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Medical Diagnosis
Vol. 12  No. 01 ( 2022 ), Article ID: 49568 , 7 pages
10.12677/MD.2022.121011

TGF-β与IL-6对胃癌发展和转移的影响

王英健，徐剑*

佳木斯大学附属第一医院，黑龙江 佳木斯

收稿日期：2022年2月7日；录用日期：2022年3月16日；发布日期：2022年3月23日

摘要

胃癌是人类消化系统中最常见的恶性肿瘤，而胃癌的发展与转移是一个十分复杂的过程，多个因素参与其中。TGF-β作为一类多功能的细胞因子，通过促进上皮–间质转化、血管生成、免疫逃避等途径，在胃癌的发展与转移中起到了关键性的作用。IL-6则是一类炎性因子，通过与其受体结合进而激活相关信号转导通路、参与细胞的上皮–间质转化、介导免疫系统等影响了胃癌发展和转移。

关键词

胃癌，TGF-β，IL-6，腹膜转移

Effects of TGF-β and IL-6 on the Development and Metastasis of Gastric Cancer

Yingjian Wang, Jian Xu*

The First Affiliated Hospital of Jiamusi University, Jiamusi Heilongjiang

Received: Feb. 7th, 2022; accepted: Mar. 16th, 2022; published: Mar. 23rd, 2022

ABSTRACT

Gastric cancer is the most common malignant tumor in human digestive system, and the development and metastasis of gastric cancer are a very complex process, in which many factors are involved. TGF-β as a kind of multifunctional cytokines, they play a key role in the development and metastasis of gastric cancer by promoting epithelial mesenchymal transformation, angiogenesis and immune escape. IL-6 is a kind of inflammatory factor, which affects the development and metastasis of gastric cancer by binding to its receptor, activating related signal transduction pathways, participating in cell epithelial mesenchymal transformation and mediating immune system.

Keywords:Gastric Cancer, TGF-β, IL-6, Peritoneal Metastasis

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

胃癌是一种消化系中比较常见的恶性肿瘤。在全球范围内新增胃癌患者人数每年大约有将近100万 [1]。在我国，胃癌的发病率排在各种恶性肿瘤的第三位，死亡率则列在第二位，已经严重地影响到了人类的生命健康 [2]。而腹膜是胃癌比较常见的转移部位，在我国，腹膜转移占到了胃癌转移的一半以上，高于肝转移及其他转移，在进展期患者中约有10%~20%存在腹膜的微小转移灶，研究表明，在新就诊的胃癌患者中，有一部分可能已经发生腹膜转移，而在晚期胃癌患者中腹膜转移发生率则更高 [3] [4]。伴有腹膜转移的胃癌患者的5年生存率仅有2%，其中位生存期仅有3~6个月 [3] [5]。而胃癌的腹膜转移需要各种细胞因子、黏附因子、血管生成因子以及蛋白水解酶等的共同参与。

2. 胃癌腹膜转移的相关机制

胃癌腹膜转移形成机制目前仍尚未明确。有相关研究 [6] 认为，胃癌腹膜转移是一个多阶段性、多因素共同参与的过程。一般认为腹膜转移是胃癌发生了以下的过程：首先具有增殖能力的癌细胞从原发灶处脱落后进入腹腔中；随后具有转移潜能的癌细胞黏附于腹膜；接着癌细胞黏附于腹膜之后进一步着床并侵袭腹膜，并且在各种促肿瘤形成及转移相关因子的共同作用下形成新生毛细血管并沿血管周围开始增殖侵袭。

目前胃癌腹膜转移较为认可的发病机制为“种子–土壤”学说 [7]。所谓的“种子–土壤”学说是指具有侵袭能力和转移潜能胃癌细胞从原发灶处脱落，成为癌转移或术后复发的“种子”。腹膜间皮细胞以及细胞外基质构成的腹腔微环境为肿瘤腹膜转移的发生提供了“土壤”。正常人的腹膜主要由单层间皮细胞及细胞外基质构成，可以有效的阻止癌细胞在腹膜上黏附。有研究认为癌细胞黏附于腹膜之前，腹膜可能就已经出现了形态及结构的改变。而腹膜纤维化就是其中一重要的表现形式 [8]。还有研究发现将肿瘤细胞和间皮细胞共同培养时，可以有效阻止肿瘤细胞向间皮下侵袭，但当有成纤维细胞存在时，间皮细胞对抵抗肿瘤细胞侵袭的作用明显减弱。上皮–间质转化(EMT)对于胃癌腹膜转移也起到重要作用，由TGF-β1刺激诱导的活化人类腹膜间皮细胞(HPMC)通过EMT有助于胃癌细胞浸润、增殖和腹膜纤维化 [9]。

3. TGF-β对胃癌发展及转移的影响

3.1. TGF-β概述

TGF-β家族包含大约40种结构相关的因子，包括TGF-β、激活素、抑制素、骨形态发生蛋白(BMP)和生长分化因子(GDF)等，而TGF-β包含3个亚型TGF-β1、TGF-β2和TGF-β3，其中TGF-β1是表达最多的一种亚型 [10]。转化生长因子β是一种分泌性多肽，已发现其具有由肿瘤细胞产生的生物活性，能够诱导培养中非癌细胞的致癌转化 [11]。细胞膜上有两种丝氨酸/苏氨酸激酶型受体，它们是TGF-β的靶标。TGF-β通过I型和II型受体的异源受体复合物发出信号，这是经典的Smad信号转导 [12]。除此之外，TGF-β1还可以通过介导免疫抑制、新血管生成和上皮–间质转化(EMT)促进癌症进展 [13]。Lv等 [14] 通过收集胃癌患者的腹膜组织以及腹腔灌洗液进行体内外研究，结果说明了通过P17肽阻断TGF-β的相关表达，可减轻腹膜的纤维化，预防胃癌细胞腹膜播散，同时该研究证实TGF-β可通过诱导腹膜纤维化促进了胃癌细胞的腹膜转移。并且TGF-β1在血清和癌组织中的高水平表达也与淋巴结受累和预后不良密切相关 [15]。

3.2. TGF-β与EMT

EMT是一种可逆的细胞程序，可以使上皮细胞暂时进入到间质细胞状态 [16]。在正常的生理条件下，EMT对于胚胎发育和组织损伤修复起着至关重要的作用 [17]。但是，在癌症等病理情况下，EMT还可以驱动肿瘤细胞转移。EMT允许肿瘤细胞将极化的上皮细胞重新编程为间充质表型，并增强其运动能力、侵袭性和抗凋亡能力。在肿瘤微环境中，TGF-β、趋化因子4/12 (CXCL4/12)、白介素-6 (IL-6)和肿瘤坏死因子-α (TNF-α)等可促进EMT。同时，肿瘤细胞还可以分泌更多的上皮生长因子，成纤维细胞生长因子(FGF)和胰岛素样生长因子(IGF)，导致微环境处于缺氧、酸性的状态，从而激活癌相关成纤维细胞(CAF)产生更多基质金属蛋白酶(MMP)并重塑肿瘤细胞外基质(ECM)，促进肿瘤的转移 [18]。而转化生长因子β (TGF-β)是EMT最重要的诱导剂，肿瘤细胞通过增加TGF-β的表达以刺激细胞外基质(ECM)沉积和组织纤维化、扰乱免疫和炎症功能，在肿瘤发生的后期通过增强肿瘤细胞的迁移、侵袭、刺激血管生成和促进EMT，从而增加肿瘤细胞的迁移和侵袭能力 [19] [20]。TGF-β介导的Smad依赖性和Smad非依赖性信号传导诱导转录因子Snail、Slug、Twist、ZEB1和ZEB2，在EMT的调节中也起到至关重要的作用，TGF-β抑制E-cadherin和occludin的启动子，使Smad3/4复合物可以直接与Snail启动子的调控区结合以诱导其转录 [21]。TGF-β在以非SMAD依赖性方式诱导EMT时，可以通过促进细胞骨架重塑，从而激活ERK [22]。细胞骨架重塑所需的ERK、SHC和GRB2相互作用形成SHC-GRB2-ERK复合物，这是TGF-β诱导的肿瘤侵袭和转移的关键成分 [23]。TGF-β还通过泛素化诱导EMT，Smad3/4复合物由此调节HDM2的表达，增加p53的泛素化和降解，从而诱导EMT进展 [24]。

3.3. TGF-β促进血管生成

新血管的形成对于正常发育和组织修复至关重要。然而，血管生成也已成为炎症过程、肿瘤进展和转移的关键因素。血管的生成受血管内皮生长因子(VEGF)、转化生长因子(TGF)-β等的调节。在直径超过1~2毫米的肿瘤中会有新的血管生成，这些新生的血管可以供应足够的血液为肿瘤的生长和转移提供营养和氧气，以加速癌症的发展 [25]。在内皮细胞中，TGF-β可以与I型受体、激活素受体样激酶1 (ALK-1)结合，促进相关细胞内和核蛋白(SMAD和Id1)的下游信号传导，进而导致促血管生成反应 [26]。

3.4. TGF-β与免疫系统

在生理条件下，免疫系统是人类抵御癌症最重要的屏障，可以通过称为免疫监视的过程抑制某些癌症的生长，如T淋巴细胞和自然杀伤细胞可以识别并特异性消除肿瘤细胞。在转移到远处器官的过程中，癌细胞的存活依赖于通过利用多种机制以逃避免疫系统检测的能力。其中肿瘤细胞可以通过TGF-β来逃避这种免疫监视 [27]。晚期癌症的肿瘤微环境通常以大量成纤维细胞生成为主要特征。这些癌症相关成纤维细胞(CAF)是一组异质细胞，产生包括胶原蛋白、弹性蛋白和纤连蛋白，以及一系列调节肿瘤特性的细胞因子，这些构成了细胞外基质(ECM)的主要成分 [28]。有相关研究表明，由癌细胞和邻近免疫细胞分泌的TGF-β可以抑制效应细胞的抗肿瘤活性，这些效应细胞包括CD8+T细胞、自然杀伤细胞和巨噬细胞 [29]。自然杀伤细胞通过直接识别肿瘤细胞和启动细胞毒性反应在免疫监视中发挥重要作用 [30]。TGF-β通过减少IL-15的产生并下调其活性受体NKG2D来抑制NK细胞活化 [31]。肿瘤相关巨噬细胞(TAM)有两种表型，经典激活的M1表型可以抑制肿瘤生长，而非经典激活的M2表型可以促进肿瘤生长。TGF-β主要驱动巨噬细胞M2表型的分化。它们产生许多不同的细胞因子，例如MMP9、CXC基序配体8 (CXCL8)和IL-10，以诱导肿瘤生长和发展 [32]。

4. IL-6对胃癌发展及转移的影响

4.1. IL-6概述

IL-6是一种多效性促炎细胞因子，它是一种含有185个氨基酸的低分子量蛋白质，参与许多生物学过程，包括癌症和自身免疫性疾病。在生理情况下，IL-6由各种正常细胞类型如巨噬细胞、单核细胞、基质细胞、造血细胞、上皮细胞和肌肉细胞产生，在炎症、免疫、生殖、新陈代谢、造血、神经发育、骨重塑和血管生成中发挥重要作用 [33]。IL-6同样被认为是炎症和癌症之间联系的关键细胞因子。在肿瘤微环境中IL-6可由肿瘤浸润性免疫细胞、基质细胞和肿瘤细胞本身等产生 [34]。Sakamoto等人的研究发现在有腹膜播散的胃癌小鼠腹腔积液中IL-6的浓度高于没有腹腔播散的小鼠，证明了IL-6是加速胃癌腹膜播散的关键介质之一 [35]。多种组织纤维化与IL-6密切相关，IL-6通过增加Twist、Vimentin、Snail、N-cadherin的表达，降低E-cadherin的表达导致了上皮–间质转化的发生，从而促进了肿瘤的侵袭 [36]。

4.2. IL-6/JAK/STAT3通路

IL-6/JAK/STAT3通路在许多人类癌症的生长和发展中起关键作用。在类风湿性关节炎和炎症性肠病等慢性炎症性疾病以及大量患有造血系统恶性肿瘤或实体瘤的患者中均可观察到IL-6水平升高 [34]。IL-6可通过与由IL-6R和gp130组成的IL-6受体复合物结合来激活Janus激酶(JAK)/转录激活因子3 (STAT3)信号转导通路 [37]。磷酸化STAT3单体可以形成二聚体并随后转移到细胞核中，以调节其靶基因的转录并最终改变基本的细胞过程 [38]。IL-6除了可以通过膜结合受体(mIL-6R)结合来执行其功能，还通过与可溶性受体(sIL-6R)结合，IL-6先与sIL-6R结合后形成IL-6-sIL-6R-复合物，然后IL-6-sIL-6R-复合物二聚化并与跨细胞gp130结合，从而激活它。在这两种途径中，gp130都被激活，这导致与gp130相关的JAK被激活并与gp130蛋白中的Box结构域结合，从而导致JAK的磷酸化和完全激活。在下游，STAT家族蛋白现在能够识别并结合激活的JAK的对接位点，以便JAK磷酸化并激活STAT [39]。信号转导通路在诱导肿瘤微环境、控制白细胞募集和肿瘤相关基质细胞的激活方面尤为重要。由于gp130不限于特定的细胞类型，因此信号转导通路可以发生在大多数细胞中 [40]。有研究发现IL-6在食管癌中通过STAT3和ERK1/2信号通路介导以促进肿瘤细胞增殖、侵袭以及抑制细胞凋亡 [41]。研究还发现胃癌患者的IL-6和STAT3表达水平上调，尤其是在有恶病质的胃癌患者中 [42]。

4.3. IL-6与免疫系统

IL-6已被证明在调节T和B淋巴细胞以及自然杀伤细胞的增殖和分化中发挥重要作用 [43]。在一项研究中，Th1细胞的MHC II表达被IL-6阻断，阻碍了IFN-γ和IL-2的分泌，从而降低了细胞毒性T淋巴细胞的活性，使癌细胞能够逃避抗癌免疫反应 [44]。IL-6/STAT3信号转导通路在肿瘤细胞的免疫逃逸也发挥重要作用，IL-6通过激活IL-6/STAT3信号通路来抑制树突状细胞(DC)的抗原呈递能力。DC中STAT3的激活显着降低了肿瘤免疫监视，进而阻断肿瘤细胞的抗肿瘤免疫反应 [44]。IL-6分泌可以上调中性粒细胞中程序性细胞死亡配体1 (PD-L1)的表达，从而抑制T细胞的活性并最终加速肿瘤细胞的免疫逃逸 [45]。

4.4. IL-6与EMT

IL-6在EMT中同样起到重要作用，它通过改变N-cadherin、vimentin、snail、twist和E-cadherin的表达来促进上皮–间质转化(EMT)，从而导致癌症转移 [46]。Sun J等 [47] 的研究发现IL-6还可能是通过下调miR-152的表达，并诱导PIK3R3的表达，进而激活PI3K/Akt信号转导通路，以调控细胞的增殖、迁移和EMT等过程，促进致癌作用。癌症相关成纤维细胞(CAF)已被认为在肿瘤发展中发挥至关重要的作用 [48]。有研究表明GC产生的CAF能分泌大量的IL-6，IL-6可通过激活GC细胞中的Janus激酶2/转录激活因子3 (JAK2/STAT3)途径诱导上皮–间质转化并增加胃癌细胞的迁移 [49]。

5. 结语

胃癌是常见的消化系肿瘤，胃癌的发展与转移对患者的预后与生存密切相关。TGF-β与IL-6对胃癌发展和转移其着重要的作用，尤其是通过介导免疫抑制、血管生成和上皮–间质转化等方式促进了胃癌的腹膜转移。目前尚缺少对于胃癌腹膜转移诊断的有效方法，对于TGF-β与IL-6的研究将有助于更有效、更及时地诊断胃癌腹膜转移提供可能的依据。

文章引用

王英健,徐 剑. TGF-β与IL-6对胃癌发展和转移的影响
Effects of TGF-β and IL-6 on the Development and Metastasis of Gastric Cancer[J]. 医学诊断, 2022, 12(01): 65-71. https://doi.org/10.12677/MD.2022.121011

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