荔 童(綜述)，張示杰(審校)

1 泡球蚴病具有與腫瘤類(lèi)似的生物學(xué)行為

泡球蚴病又稱(chēng)泡型包蟲(chóng)病(alveolar echinococcosis，AE)，是由多房棘球絳蟲(chóng)(Echinococcusmultilocularis，E.m)的幼蟲(chóng)寄生于人體引起的人獸共患寄生蟲(chóng)病，在我國(guó)的新疆、甘肅、四川、寧夏、青海、西藏等地區(qū)均有流行,嚴(yán)重危害牧民生命健康安全。研究證實(shí)泡球蚴病的自然發(fā)展過(guò)程還是不明確的[1]，如何預(yù)防和早發(fā)現(xiàn)、早治療泡球蚴病正在被世界上一些泡球蚴疾病流行的城市所日漸關(guān)注[2]。目前該病已被列入國(guó)家免費(fèi)救治項(xiàng)目。

泡球蚴病發(fā)病率約為0.3%～4.8%，在某些牧區(qū)高達(dá)10%[3-6]。通常初次感染10年或10年以上才出現(xiàn)明顯的臨床癥狀[7],外科手術(shù)仍是其首選方法，根治性肝切除是國(guó)內(nèi)外學(xué)者公認(rèn)有效的治療方法。但因該病起病隱匿，大多數(shù)患者就診時(shí)己有較廣泛的肝浸潤(rùn)和轉(zhuǎn)移，失去最佳治療時(shí)機(jī)，故該病手術(shù)根治率低，約為20%～26%[8-9]。長(zhǎng)期使用藥物阿苯達(dá)唑控制絳蟲(chóng)生長(zhǎng)是晚期泡球蚴病患者的關(guān)鍵手段。隨著新的藥物劑型不斷的研制和應(yīng)用，藥物治療效果有所提高，但仍不理想[10-13]，對(duì)于抑制泡球蚴病的侵襲性生長(zhǎng)方面的藥物研究較少。

泡球蚴病幾乎均原發(fā)于肝臟，呈癌樣浸潤(rùn)生長(zhǎng)，并可經(jīng)血液向肺、腦等遠(yuǎn)處轉(zhuǎn)移，其危害性較大，不經(jīng)治療者10年死亡率達(dá)93%以上[14]。泡狀棘球蚴進(jìn)入宿主肝內(nèi)發(fā)育成泡囊，其周?chē)l(fā)生肉芽腫反應(yīng)，可見(jiàn)纖維結(jié)締組織增生以及嗜酸性粒細(xì)胞、淋巴細(xì)胞、漿細(xì)胞和多核巨細(xì)胞浸潤(rùn)，形成泡球蚴結(jié)節(jié)。泡囊呈外向性生長(zhǎng)，先是向外伸出偽足，后呈串珠狀或原生質(zhì)樣條索向周?chē)M織浸潤(rùn)性生長(zhǎng)，隨著時(shí)間的推移，中央逐漸形成微囊，病變與正常組織之間沒(méi)有纖維包膜，往往出現(xiàn)由纖維細(xì)胞、成纖維細(xì)胞、上皮樣細(xì)胞以及淋巴細(xì)胞、漿細(xì)胞、嗜酸細(xì)胞組成的細(xì)胞反應(yīng)帶，其浸潤(rùn)導(dǎo)致周?chē)?xì)血管增生。隨著原頭蚴的繁殖，病灶擴(kuò)大，肝臟會(huì)遭到嚴(yán)重破壞，病灶中心可出現(xiàn)大片干酪樣壞死，并出現(xiàn)特征性的鈣鹽沉積[15-16]；同時(shí)可發(fā)生似惡性腫瘤樣轉(zhuǎn)移，故有“惡性包蟲(chóng)病”或“蟲(chóng)癌”之稱(chēng)。目前，有關(guān)泡狀棘球蚴在宿主體內(nèi)浸潤(rùn)性生長(zhǎng)和轉(zhuǎn)移的機(jī)制的研究較少，有待進(jìn)一步研究。

2 血管新生與泡球蚴侵襲性生長(zhǎng)及轉(zhuǎn)移關(guān)系密切

血管新生(Angiogenesis)在正常組織中是被高度管制的行為，但是已經(jīng)證明異常情況下的血管新生是惡性腫瘤的關(guān)鍵標(biāo)志之一[17]。血管新生中關(guān)鍵的介質(zhì)之一是血管內(nèi)皮生長(zhǎng)因子(vascular endothelial growth factor，VEGF)。

VEGF又稱(chēng)血管通透因子( vascular permeability factor , VPF)或血管調(diào)理素( vasculotropin) ,由 Ferrara等于1989年率先從牛垂體濾泡星狀細(xì)胞的體外培養(yǎng)液中純化得到( Biochem Biophys Res Commun, 1989年),其是內(nèi)皮細(xì)胞的特異性有絲分裂原,同時(shí)也是一種有效的促血管形成和增加血管通透性的誘導(dǎo)因子[18]。

VEGF的功能促進(jìn)惡性腫瘤侵襲性生長(zhǎng)：(1)VEGF促進(jìn)腫瘤血管生長(zhǎng),VEGF與血管內(nèi)皮細(xì)胞上酪氨酸激酶受體(VEGFR)的細(xì)胞外結(jié)合域結(jié)合后,使每?jī)蓚€(gè)單體受體分子在膜上形成二聚體,并致受體細(xì)胞內(nèi)結(jié)合域尾部酪氨酸殘基發(fā)生磷酸化,進(jìn)而激活不同信號(hào)傳導(dǎo),刺激腫瘤血管生長(zhǎng)[19-20]。另外,VEGF可通過(guò)誘導(dǎo)纖溶酶原激活物(uPA)、纖溶酶原激活物受(uPAR)及抑制因子(TIMPs)的合成與釋放,促進(jìn)血管細(xì)胞外基質(zhì)的降解[21-22],或通過(guò)低氧誘導(dǎo)因子的作用誘導(dǎo)一氧化氮(NO)產(chǎn)生,進(jìn)一步激活VEGF表達(dá),促進(jìn)腫瘤血管擴(kuò)張和血流增加[23]。(2)VEGF阻礙腫瘤細(xì)胞被免疫系統(tǒng)識(shí)別和破壞,VEGF抑制造血祖細(xì)胞(HPCS)核轉(zhuǎn)錄因子KappaB，阻止其多向分化，影響免疫細(xì)胞生成,Price[24]等在對(duì)乳腺癌的研究中發(fā)現(xiàn)，VEGF誘導(dǎo)細(xì)胞外調(diào)節(jié)激酶-1,2和磷脂酰激酶-3活動(dòng)，刺激乳腺癌細(xì)胞-T47D導(dǎo)致細(xì)胞信號(hào)改變。(3)Beate M. Lichtenberger[25]等研究顯示：除了促進(jìn)血管新生之外，VEGF還被認(rèn)為是一個(gè)上皮細(xì)胞腫瘤的促進(jìn)因子。

大量證據(jù)顯示VEGF與肝臟腫瘤的侵襲生長(zhǎng)和發(fā)展有關(guān)：(1)研究證實(shí)[2-29]相較于非惡性變肝腫瘤中，肝細(xì)胞癌的VEGF表達(dá)水平要高的多，而且在肝細(xì)胞癌中VEGF高表達(dá)水平往往和不良預(yù)后相關(guān)。(2)肝細(xì)胞腫瘤患者血清中VEGF含量高與腫瘤負(fù)擔(dān)(Tumor Burden)和臨床腫瘤侵襲現(xiàn)象有關(guān)[30-32]。(3)研究顯示VEGF表達(dá)水平在肝細(xì)胞癌切除術(shù)后及肝動(dòng)脈栓塞化療后早期復(fù)發(fā)階段升高[33-34]。

CD34是高度糖基化的Ⅰ型跨膜蛋白,屬于表面分子涎酸粘蛋白家族成員之一，臨床研究發(fā)現(xiàn)CD34除有造血作用外，在腫瘤新生血管形成過(guò)程中也起著重要的作用[35-36]。 CD34具有促進(jìn)血管內(nèi)皮細(xì)胞轉(zhuǎn)移的作用：在血管新生初期靜止的內(nèi)皮細(xì)胞是如何轉(zhuǎn)化為樹(shù)突狀細(xì)胞被視為是血管新生初期最重要的機(jī)制之一。Martin J[37]等研究顯示：全基因組mRNA分析(Genome-wide mRNA profiling analysis )顯示CD34陽(yáng)性的血管內(nèi)皮細(xì)胞被證實(shí)主要具有強(qiáng)大的血管新生和遷移的生物功能，與之相反的是CD34陰性的血管內(nèi)皮細(xì)胞卻主要具有增值能力，缺乏血管新生和遷移的生物功能，說(shuō)明CD34在血管新生過(guò)程中有促進(jìn)作用。

3 血管新生可能是泡球蚴病浸潤(rùn)、轉(zhuǎn)移等生物學(xué)行為的重要環(huán)節(jié)之一

肝癌在發(fā)生發(fā)展中血管生成與其生物學(xué)行為關(guān)系密切,其中CD34被認(rèn)為是所有血管內(nèi)皮標(biāo)記物中最能特異性標(biāo)記肝癌中新生血管的指標(biāo)。目前認(rèn)為,VEGF是最強(qiáng)的促血管生成因子之一。肝臟泡球蚴的侵襲性生長(zhǎng)方式與肝癌極其相似。因此初步探討血管生成在泡球蚴侵襲性中的作用及抗血管生成藥物對(duì)泡球蚴生長(zhǎng)的影響是為臨床上泡球蚴病晚期患者的保守治療、手術(shù)后預(yù)防復(fù)發(fā)以及手術(shù)、藥物的輔助治療提供一個(gè)新途徑，也是治療的新靶點(diǎn)。

4 展 望

綜上所述，包蟲(chóng)病與血管生成關(guān)系密切，在我們前期研究中發(fā)現(xiàn)，肉眼觀察泡球蚴組織在生長(zhǎng)時(shí)組織內(nèi)外部均有血管生成，CD34免疫組化實(shí)驗(yàn)顯示：在沙鼠泡球蚴病模型中血管內(nèi)皮細(xì)胞胞漿內(nèi)有大量黃褐色沉淀。初步說(shuō)明了泡球蚴組織中確實(shí)存在血管新生的跡象。我們認(rèn)為：對(duì)肝包蟲(chóng)病血管形成的更深入的研究可能有助于深入了解包蟲(chóng)病病發(fā)展過(guò)程的作用，同時(shí)也揭示在肝包蟲(chóng)病的治療中，如何應(yīng)用抗血管生成藥物從而達(dá)到治療肝包蟲(chóng)的目的。

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