外泌體與消化道腫瘤化療耐藥的研究進(jìn)展

倪修凡　張尤歷　徐岷

[摘要] 消化道腫瘤包括食管癌、胃癌、結(jié)直腸癌、肝癌、胰腺癌等，均具有較高的發(fā)病率和死亡率。目前，化療是臨床治療消化道腫瘤的方法之一，但長(zhǎng)期應(yīng)用化療藥物常導(dǎo)致腫瘤細(xì)胞對(duì)化療藥物產(chǎn)生耐藥性，是目前腫瘤治療的重要挑戰(zhàn)之一。外泌體是由雙層膜構(gòu)成的直徑為30～100 nm的小囊泡，其內(nèi)部包含蛋白質(zhì)、核酸、脂質(zhì)等。近年來(lái)發(fā)現(xiàn)其通過(guò)介導(dǎo)細(xì)胞間通訊、調(diào)節(jié)腫瘤微環(huán)境參與到腫瘤一系列發(fā)生發(fā)展中，尤其對(duì)于腫瘤的化療耐藥性具有重要影響。本文主要總結(jié)了國(guó)內(nèi)外關(guān)于外泌體參與消化道腫瘤化療耐藥的研究，旨在更直觀地闡述外泌體介導(dǎo)消化道腫瘤化療耐藥的機(jī)制，為腫瘤耐藥的研究提供新思路。

[關(guān)鍵詞] 外泌體;消化道腫瘤;化療耐藥;腫瘤微環(huán)境

[中圖分類號(hào)] R735? ? ? ? ? [文獻(xiàn)標(biāo)識(shí)碼] A? ? ? ? ? [文章編號(hào)] 1673-7210（2020）06（c）-0049-04

[Abstract] The digestive system tumor including esophageal cancer， gastric cancer， colorectal cancer， liver cancer， pancreatic cancer， which have high morbidity and mortality. At present， chemotherapy is one of the treatments for digestive system tumors， but long-term application of chemotherapy drugs often causes drug resistance in tumor cells， which is one of the important challenge in tumor treatment. Exosomes are small vesicles with a diameter of 30-100 nm， which are composed of bilayer membrane. The exosomes contain proteins， nucleic acids， lipids， etc. In recent years， it has been found that exosomes participate in a series of tumor development and development by mediating intercellular communication and regulating tumor microenvironment， especially having an important impact on tumor chemotherapy resistance. This paper mainly summarized the domestic and foreign studies on the involvement of exosomes in the chemotherapy resistance of digestive system tumors， aiming to intuitively expound the mechanism of exosomes mediating the chemotherapy resistance of digestive system tumors， and provide new ideas for the study of tumor resistance.

[Key words] Exosome; Gastrointestinal tumors; Chemotherapeutic resistance; Tumor microenvironment

消化道腫瘤包括食管癌、胃癌、肝癌、結(jié)直腸癌、胰腺癌等，在腫瘤的致死組成中占1/4，其特點(diǎn)是發(fā)病率高、預(yù)后差[1]?；熌壳笆窍滥[瘤的一種重要治療方式，尤其對(duì)于晚期患者，化療效果與其預(yù)后密切相關(guān)，但患者往往會(huì)產(chǎn)生耐藥性。而外泌體在化療耐藥的過(guò)程中發(fā)揮了重要的作用。

外泌體是直徑在30～100 nm的小囊泡，起源于細(xì)胞內(nèi)吞途徑中的多泡體，通過(guò)胞膜內(nèi)陷形成囊泡釋放至細(xì)胞基質(zhì)中[2]。其內(nèi)包含核酸、脂質(zhì)及蛋白質(zhì)等多種成分，這些成分在外泌體磷脂雙分子層包裹下有更強(qiáng)的穩(wěn)定性，同時(shí)因其膜上的特異性蛋白，從而賦予傳遞信息物質(zhì)的特異性[3]。外泌體參與了腫瘤發(fā)展的各個(gè)過(guò)程，尤其在腫瘤耐藥性提升過(guò)程中，外泌體包裹的核酸、蛋白等物質(zhì)起到了關(guān)鍵作用。故明確外泌體的作用方式及其介導(dǎo)的關(guān)鍵核酸、蛋白對(duì)探索腫瘤化療耐藥新方法具有重要的指導(dǎo)意義。

1 外泌體與消化道腫瘤

外泌體在消化道腫瘤進(jìn)展中具有重要作用，參與調(diào)控腫瘤微環(huán)境、調(diào)節(jié)上皮-間充質(zhì)轉(zhuǎn)化（EMT）及提升腫瘤細(xì)胞耐藥性等過(guò)程。Wang等[4]發(fā)現(xiàn)缺氧誘導(dǎo)的胰腺癌細(xì)胞通過(guò)外泌體傳遞miR-301a-3p激活PTEN/PI3Kγ通路誘導(dǎo)巨噬細(xì)胞的M2極化，進(jìn)而促進(jìn)胰腺癌細(xì)胞的增殖與遷移。結(jié)腸癌SW480細(xì)胞分泌的外泌體被HepG2細(xì)胞攝取后，促進(jìn)信號(hào)調(diào)節(jié)激酶ERK1/2磷酸化，激活MAPK信號(hào)通路促進(jìn)結(jié)腸癌細(xì)胞的轉(zhuǎn)移[5]。此外，外泌體所包含的特異性蛋白及核酸作為腫瘤診斷標(biāo)志物目前也有諸多報(bào)道。以下將對(duì)外泌體與消化道腫瘤化療耐藥的關(guān)系展開(kāi)敘述，總結(jié)外泌體參與這一過(guò)程的主要方式及具體機(jī)制。

2 外泌體參與消化道腫瘤化療耐藥

近來(lái)發(fā)現(xiàn)外泌體對(duì)到消化道腫瘤化療耐藥這一過(guò)程具有重要影響。其主要通過(guò)兩個(gè)方面參與腫瘤耐藥：①耐藥細(xì)胞通過(guò)外泌體賦予敏感細(xì)胞耐藥性;②微環(huán)境中腫瘤相關(guān)基質(zhì)細(xì)胞的外泌體參與調(diào)節(jié)腫瘤細(xì)胞耐藥。下面，將對(duì)消化道各腫瘤化療耐藥展開(kāi)詳細(xì)的論述。

4 展望

隨著醫(yī)療技術(shù)的發(fā)展，消化道腫瘤在診斷、治療方面已取得了長(zhǎng)足的進(jìn)步，但仍需進(jìn)一步明確腫瘤的發(fā)生發(fā)展機(jī)制?；熥鳛槟壳澳[瘤治療的關(guān)鍵點(diǎn)，需要找到腫瘤耐藥的根源，更好地解決化療耐藥這一難題。外泌體作為重要的細(xì)胞間信息交流的媒介，在腫瘤耐藥發(fā)生的過(guò)程中起到了關(guān)鍵作用，盡管尚未完全明確各腫瘤之間外泌體攜帶物的差異及明確機(jī)制，但外泌體在耐藥中的研究已得到了初步揭示。在今后的研究中，明確各腫瘤化療耐藥過(guò)程中外泌體介導(dǎo)的具體分子變得尤其重要，可為靶向治療及利用外泌體的新型治療提供重要的理論依據(jù)。

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（收稿日期：2020-02-14? 本文編輯：劉明玉）