Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
Cancer Lett. 2022 Jun 28;536:215664. doi: 10.1016/j.canlet.2022.215664. Epub 2022 Mar 26.
Despite technological advances in diagnostic abilities and improved treatment methods, the burden of cancers remains high, leading to significant morbidity and mortality. One primary reason is that cancer cell secretory factors modulate the tumor microenvironment, supporting tumor growth and circumvents anticancer activities of conventional therapies. Macrophage inhibitory cytokine-1 (MIC-1) is a pleiotropic cytokine elevated in various cancers. MIC-1 regulates various cancer hallmarks, including sustained proliferation, tumor-promoting inflammation, avoiding immune destruction, inducing invasion, metastasis, angiogenesis, and resisting cell death. Despite these facts, the molecular regulation and downstream signaling of MIC-1 in cancer remain elusive, partly because its receptor (GFRAL) was unknown until recently. Binding of MIC-1 to GFRAL recruits the coreceptor tyrosine kinase RET to execute its downstream signaling. So far, studies have shown that GFRAL expression is restricted to the brain stem and is responsible for MIC-1/GFRAL/RET-mediated metabolic disorders. Nevertheless, abundant levels of MIC-1 expression have been reported in all cancer types and have been proposed as a surrogate biomarker. Given the ubiquitous expression of MIC-1 in cancers, it is crucial to understand both upstream regulation and downstream MIC-1/GFRAL/RET signaling in cancer hallmark traits.
尽管在诊断能力和改进治疗方法方面取得了技术进步，但癌症的负担仍然很高，导致发病率和死亡率显著增加。一个主要原因是癌细胞分泌因子调节肿瘤微环境，支持肿瘤生长，并规避传统疗法的抗癌活性。巨噬细胞抑制因子 1（MIC-1）是一种在多种癌症中升高的多功能细胞因子。MIC-1 调节各种癌症的特征，包括持续增殖、促进肿瘤的炎症、避免免疫破坏、诱导侵袭、转移、血管生成和抵抗细胞死亡。尽管有这些事实，但 MIC-1 在癌症中的分子调节和下游信号仍然难以捉摸，部分原因是其受体（GFRAL）直到最近才被发现。MIC-1 与 GFRAL 的结合招募了核心受体酪氨酸激酶 RET 来执行其下游信号。到目前为止，研究表明，GFRAL 表达仅限于脑干，并负责 MIC-1/GFRAL/RET 介导的代谢紊乱。然而，大量的 MIC-1 表达已在所有癌症类型中报道，并被提议作为替代生物标志物。鉴于 MIC-1 在癌症中的普遍表达，了解癌症特征中 MIC-1 的上游调节和下游 GFRAL/RET 信号至关重要。
