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-*-*-*- Study reveals how fatty liver promotes colorectal cancer spread 研究揭示了脂肪肝如何促进结肠癌症扩散 Investigators at Cedars-Sinai Cancer found that fatty liver, a condition closely associated with obesity, promotes the spread of colorectal cancer to the liver. Their study, published today in the journal Cell Metabolism, details the process at the cellular level and could change the way doctors manage the disease in some patients. Cedars-Sinai癌症的研究人员发现，脂肪肝是一种与肥胖密切相关的疾病，它会促使结直肠癌向肝脏扩散。他们的研究今天发表在《细胞代谢》杂志上，详细介绍了细胞水平的过程，并可能改变医生对一些患者的疾病管理方式。 'Currently 25% to 30% of U.S. adults are obese, making it likely that they also have fatty liver,' said Ekihiro Seki, MD, Ph.D., professor of Medicine and Biomedical Sciences at Cedars-Sinai and senior author of the study. 'Our study found that fatty liver cells secrete sacs of proteins and genetic material that promote the spread of colorectal cancer to the liver, suggesting doctors should manage colorectal cancer patients with fatty liver differently.' Cedars-Sinai大学医学和生物医学教授、该研究的高级作者、医学博士Ekihiro Seki说：“目前，25%至30%的美国成年人肥胖，他们很可能也患有脂肪肝。”。“我们的研究发现，脂肪肝细胞分泌蛋白质和遗传物质，促进结直肠癌癌症向肝脏扩散，建议医生应对患有脂肪肝的癌症患者采取不同的管理方式。” Seki noted that the study examined a mild form of fatty liver—one that clinicians might not be aware of or on the lookout for. He further emphasized that this condition is likely underdiagnosed. Seki指出，这项研究检查了一种轻度脂肪肝，临床医生可能不知道或不注意这种情况。他进一步强调，这种情况可能诊断不足。 'Our study showed that even mild fatty liver increased the risk of cancer spread,' Seki said. 'Thus, we are urging doctors to really pay attention to colorectal cancer patients who might have fatty liver. Among our patient samples, we noted that more than 40% of patients had fatty liver, but doctors often do not order the specialized MRI required to detect it, meaning many cases are missed.' Seki说：“我们的研究表明，即使是轻度脂肪肝也会增加癌症传播的风险。”。“因此，我们敦促医生真正关注可能患有脂肪肝的结直肠癌患者。在我们的患者样本中，我们注意到超过40%的患者患有脂肪肝，但医生通常不会进行专业所需的MRI检测脂肪肝，这意味着许多病例会被遗漏。” Ultimately, 70% of patients with colorectal cancer will develop liver metastasis, which is the major cause of death for these patients, according to Seki. He and fellow investigators sought to discover why some patients develop aggressive metastasis while others do not, and to determine why only some patients respond well to therapy. Seki说，最终，70%的结直肠癌患者会发生肝转移，这是这些患者死亡的主要原因。他和其他研究人员试图发现为什么一些患者出现侵袭性转移，而另一些患者没有，并确定为什么只有一些患者对治疗反应良好。 'Our hypothesis was that fatty liver does something to cause these differences,' Seki said. Seki说：“我们的假设是脂肪肝会导致这些差异。”。 Seki and his team examined laboratory mice with colorectal cancer liver metastasis, some of which had been fed a high-fat diet that caused them to develop fatty liver. They noted that liver cells in the mice with fatty liver produced greater amounts of extracellular vesicles—particles that are released from cells and carry proteins and genetic material from the parent cell. Seki和他的团队对患有结直肠癌肝转移的实验小鼠进行了检查，其中一些小鼠被喂以高脂肪饮食，导致其发展为脂肪肝。他们指出，患有脂肪肝的小鼠的肝细胞产生了大量的细胞外囊泡颗粒，这些颗粒从细胞中释放出来，携带来自母体细胞的蛋白质和遗传物质。 'The extracellular vesicles produced by fatty liver cells contain three types of microRNA that stimulate cancer proliferation, migration and invasion,' Seki said. 'The cancer cells take in these extracellular vesicles and these microRNA react with another protein called yes-associated protein to promote tumor growth. So the primary cancer in fatty liver mice becomes more aggressive and more metastatic.' Seki说：“脂肪肝细胞产生的细胞外小泡含有三种类型的microRNA，可以刺激癌症的增殖、迁移和侵袭。”。“癌症细胞吸收这些细胞外小泡，这些microRNA与另一种叫做Yes相关蛋白的蛋白质反应，促进肿瘤生长。因此，脂肪肝小鼠的原发性癌症变得更具侵袭性和转移性。” These yes-associated proteins also suppress the immune system in the environment immediately surrounding tumors, which Seki theorized could make them resistant to immunotherapy, a common cancer-fighting treatment. 这些yes相关蛋白还抑制肿瘤周围环境中的免疫系统，Seki认为这可能会使肿瘤对免疫治疗产生抵抗，这是一种常见的癌症治疗方法。 The investigators found the same types of conditions when they compared tissue samples from human patients with and without fatty liver who also had colorectal cancer liver metastasis. 研究人员在比较患有和不患有脂肪肝且患有结直肠癌肝转移的患者的组织样本时发现了相同类型的情况。 Seki said further studies are needed to examine whether fatty liver in lean patients, which is common in Asian populations, has the same effect on cancer spread. Additional research could also help determine whether metastatic colorectal cancer is resistant to immunotherapy in patients with fatty liver, and how that resistance might be reversed. Seki说，需要进一步研究，以检查瘦患者中的脂肪肝是否对癌症传播有同样的影响，这在亚洲人群中很常见。额外的研究也可能有助于确定脂肪肝患者的转移性结直肠癌是否对免疫治疗有阻力，以及如何逆转这种阻力。 'This study provides new insight into the mechanisms behind the fatty liver's promotion of colorectal cancer metastasis, and into distinct tumor microenvironments in patients with fatty liver that may contribute to weak response to anti-cancer therapies,' said Dan Theodorescu, MD, Ph.D., director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. Cedars-Sinai癌症主任Dan Theodorescu医学博士和PHASE ONE杰出主席表示：“这项研究为脂肪肝促进结直肠癌转移隐藏的机制提供了新的见解，并为脂肪肝患者不同的肿瘤微环境提供了新视角，这些微环境可能会导致抗癌治疗反应较弱。”。 'We have ongoing efforts aimed at populations at high risk of fatty liver disease, and this study suggests we need to redouble our efforts especially in those who have colorectal cancer.' “我们正在针对脂肪肝高危人群进行努力，这项研究表明，我们需要加倍努力，尤其是在患有癌症的人群中。” 来自：https:///news/2023-05-reveals-fatty-liver-colorectal-cancer.html -*-*-*-*- Extracellular vesicles in fatty liver promote a metastatic tumor microenvironment 脂肪肝细胞外小泡促进转移性肿瘤微环境 Highlights 重点 Fatty liver upregulates hepatic Rab27a expression, promoting EV production 脂肪肝上调肝脏Rab27a的表达，促进EV的产生 Fatty liver-derived EVs enhance YAP activity in CRC liver metastasis 来自脂肪肝的EVs（细胞外小泡）在CRC肝转移中增强YAP活性 Enhanced YAP induces CYR61 expression in CRC liver metastasis 增强的YAP诱导CRC肝转移CYR61的表达 CYR61 modulates the immunosuppressive environment in CRC liver metastasis CYR61调节CRC肝转移的免疫抑制环境
Summary 总结 Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). Fatty liver promotes liver metastasis, but the underlying mechanism remains unclear. We demonstrated that hepatocyte-derived extracellular vesicles (EVs) in fatty liver enhanced the progression of CRC liver metastasis by promoting oncogenic Yes-associated protein (YAP) signaling and an immunosuppressive microenvironment. Fatty liver upregulated Rab27a expression, which facilitated EV production from hepatocytes. In the liver, these EVs transferred YAP signaling-regulating microRNAs to cancer cells to augment YAP activity by suppressing LATS2. Increased YAP activity in CRC liver metastasis with fatty liver promoted cancer cell growth and an immunosuppressive microenvironment by M2 macrophage infiltration through CYR61 production. Patients with CRC liver metastasis and fatty liver had elevated nuclear YAP expression, CYR61 expression, and M2 macrophage infiltration. Our data indicate that fatty liver-induced EV-microRNAs, YAP signaling, and an immunosuppressive microenvironment promote the growth of CRC liver metastasis. 肝转移是癌症患者死亡的主要原因。脂肪肝促进肝转移，但其潜在机制尚不清楚。我们证明，脂肪肝中肝细胞产生的细胞外小泡（EVs）通过促进致癌的Yes相关蛋白（YAP）信号传导和免疫抑制微环境，增强了结直肠癌的肝转移的进展。脂肪肝上调Rab27a的表达，从而促进肝细胞产生EV。在肝脏中，这些细胞外小泡通过抑制LATS2将YAP信号调节microRNAs转移到癌症细胞以增强YAP活性。在伴脂肪肝结直肠癌的肝转移，YAP活性升高，通过产生CYR61, M2巨噬细胞浸润，促进癌细胞生长和免疫抑制微环境。结直肠癌肝转移和脂肪肝患者核YAP表达、CYR61表达和M2巨噬细胞浸润升高。我们的资料表明，脂肪肝诱导的细胞外小泡microRNA、YAP信号传导和免疫抑制微环境促进结直肠癌肝转移的生长。 来自：https://www./cell-metabolism/fulltext/S1550-4131(23)00140-7 -*-*-*-*- |
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