細胞因子參與胃癌發(fā)生和發(fā)展研究進展

李　康(綜述),旦　增(審校)

(西藏自治區(qū)人民醫(yī)院內(nèi)四科,拉薩 850000)

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細胞因子參與胃癌發(fā)生和發(fā)展研究進展

李康※(綜述),旦增(審校)

(西藏自治區(qū)人民醫(yī)院內(nèi)四科,拉薩 850000)

摘要：細胞因子是一類能在細胞間傳遞信息、發(fā)揮免疫調(diào)節(jié)的蛋白質(zhì)或小分子多肽；其表達異常誘發(fā)多種疾病，包括胃癌。細胞因子參與調(diào)控細胞的癌變、侵襲與轉(zhuǎn)移、血管生成，并通過調(diào)控腫瘤相關(guān)抗原的抗原遞呈、淋巴細胞的活化參與胃癌的免疫逃逸，且在胃癌細胞抵抗放化療治療中發(fā)揮重要作用。因此，調(diào)節(jié)機體細胞因子的水平，促使機體形成對胃癌的抗腫瘤也就成為胃癌治療的新方向。

關(guān)鍵詞：胃癌；細胞因子；免疫逃逸

細胞因子是由多種細胞產(chǎn)生的，具有廣泛調(diào)節(jié)細胞功能作用的多肽分子，細胞因子不僅作用于免疫系統(tǒng)和造血系統(tǒng)，還廣泛作用于神經(jīng)、內(nèi)分泌系統(tǒng)，對細胞間相互作用、細胞的增殖分化和效應(yīng)功能有重要的調(diào)節(jié)作用。細胞因子分為白細胞介素(interleukin,IL)、干擾素、腫瘤壞死因子 (tumor necrosis factor,TNF)超家族、集落刺激因子、趨化因子、生長因子等。眾多細胞因子在體內(nèi)通過旁分泌、自分泌或內(nèi)分泌等方式發(fā)揮作用，具有多效性、重疊性、拮抗性、協(xié)同性等多種生理特性，形成了十分復(fù)雜的細胞因子調(diào)節(jié)網(wǎng)絡(luò)，參與人體多種重要的生理功能。研究表明，細胞因子的表達異常伴有炎癥反應(yīng)、組織壞死及腫瘤的發(fā)生。其中在惡性腫瘤發(fā)生中，細胞因子能促進細胞的增殖、轉(zhuǎn)移、血管生成，并參與腫瘤的放、化療抵抗及腫瘤的免疫逃逸[1]。

胃癌是常見的惡性腫瘤之一，流行病學(xué)調(diào)查研究顯示胃癌的發(fā)病率在消化道腫瘤中居首，相關(guān)病死率位居腫瘤第2位[2]。我國是胃癌的高發(fā)地區(qū)，胃癌病死率男性為40.8/10萬，女性為18.6/10萬；分別是歐美等發(fā)達國家的4.2～7.9 和3.8～8.0倍[3-4]。病例報道顯示，多種細胞因子在胃癌患者中表達異常，并與腫瘤的分級、分期，腫瘤的預(yù)后不良密切相關(guān)[5-6]，提示細胞因子的異常參與了胃癌的發(fā)生、發(fā)展，并極可能發(fā)揮了重要作用，調(diào)節(jié)細胞的表達水平可能成為胃癌治療的新途徑。現(xiàn)就細胞因子在胃癌發(fā)生、發(fā)展中的作用，以及利用細胞因子治療胃癌的最新研究進展予以綜述，期望為胃癌的治療帶來新的啟示。

1細胞因子與胃癌發(fā)生、發(fā)展

1.1細胞因子參與的炎癥反應(yīng)與胃癌慢性炎癥被認為是腫瘤發(fā)生的主要病因?qū)W之一，包括胃癌。其中75%的胃癌發(fā)生與幽門螺桿菌(Helicobacter pylori,Hp)感染有關(guān)，細菌的毒力因素和機體的免疫系統(tǒng)互相作用形成慢性炎癥反應(yīng)，導(dǎo)致胃萎縮、腸化生、胃癌發(fā)生[7]；其中多種細胞因子發(fā)揮促炎作用。Hp感染活化核苷酸結(jié)合寡聚化結(jié)構(gòu)域通路增強干擾素γ信號通路中的信號傳導(dǎo)與轉(zhuǎn)錄激活子(signal transducer and activator of transcription,STAT)1和人干擾素調(diào)節(jié)因子的表達，促進炎性細胞因子IL-8和干擾素γ誘導(dǎo)表達，炎癥反應(yīng)加劇[8]。Hp感染導(dǎo)致少兒胃組織Toll樣受體(Toll like receptors,TLR)2、TLR-4、TLR-5和TLR-9表達顯著升高，細胞因子IL-8、IL-10 和 TNF-α 的表達也顯著增加，胃組織的慢性炎癥反應(yīng)增強[9]。Hp感染后，IL-1β活化表達誘導(dǎo)胃組織的炎癥反應(yīng)，并誘導(dǎo)多個基因的甲基化，促使腫瘤的發(fā)生[10]。此外，IL-32調(diào)控趨化因子配體分子1、趨化因子配體分子2、IL-8、核因子κB(nuc-lear factor κB，NF-κB)的表達參與Hp感染誘導(dǎo)的炎癥反應(yīng)[11]。同時細胞因子的多態(tài)性與胃癌發(fā)生的風(fēng)險密切相關(guān),例如IL-1β及其受體基因的多態(tài)性影響Hp感染所致的炎癥反應(yīng)結(jié)果[12-13]；轉(zhuǎn)化生長因子β1(transforming growth factor β1,TGF-β1)基因-509T胃癌具有更高易患性[14]；TNF-α-857C/T、IL-8-845T/C、IL-10-592C/A基因表型增強胃部的炎癥反應(yīng)和胃癌的發(fā)生[15]；TLR1- 602基因的多態(tài)性影響自然殺傷細胞和T細胞干擾素γ的產(chǎn)生，進而影響Hp誘導(dǎo)的胃部炎癥反應(yīng)[16]；IL-6基因-174 C/G 和-572 C/G增加胃的炎癥反應(yīng)和胃癌發(fā)生的風(fēng)險[17]；IL-10-592基因多態(tài)性影響胃組織的炎癥反應(yīng)，增加胃癌的易患性[18-19]。

自身免疫性胃炎是一種器官特異性的自身免疫病，常伴有胃酸匱乏、貧血、胃息肉、胃良性腫瘤、胃腺癌，TNF-α 和IL-21 是其發(fā)生的關(guān)鍵因素，它們誘導(dǎo)表達的細胞因子在胃癌的發(fā)生中起重要作用[20]。如炎性因子IL-1β、IL-2、 IL-4、IL-6、 IL-10、TNF-α和干擾素γ的表達增加胃癌發(fā)生率；IL-8的表達增加使胃癌發(fā)生率提高2倍[21]。IL-6/JAK2信號活化轉(zhuǎn)錄因子STAT3通過調(diào)控Skp2/p27/p21通路調(diào)控細胞的增殖和轉(zhuǎn)移[22]。三葉因子1是腫瘤抑制因子，表達于正常的胃上皮細胞中，主要維持上皮細胞結(jié)構(gòu)和功能；但在胃癌組織中，胃組織炎性因子IL-1β和TNF-α活化轉(zhuǎn)錄因子NF-κB顯著下調(diào)三葉因子1表達，加速胃癌組織癌變[23]。IL-26通過活化STAT3上調(diào)抗凋亡基因Bcl-2、 Bcl-xL和c-myc促進細胞增殖[24]。炎性環(huán)境下TNF-α誘導(dǎo)NF-κB活化，使p65亞基結(jié)合組織中叉頭樣轉(zhuǎn)錄因子3(forkhead box protein 3,FOXP3)，抑制FOXP3結(jié)合p21到啟動子區(qū)，抑制p21的表達，促進胃癌細胞的生長[25]。

1.2細胞因子參與調(diào)控細胞生長、轉(zhuǎn)移與胃癌細胞因子具有調(diào)節(jié)細胞的生長、轉(zhuǎn)移的功能，在胃癌發(fā)生、發(fā)展過程中細胞因子發(fā)揮了重要作用。Cten是細胞黏附分子，在正常組織中低表達；但腫瘤組織中?，F(xiàn)高表達并促進腫瘤的侵襲和轉(zhuǎn)移，生長因子能夠上調(diào)Cten的表達，介導(dǎo)腫瘤細胞的快速遷移[26]。IL-17調(diào)控腫瘤微環(huán)境，促進腫瘤血管生成，參與胃癌進程[27]。肝細胞生長因子能誘導(dǎo)活化促胃液素釋放肽，介導(dǎo)轉(zhuǎn)錄因子Ets-1的活化上調(diào)IL-8的表達，促進血管生成，腫瘤侵襲和轉(zhuǎn)移[28]；并具有活化腫瘤基質(zhì)纖維母細胞促進胃癌的生成作用[29]。TGF-β1通過上調(diào)結(jié)蹄組織生長因子的表達促進腫瘤細胞的上皮間質(zhì)轉(zhuǎn)化，促進腫瘤細胞黏附與腹膜間質(zhì)[30]。炎性因子前列腺素E2和IL-1處理SNU719細胞后，細胞表達的上皮鈣黏素減少，Snail表達增多，增強細胞的上皮間質(zhì)轉(zhuǎn)化，促進細胞遷徙[31]。纖維母細胞生長因子9能促進多種細胞的分裂增殖，在胃癌中纖維母細胞生長因子9高表達促進胃癌的生長和轉(zhuǎn)移[32]。

1.3細胞因子參與胃癌免疫逃逸與化療抵抗機體發(fā)揮抗腫瘤免疫應(yīng)答，主要通過DC細胞的抗原呈遞，激活機體的細胞免疫和體液免疫，形成對腫瘤的殺傷和清除腫瘤組織作用。但機體中存在復(fù)雜的免疫負調(diào)節(jié)，能形成免疫耐受，促進腫瘤的生長與轉(zhuǎn)移。細胞因子能參與調(diào)節(jié)機體的免疫應(yīng)答，在腫瘤免疫中形成正向或負向作用，腫瘤發(fā)生時常介導(dǎo)腫瘤的免疫逃逸。胃癌發(fā)生時，多種細胞因子誘導(dǎo)免疫耐受，促進胃癌的生長轉(zhuǎn)移。TGF-β1和 TGF-β2與胃癌的不良預(yù)后密切相關(guān)，在胃癌發(fā)生時，外周血淋巴細胞中TGF-β1和 TGF-β2表達升高，抑制外周血單核細胞的活性，促進早期腫瘤的轉(zhuǎn)移[33]。黏著斑蛋白誘導(dǎo)表達的炎性因子IL-10、 IL-17b等能調(diào)控腫瘤相關(guān)巨噬細胞促進腫瘤的轉(zhuǎn)移[34]。IL-32能促進IL-6、IL-8和血管內(nèi)皮生長因子分泌形成免疫耐受的微環(huán)境，促進細胞免疫逃逸[6]。Hp感染后，免疫抑制性細胞因子IL-10 和TGF-β1的表達顯著上調(diào)，而殺傷性免疫因子干擾素γ表達下調(diào)，調(diào)節(jié)性T細胞CD4+IL-10+細胞 和CD4+CD25+FoxP3+細胞增多；同時參與胃組織修復(fù)的骨間充質(zhì)干細胞進一步提高IL-10/干擾素γ、Treg/Th17比例，形成更強的免疫耐受；并活化Wnt和TGF-β信號，重新獲取和維持腫瘤干細胞生長的優(yōu)越微環(huán)境，加速胃癌發(fā)生進程[35-36]。此外，腫瘤細胞分泌細胞因子能增強胃癌的化療抵抗，如血管內(nèi)皮生長因子介導(dǎo)腫瘤的侵襲和轉(zhuǎn)移，增加胃癌細胞化療抵抗能力[37-38]；TGF-β1外分泌能激活受損的胃上皮細胞中的成纖維細胞啟動組織再生反應(yīng)，增加化療藥物的抵抗性[39]； IL-8過表達顯著促進胃癌細胞MKN-45的快速增殖、侵襲轉(zhuǎn)移和化療藥物耐藥性[40]等。

2細胞因子與胃癌的靶向治療

細胞因子調(diào)控的炎癥反應(yīng)，細胞的生長、侵襲轉(zhuǎn)移與胃癌的形成密切相關(guān)，干擾細胞因子調(diào)節(jié)腫瘤的生長，形成的免疫耐受對胃癌的治療具有重要作用。IL-6家族在炎性相關(guān)腫瘤胃癌中活化gp130/STAT3信號，介導(dǎo)腫瘤的發(fā)生；IL-11是IL-6 家族成員之一，在胃癌組織中，IL-11與STAT3活化有很強的相關(guān)性，且是IL-6家族與胃癌發(fā)生的最主要成員，在裸鼠移植實驗中，靶向抑制IL-11，能有效抑制STAT3的活化，抑制腫瘤細胞的增殖、侵襲和腫瘤的生長，提示抑制IL-11可能是胃癌治療的靶標[41]。細胞因子信號轉(zhuǎn)導(dǎo)抑制蛋白1(suppressor of cytokine signaling 1，SOCS1)是一個細胞因子活化的關(guān)鍵抑制分子，其通過DCs控制細胞因子反應(yīng)和抗原呈遞；使用SOCS1特異性地抑制性短肽pJAK2(1001-1013)能有效抑制JAK/STAT 信號活化，抑制SOCS1的生物學(xué)作用，上調(diào)DCs成熟標記分子CD83和共刺激分子CD86的表達，增強DCs誘導(dǎo)T細胞增殖、分泌前炎性因子的能力，增強腫瘤抗原特異性殺傷作用，提示靶向抑制SOCS1可能成為抗胃癌治療的有效靶點[42]。荊棘是傳統(tǒng)中藥，主要治療水腫、化膿、疼痛等表皮性疾病，研究顯示其乙醇提取物能抑制腫瘤細胞的增殖和轉(zhuǎn)移，主要表現(xiàn)在活化p38絲裂原激活的蛋白激酶上調(diào)p21蛋白的表達、抑制細胞周期蛋白的表達，抑制TNF-α 誘導(dǎo)的NF-κB 和激活劑蛋白1的活化，基質(zhì)金屬蛋白酶9的表達[43]；而另一組研究則顯示，穩(wěn)定表達TNF-α的臍帶血間充質(zhì)干細胞可以有效地抑制裸鼠移植瘤的生長，提示不同環(huán)境下調(diào)控TNF-α的表達可以發(fā)揮不同的抗腫瘤作用[44]。腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體分子能逆轉(zhuǎn)腫瘤耐藥基因多藥耐藥性 1、肺耐藥蛋白、谷胱甘肽S-轉(zhuǎn)移酶-π的表達，增加化療介導(dǎo)的細胞凋亡和生長抑制，提示其可能成為反轉(zhuǎn)胃癌化療抵抗的有效靶點[45]。胃動蛋白在胃黏膜防御，胃癌發(fā)生中發(fā)揮重要的抑制作用；胃動蛋白的高表達能顯著抑制NF-κB和環(huán)加氧酶2的表達，調(diào)節(jié)細胞因子的表達，抑制腫瘤細胞的增殖和侵襲能力，促進細胞的凋亡[46]。巨噬細胞具有兩種類型，分別為M1型和M2型，M1型巨噬細胞抑制腫瘤生長，而M2型則促進腫瘤生長；使用IL-12和干擾素γ處理前胃癌耐受小鼠M2巨噬細胞，促使小鼠巨噬細胞向M1轉(zhuǎn)化，回輸后能有效抑制前胃癌移植瘤的生長，提示細胞因子處理巨噬細胞M1型轉(zhuǎn)化是一種胃癌免疫治療的可能手段[47]。趨化因子配體18(CCL18)是樹突狀細胞趨化細胞因子，表達于多種淋巴細胞中，作用的靶細胞為CD4+、CD8+、CD45RA+和B淋巴細胞，其可作為胃癌預(yù)后的特異性標志物，CCL18的高表達預(yù)示著更好的預(yù)后，提示靶向上調(diào)CCL18的表達可以有效抑制胃癌的生長[48]。綜上所述，細胞因子能從調(diào)控腫瘤細胞生長、侵襲與轉(zhuǎn)移，機體的免疫系統(tǒng)殺傷等多角度抑制胃癌的生長，達到抗腫瘤治療的目的。因此有理由相信，靶向調(diào)控細胞因子的水平可成為抗腫瘤治療的新途徑。

3小結(jié)

細胞因子具有調(diào)節(jié)細胞生成、細胞生長以及損傷組織修復(fù)等多種功能。胃癌的發(fā)生、發(fā)展過程中，細胞因子調(diào)控細胞增殖轉(zhuǎn)移信號及腫瘤生長微環(huán)境(炎癥反應(yīng)和免疫抑制)為胃癌的發(fā)生、發(fā)展提供了良好的“沃土”。靶向細胞因子調(diào)節(jié)腫瘤的生長、侵襲與轉(zhuǎn)移，打破腫瘤的免疫耐受成為胃癌治療的新方向。但細胞因子與胃癌的關(guān)系還未闡明，多種細胞因子與胃癌的作用是雙向的，在胃癌發(fā)展不同時期分別發(fā)揮促進或抑制胃癌的作用；因此未來應(yīng)重點關(guān)注這種多向分子，系統(tǒng)闡明調(diào)控這些細胞因子表達的機制，不同環(huán)境中細胞因子的生物學(xué)作用及其基因多態(tài)性與胃癌發(fā)生、發(fā)展的作用，逐步闡明胃癌不同時期細胞因子的作用機制；從而應(yīng)用細胞因子進行胃癌的個體化靶向治療，為胃癌的治療提供新途徑。

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Progress in the Study of Cellular Factors Involved in the Occurrence and Development of Gastric CancerLIKang，DANZeng.(DepartmentFourofInternalMedicine,People′sHospitalofTibetAutonomousRegion,Lhasa850000,China)

Abstract：Cytokines are a kind of protein or small molecular peptides and play a role in passing information between the cells or regulating immune response.The abnormal expressions of cytokines often cause a variety of diseases,including stomach cancer.Cytokines are involved in the regulation of gastric cancer cells carcinogenesis,invasion and metastasis,angiogenesis and immune escape by regulating tumor related antigen presentation and lymphocytes activation.What′s more,cytokines also play an important role in gastric cancer cells resisting radiation and chemotherapy.Therefore,regulation of the body′s cytokines levels to form the antitumor effect of gastric cancer has become a new trend for the treatment of gastric cancer.

Key words：Gastric cancer; Cytokines; Immune escape

收稿日期:2015-01-28修回日期:2015-06-09編輯：薛惠文

基金項目：國家自然科學(xué)基金(81060165)

doi：10.3969/j.issn.1006-2084.2015.20.019

中圖分類號：R34

文獻標識碼：A

文章編號：1006-2084(2015)20-3697-04