IF=43.474！Immunity｜宋威團隊揭示癌癥惡液質(zhì)的致病機理：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，武漢大學免疫與代謝前沿科學中心/中南醫(yī)院醫(yī)學研究院/泰康生命醫(yī)學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)細菌增殖和系統(tǒng)IMD-NF-κB活化，延長荷瘤果蠅的壽命。遺傳學上回復(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）表達也可以在不影響腸道腫瘤的前提下抑制細菌增殖和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、促進機體死亡；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)致機體死亡的重要因素，且獨立于目前已知的腫瘤相關(guān)的機體消耗，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

Argiles, J.M., Busquets, S., Stemmler, B., and Lopez-Soriano, F.J. (2014). Cancer cachexia: understanding the molecular basis. Nature reviews Cancer 14, 754-762.

Baracos, V.E., Martin, L., Korc, M., Guttridge, D.C., and Fearon, K.C.H. (2018). Cancer-associated cachexia. Nat Rev Dis Primers 4, 17105.
Cani, P.D. (2017). Gut microbiota - at the intersection of everything? Nat Rev Gastroenterol Hepatol 14, 321-322.
Ding, G., Xiang, X., Hu, Y., Xiao, G., Chen, Y., Binari, R., Comjean, A., Li, J., Rushworth, E., Fu, Z., et al. (2021). Coordination of tumor growth and host wasting by tumor-derived Upd3. Cell reports 36.
Figueroa-Clarevega, A., and Bilder, D. (2015). Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting. Dev Cell 33, 47-55.
Kwon, Y., Song, W., Droujinine, Ilia A., Hu, Y., Asara, John M., and Perrimon, N. (2015). Systemic Organ Wasting Induced by Localized Expression of the Secreted Insulin/IGF Antagonist ImpL2. Developmental Cell 33, 36-46.
Lodge, W., Zavortink, M., Golenkina, S., Froldi, F., Dark, C., Cheung, S., Parker, B.L., Blazev, R., Bakopoulos, D., Christie, E.L., et al. (2021). Tumor-derived MMPs regulate cachexia in a Drosophila cancer model. Dev Cell 56, 2664-2680 e2666.
Lok, C. (2015). Cachexia: The last illness. Nature 528, 182-183.
Shin, H.S., Lee, H.R., Lee, D.C., Shim, J.Y., Cho, K.H., and Suh, S.Y. (2006). Uric acid as a prognostic factor for survival time: a prospective cohort study of terminally ill cancer patients. J Pain Symptom Manage 31, 493-501.
Song, W., Kir, S., Hong, S., Hu, Y., Wang, X., Binari, R., Tang, H.W., Chung, V., Banks, A.S., Spiegelman, B., et al. (2019). Tumor-Derived Ligands Trigger Tumor Growth and Host Wasting via Differential MEK Activation. Dev Cell 48, 277-286 e276.
Strasak, A.M., Rapp, K., Hilbe, W., Oberaigner, W., Ruttmann, E., Concin, H., Diem, G., Pfeiffer, K.P., Ulmer, H., Vhm, et al. (2007). Serum uric acid and risk of cancer mortality in a large prospective male cohort. Cancer Causes Control 18, 1021-1029.