IF=43.474！Immunity｜宋威團(tuán)隊揭示癌癥惡液質(zhì)的致病機(jī)理：腸道-腎臟免疫軸和尿酸代謝

日期：2023-04-03 09:20:46

癌癥惡液質(zhì)（cancer cachexia）或腫瘤誘導(dǎo)的宿主消耗（host wasting）常見于多種癌癥，如胰腺癌，胃癌，肺癌，結(jié)直腸癌等，是癌癥患者死亡的重要原因之一，超過60%的癌癥病人受惡液質(zhì)的影響。癌癥惡液質(zhì)伴隨著患者肌肉和脂肪組織導(dǎo)致的體重持續(xù)降低、高血糖和高死亡率(Argiles et al., 2014)。因其發(fā)病機(jī)理不明，目前缺乏有效的治療手段，因此癌癥惡液質(zhì)也被評為“人類最后的疾病”(Lok, 2015)。

以往利用不同的小鼠腫瘤模型，研究人員發(fā)現(xiàn)惡性腫瘤可通過分泌蛋白，如IL-6、TNF-a、Activin A、LIF等，促進(jìn)宿主消耗(Baracos et al., 2018)。然而這些研究通常在無特定病原微生物（SPF）條件下完成，因此忽視了環(huán)境中微生物如細(xì)菌、真菌、病毒等以及宿主免疫反應(yīng)的作用。

利用果蠅惡液質(zhì)模型，研究人員鑒定了一系列腫瘤分泌蛋白，如ImpL2、Pvf1和Upd3等，分別通過insulin、MEK和Jak/Stat信號通路來遠(yuǎn)程破壞宿主器官代謝平衡，造成宿主消耗(Ding et al., 2021; Kwon et al., 2015; Lodge et al., 2021; Song et al., 2019)。

2022年8月26日，武漢大學(xué)免疫與代謝前沿科學(xué)中心/中南醫(yī)院醫(yī)學(xué)研究院/泰康生命醫(yī)學(xué)中心的宋威課題組在《Immunity》雜志上發(fā)表題為"Renal NF-kB activation impairs uric acid homeostasis to promote tumor-associated mortality independent of wasting"的研究論文。

3SA(人體YAP1同源物)，誘導(dǎo)腸道干細(xì)胞過度增殖形成腸道惡性腫瘤。在該研究中，研究人員首先發(fā)現(xiàn)yki3SA果蠅體內(nèi)細(xì)菌增殖和系統(tǒng)IMD-NF-κB活化，延長荷瘤果蠅的壽命。遺傳學(xué)上回復(fù)腸道PGRP-SC2（在本研究中被鑒定為一種全新的具有廣譜抗菌功能的分泌型酰胺酶）表達(dá)也可以在不影響腸道腫瘤的前提下抑制細(xì)菌增殖和IMD-NF-κB活化、延長果蠅壽命。

3SA果蠅馬氏管中的IMD-NF-κB通路，而不是傳統(tǒng)認(rèn)為的肌肉、脂肪和大腦組織，可以有效緩解yki3SA荷瘤果蠅的馬氏管中IMD-NF-κB活化可以造成尿酸堆積、促進(jìn)機(jī)體死亡；喂食別嘌呤醇（Allopurinol）抑制尿酸合成或在馬氏管中特異阻斷IMD-NF-κB通路可有效緩解yki

總之，該研究發(fā)現(xiàn)環(huán)境微生物、腸道細(xì)菌、腎臟IMD-NF-κB免疫反應(yīng)和尿酸代謝是惡性腫瘤導(dǎo)致機(jī)體死亡的重要因素，且獨立于目前已知的腫瘤相關(guān)的機(jī)體消耗，為深入理解腫瘤-宿主互作、實現(xiàn)荷瘤生存提供了新的角度。

參考文獻(xiàn)

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