tumor progression. Herewe review studies that significantly increased our understanding of the molecular mechanism of action of receptors engaged by eCBs and cannabinoid-like compounds expressed by GBM tumor cells and TAMs. This evidence provides a strong rationale for developing new therapeutics that target the eCB signaling of TAMs for the treatment of GBM while minimizing the typical side effects associated with standard care.
机译:胶质母细胞瘤多形(GBM)是原发性脑肿瘤最常见的形式,仅在美国,每年约有15,000人被诊断出。无法治愈这种类型的癌症,目前的护理水平几乎没有任何好处,并且与使人衰弱的副作用有关。最近的证据表明,大量与肿瘤相关的巨噬细胞(TAM)侵入GBM肿瘤质量并分泌直接和间接促进肿瘤生长的因素。 TAMS表达了一组独特的受体,可以针对治疗益处。一种这样的受体,大麻素受体2(CB2)是内源性大麻素(ECB)信号系统的成员,已证明其激活能够严格控制巨噬细胞和小胶质细胞的迁移和表型。巨噬细胞和小胶质细胞表达了其他受体,也由ECB和大麻素样化合物参与。这些受体还控制细胞迁移和表型,但表现出独特的药理特征,并通过不同的作用机理运行。在过去的十年中积累的有力证据表明,由TAM表达的膜受体代表了治疗GBM肿瘤进展的新型靶向机会。在这里,我们回顾了我们对GBM肿瘤细胞和TAM表达的ECB和大麻素样化合物所参与的受体作用的分子机理的理解。该证据为开发新的治疗剂提供了有力的理由,该治疗剂针对TAM的欧洲央行信号用于治疗GBM,同时最大程度地减少与标准护理相关的典型副作用。

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