我校基础医学院生物化学与分子生物学教研室缪洪明副主任团队在Signal Transduction and Targeted Therapy发表研究成果——高脂膳
发布人:zhangyilin 发布时间:4/2/2021 4:26:01 PM  浏览次数:689次
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高脂膳食通过脂肪组织相关巨噬细胞TLR4/CXCL10信号轴抑制结直肠癌细胞的腹腔种植

祥蔚,时荣臣,袁静,缪洪明

结直肠癌是严重危害人类健康的重大疾病。结直肠癌腹腔种植转移(Peritoneal carcinomatosis, PC)在肠癌术后患者中占比较高,治疗手段欠缺、预后极差。然而,关于PC发生发展的基础研究非常匮乏,这可能也是PC防治策略久无进展的原因。

鉴于此,我们首先通过腹腔注射肠癌细胞的方法,模拟肠癌术后发生的癌细胞腹腔播散过程,构建了小鼠的PC模型。然后,分别给予小鼠正常饲料或者模拟高脂膳食的高脂饲料。令人意外的是,似乎相悖于传统的“高脂促癌”、“肥胖促癌”等观念,我们发现高脂膳食居然可显著抑制PC进展。我们进一步深入探究了高脂膳食抗PC的机制,发现:短期高脂膳食可通过一种位于细胞膜上的受体TLR-4来激活内脏脂肪巨噬细胞(adipose tissue macrophage, ATM)的吞瘤能力,并分泌Ⅰ型促炎因子和CXCL10等趋化因子进一步募集活化外周血T细胞,从而发挥抗PC作用。最后,我们还在小鼠肿瘤模型上证实: 高脂膳食与传统的奥沙利铂、5氟尿嘧啶等化疗药物有良好的协同抗PC作用。

 

 

本研究成果于202010月发表于《Signal Transduction and Targeted Therapy(IF=13.493)陆军军医大学基础医学院 缪洪明副教授为唯一通讯作者,祥蔚、时荣臣为本文共同第一作者。STTT杂志编辑部撰写述评(Sig Transduct Target Ther 5, 257 (2020). https://doi.org/10.1038/s41392-020-00386-2),对该研究成果进行了Highlight,指出:“该研究提出一种简单、经济、有效且无副作用的饮食防瘤策略,具有首创性和颠覆性。”该研究负责人缪洪明副教授强调“该研究结论是基于小鼠实验的初步结果,有待临床实验的证实”。

 

附:英文摘要

Dietary fats suppress the peritoneal seeding of colorectal cancer cells through the TLR4/Cxcl10 axis in adipose tissue macrophages

Wei Xiang# , Rongchen Shi#, Dapeng ZhangXia Kang , Lili Zhang , Jing YuanXuan Zhang , Hongming Miao*

Abstract

Rationale: Peritoneal carcinomatosis (PC) of colorectal cancer (CRC) is a terminal phase of malignancy with no effective strategies for the prevention of this condition.

Method and Results: Here we established PC models in mice by intraperitoneal engraftment of CRC cells and revealed an unexpected role for a high-fat diet (HFD) in preventing metastatic seeding in the visceral fat. Mechanistically, the HFD stimulated the activation of adipose tissue macrophages (ATMs) toward an M1-like phenotype and enhanced ATM tumor phagocytosis in a TLR4-dependent manner. Furthermore, the TLR4-Cxcl10 axis in ATMs promoted T cell recruitment, and M1-like macrophages stimulated T cell activation in tumor-seeded fats. The inhibitory effect of the HFD on tumor seeding was abolished with the ablation of macrophages, inactivation of T cells, or blockade of the TLR4-Cxcl10 axis in macrophages. Finally, we showed that a HFD and conventional chemotherapeutic agents (oxaliplatin or 5-fluorouracil) synergistically improved the survival of tumor-seeded mice. Conclusion: Collectively, our findings demonstrate that peritoneal seeding of CRC can be suppressed by short-term treatment with a HFD in the early phase, providing a novel concept for the management of these patients in the clinic.

Key words: dietary fats, colorectal cancer, macrophage, adipose tissue, TLR4, Cxcl10

全文链接:DOI: 10.1038/s41392-020-00327-z


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