崔海濤 張麗敏 趙琳 劉廣芝(鄭州大學(xué)人民醫(yī)院婦產(chǎn)科 河南鄭州 450003)

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卵巢癌患者血小板增多的相關(guān)研究進(jìn)展

崔海濤 張麗敏 趙琳 劉廣芝
(鄭州大學(xué)人民醫(yī)院婦產(chǎn)科 河南鄭州 450003)

【關(guān)鍵詞】卵巢癌;血小板增多;發(fā)生機(jī)制;生物學(xué)意義;治療

卵巢癌發(fā)病率在婦科惡性腫瘤中居第3位,因其缺少可靠的篩查手段,且疾病發(fā)生隱匿,早期癥狀不典型,初次診斷常為晚期,是死亡率最高的婦科腫瘤,5年生存率低于40%[1]?卵巢癌發(fā)生機(jī)制不詳,近期研究表明,血小板存在于癌細(xì)胞周?chē)h(huán)境中,對(duì)腫瘤生長(zhǎng)有促進(jìn)作用?國(guó)內(nèi)外報(bào)道,卵巢癌?宮頸癌?子宮內(nèi)膜癌均與血小板(PLT)增多有關(guān)[2]?本研究綜述卵巢癌患者中血小板增多的臨床意義?發(fā)生機(jī)制及生物學(xué)意義,總結(jié)已有觀(guān)點(diǎn),討論以PLT作為標(biāo)志物的證據(jù)和針對(duì)血小板增多的新型治療方案?

1 卵巢癌患者血小板增多的臨床意義

國(guó)內(nèi)外大多數(shù)文獻(xiàn)將血小板計(jì)數(shù)>400×109/L稱(chēng)為血小板增多,研究發(fā)現(xiàn)卵巢癌患者中血小板增多的發(fā)生率約為30% (22.3%～38%)[3]?Man等[4]對(duì)190例上皮性卵巢癌患者進(jìn)行研究,其中86例合并血小板增多(45.26%),卵巢癌分期?能否行根治術(shù)與術(shù)前血小板計(jì)數(shù)相關(guān),差異有統(tǒng)計(jì)學(xué)意義(P＜0.001),對(duì)卵巢癌預(yù)后進(jìn)行單因素生存分析,與術(shù)前血小板計(jì)數(shù)正常組相比,術(shù)前血小板增多組3 a無(wú)進(jìn)展生存期(progres-sion free survival,PFS)和總生存期(overal survival,OS)明顯縮短,差異有統(tǒng)計(jì)學(xué)意義(P＜0.001),多因素生存分析顯示術(shù)前血小板增多與不良FPS和OS相關(guān),差異有統(tǒng)計(jì)學(xué)意義(P＜0.001)?Li等[5]對(duì)183名侵襲性上皮性卵巢癌和腹膜癌患者進(jìn)行研究,發(fā)現(xiàn)血小板增多者更易發(fā)生淋巴結(jié)轉(zhuǎn)移,且不易實(shí)行理想的減瘤術(shù)?血小板增多與上皮性卵巢癌復(fù)發(fā)有關(guān),可作為上皮性卵巢癌患者復(fù)發(fā)及死亡的獨(dú)立危險(xiǎn)因素[3]?Botsford-Miler[6]對(duì)復(fù)發(fā)性卵巢癌患者進(jìn)行研究,發(fā)現(xiàn)平均血小板計(jì)數(shù)為409×109/L(134×109/L～1 122×109/L),32%的患者平均血小板計(jì)數(shù)大于450×109/L,復(fù)發(fā)時(shí)血小板計(jì)數(shù)較初次診斷時(shí)升高49%,提示血小板可能是監(jiān)測(cè)疾病復(fù)發(fā)的標(biāo)志物,血小板增多影響二次腫瘤細(xì)胞減滅術(shù)對(duì)病灶的切除效果?血小板相關(guān)參數(shù)與卵巢癌病情與預(yù)后相關(guān)?平均血小板體積(mean platelet volume,MPV)是評(píng)估血小板功能和活化程度的指標(biāo),可反映血小板產(chǎn)生速率[7]?研究表明卵巢癌患者術(shù)前MPV與對(duì)照組相比明顯升高(8.26 fl比7.71 fl,P=0.004),術(shù)后MPV明顯降低(8.26 fl比7.61 fl,P=0.001),認(rèn)為MPV與卵巢癌腫瘤負(fù)荷相關(guān)[8]?卵巢癌患者血小板最大聚集率(maximal aggrega-tion rate,MAR)高于對(duì)照組(71.96%比57.03%,P=0.025),MAR與血小板增多間具有關(guān)聯(lián)性(r=0.694,P＜0.001),卵巢癌患者中同時(shí)具有血小板增多和較高M(jìn)AR的人群有更短的PFS(P=0.000 1)和OS(P=0.000 4)[9]?

2 血小板增多發(fā)生機(jī)制

Bambace等[10]研究發(fā)現(xiàn),約40%的血小板增多癥與癌癥發(fā)生相關(guān),其中常見(jiàn)的是消化道腫瘤?肺癌和卵巢癌?但是,至今我們并不清楚惡性腫瘤患者血小板增多發(fā)生的確切機(jī)制?Stone等[11]進(jìn)行了一項(xiàng)多中心研究,包括619名上皮性卵巢癌患者,發(fā)現(xiàn)血小板增多與血漿促血小板生成素(thrombopoietin,TPO)和白細(xì)胞介素-6(interleukin 6,IL-6)水平升高相關(guān)?動(dòng)物實(shí)驗(yàn)表明,腫瘤組織分泌IL-6作用于肝細(xì)胞,促進(jìn)肝細(xì)胞合成TPO,TPO作用于骨髓,使血小板過(guò)度生成,最終導(dǎo)致血小板增多,血小板促進(jìn)腫瘤增殖和侵襲,進(jìn)而產(chǎn)生更多的IL-6,如此形成惡性循環(huán)?卵巢癌細(xì)胞可黏附血小板并激活血小板增殖,研究表明IL-6增強(qiáng)腫瘤細(xì)胞生存能力和腫瘤組織血管新生,血漿IL-6水平升高與卵巢癌的不良預(yù)后相關(guān)[11]?研究表明卵巢癌患者術(shù)前TPO值顯著高于卵巢良性腫瘤(中位TPO 98 pg/ml比27 pg/ml,P=0.004),Ⅲ～Ⅳ期卵巢癌患者術(shù)前TPO值高于Ⅰ～Ⅱ期(中位TPO 127 pg/ml比58 pg/ml,P=0.017),手術(shù)治療或化療后TPO水平顯著下降(P=0.002),但是,治療效果優(yōu)劣與TPO值無(wú)明顯關(guān)系(P=0.907)[12]?

3 血小板增多的生物學(xué)意義

惡性腫瘤發(fā)生部位腫瘤細(xì)胞與血小板之間相互作用,一方面可導(dǎo)致血栓形成,另一方面也可促進(jìn)腫瘤細(xì)胞增殖?侵襲和血管形成[13]?受腫瘤細(xì)胞影響,活化的血小板和釋放的血小板微粒促進(jìn)癌癥侵襲,隨著血小板的活化,血小板微粒釋放進(jìn)入癌旁,促進(jìn)腫瘤細(xì)胞增殖和血管新生,增強(qiáng)腫瘤侵襲能力,并能抑制機(jī)體對(duì)腫瘤發(fā)生免疫反應(yīng)[14]?研究表明,卵巢癌細(xì)胞增殖可由轉(zhuǎn)化生長(zhǎng)因子β1(transforming growth factorβ1,TGF-β1)介導(dǎo)完成,癌細(xì)胞分泌IL-6,通過(guò)肝臟產(chǎn)生TPO刺激骨髓巨核細(xì)胞和血小板產(chǎn)生TGF-β1,促進(jìn)癌細(xì)胞增殖和轉(zhuǎn)移,癌細(xì)胞與血小板直接接觸激活NF-κB通路,協(xié)同TGF-β1/Smad通路導(dǎo)致癌細(xì)胞由表皮到間質(zhì)的轉(zhuǎn)化?外滲?侵襲和轉(zhuǎn)移[15]?

血管新生在卵巢癌生長(zhǎng)和轉(zhuǎn)移過(guò)程中起重要作用?血小板攜帶多種影響血管形成的介質(zhì),包括促血管形成與抑制血管形成兩種,兩者之間的平衡最終影響血管形成,這種平衡由腫瘤微環(huán)境決定?促進(jìn)血管形成和抑制血管形成介質(zhì)被包裹在血小板α顆粒中,選擇性識(shí)別血小板受體影響癌細(xì)胞-血小板栓子形成,此過(guò)程可釋放血管形成相關(guān)介質(zhì)[16]?促進(jìn)血管形成的介質(zhì)包括血管內(nèi)皮生長(zhǎng)因子(vascular endothelial growth factor,VEGF)?血小板衍化生長(zhǎng)因子(platelet-derived growth factor,PDGF)?胰島素樣生長(zhǎng)因子(insulin-like growth factor-1,IGF-1)等?VEGF通過(guò)刺激內(nèi)皮細(xì)胞遷移和增殖促進(jìn)腫瘤血管形成,VEGF介導(dǎo)腫瘤細(xì)胞之間信號(hào)傳導(dǎo)和腫瘤發(fā)生,包括腫瘤干細(xì)胞在腫瘤發(fā)生和增殖中的作用,VEGF可能是抑制腫瘤血管生成和轉(zhuǎn)移的良好作用靶點(diǎn)[17]?PDGF接受來(lái)自酪氨酸激酶受體活化的信號(hào)促進(jìn)腫瘤增殖和分化,PDGFα通過(guò)抑制細(xì)胞凋亡信號(hào)傳導(dǎo)而在促進(jìn)腫瘤生長(zhǎng)?提高生存率中起重要作用,這也與上皮性卵巢癌PDGFRα表達(dá)陽(yáng)性率高達(dá)56%～97%相符[18]?動(dòng)物實(shí)驗(yàn)表明,應(yīng)用中和抗體封閉PDGFRα可增強(qiáng)紫衫烷類(lèi)抗卵巢癌細(xì)胞活性[19]?IGF-1與其受體結(jié)合傳遞信號(hào)至細(xì)胞核和線(xiàn)粒體促進(jìn)腫瘤血管生成,具體機(jī)制目前不清[20]?血小板促進(jìn)腫瘤血管形成的原因和機(jī)制是目前研究熱點(diǎn),有望為卵巢癌新型治療提供依據(jù)?

血小板與腫瘤轉(zhuǎn)移和侵襲密切相關(guān),腫瘤細(xì)胞可作為獨(dú)立單元轉(zhuǎn)移到遠(yuǎn)處,也可以與血小板結(jié)合形成聚合體(platelettumor cel aggregates,PTAs)發(fā)生轉(zhuǎn)移?血小板包繞腫瘤細(xì)胞形成PTAs可被機(jī)體視為正常機(jī)體成分而被接受,同時(shí),腫瘤細(xì)胞表面表達(dá)血小板表面標(biāo)志物,最終逃避T細(xì)胞殺傷作用[21]?血小板活化釋放大量的三磷酸腺苷(ATP),破壞血管內(nèi)皮,使腫瘤細(xì)胞穿透血管轉(zhuǎn)移成為可能[22]?血小板直接孵育卵巢癌A2780?HeyA8和SKOC3-ipl細(xì)胞系,發(fā)現(xiàn)細(xì)胞凋亡分別降低46.7%(P=0.002),64.4%(P＜0.001)和47.3%(P=0.004),多西他賽聯(lián)合血小板直接孵育A2780,HeyA8和SKOC3-ipl細(xì)胞系,發(fā)現(xiàn)細(xì)胞凋亡分別降低20.4%(P=0.004),74.0%(P＜0.001)和15.1%(P=0.007),以上表明血小板具有抗卵巢癌細(xì)胞凋亡作用[6]?

4 抗血小板治療作為卵巢癌治療策略

卵巢癌一線(xiàn)治療方案是外科手術(shù)聯(lián)合化療,鉑類(lèi)聯(lián)合紫杉醇是目前常用的化療方案,卵巢癌有很高的復(fù)發(fā)率且復(fù)發(fā)性卵巢癌患者常表現(xiàn)為多重化療耐藥,因此我們需要更有效的卵巢癌治療方案?Stone等[11]研究表明對(duì)卵巢癌小鼠模型應(yīng)用抗IL-6抗體(Siltuximab)可阻止血小板增多癥的發(fā)生,與單純應(yīng)用紫杉醇組比較,聯(lián)合應(yīng)用Siltuximab和紫杉醇能更有效抑制腫瘤細(xì)胞生長(zhǎng)?同時(shí),每2周對(duì)卵巢癌患者應(yīng)用1次Siltuximab治療,3周后血小板計(jì)數(shù)降至正常,通過(guò)影像學(xué)檢查,8名卵巢癌患者中有4名疾病穩(wěn)定期超過(guò)6個(gè)月,其中1名患者CA-125水平降至正常時(shí)間超過(guò)12周,可知,IL-6抗體(Siltuximab)可有效阻止血小板增多癥的發(fā)生,抑制腫瘤生長(zhǎng),提升治療效果?

動(dòng)物實(shí)驗(yàn)研究表明LMWH可抑制腫瘤血管新生,抑制腫瘤生長(zhǎng),減少腫瘤肺轉(zhuǎn)移[23]?一項(xiàng)Ⅱ期臨床試驗(yàn)顯示,達(dá)肝素鈉(dalteparin)可安全應(yīng)用于上皮性卵巢癌化療患者,對(duì)上皮性卵巢癌化療患者應(yīng)用3個(gè)月達(dá)肝素鈉是安全的,未發(fā)現(xiàn)嚴(yán)重的不良反應(yīng),雖然它們之間沒(méi)有明顯的劑量-效應(yīng)關(guān)系,100 IU/kg達(dá)肝素鈉組有最好的治療反應(yīng)率,CA125下降50%以上者占92%,因缺少對(duì)照組,低分子肝素抗腫瘤和預(yù)后方面的作用并不能得到證實(shí)[24]?

VEGF和PDGF在腫瘤血管形成中起重要作用,抗VEGF抗體和VEGF受體抑制劑已經(jīng)在臨床中得到應(yīng)用?貝伐單抗是一種抗VEGF抗體,通過(guò)與VEGF競(jìng)爭(zhēng)性結(jié)合相應(yīng)受體,進(jìn)而阻斷VEGF信號(hào)傳導(dǎo),抑制腫瘤新生血管形成,可有效應(yīng)用于卵巢癌初始治療和復(fù)發(fā)性卵巢癌的治療[25]?貝伐單抗聯(lián)合以鉑類(lèi)為基礎(chǔ)化療方案可有效提高晚期卵巢癌總反應(yīng)率[26],多項(xiàng)Ⅱ期臨床研究顯示,貝伐單抗聯(lián)合多西他賽?奧沙利鉑治療晚期卵巢癌可有效延長(zhǎng)患者PFS和OS,其中,中位PFS 16.3個(gè)月,中位OS 47.3個(gè)月[27]?術(shù)前對(duì)卵巢癌患者行貝伐單抗聯(lián)合卡鉑化療可有效降低術(shù)后腫瘤殘留[28]?貝伐單抗治療卵巢癌使血漿VEGF水平降低,血漿VEGF水平變化反映不同卵巢癌治療手段的效果[29]?伊馬替尼(imatinib)是一種選擇性PDGF受體抑制劑,抑制卵巢癌細(xì)胞表達(dá)PDGF受體,阻斷細(xì)胞有絲分裂的G0～G1期[30],可增強(qiáng)紫杉醇抗腫瘤活性,有效延長(zhǎng)患者PFS,研究期間并未見(jiàn)到明顯不良反應(yīng)[31]?

5 結(jié)語(yǔ)

血小板在卵巢癌發(fā)生發(fā)展過(guò)程中起重要作用?腫瘤細(xì)胞分泌IL-6促進(jìn)肝細(xì)胞合成TPO,TPO作用于骨髓,導(dǎo)致血小板增多,血小板增多又可以促進(jìn)腫瘤發(fā)生發(fā)展,此惡性循環(huán)可能是血小板增多的發(fā)生機(jī)制[11]?血小板增多參與卵巢癌發(fā)生和新生血管形成,促進(jìn)卵巢癌進(jìn)展和轉(zhuǎn)移,與卵巢癌病情和預(yù)后密切相關(guān),因此,血小板可能是一種有重要意義的腫瘤標(biāo)志物,抗血小板治療作為輔助治療策略可明顯提高卵巢癌治療效果,可能是一種有效的治療手段?

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(收稿日期:2015-07-14)

【中圖分類(lèi)號(hào)】R 737.31

doi:10.3969/j.issn.1004-437X.2016.01.039

通訊作者:劉廣芝,E-mail:guangzhi72@126.com?