王祥宇　鄭　燕,3　魯　明 (綜述)　欽倫秀,3△ (審校)

(1復(fù)旦大學(xué)附屬華山醫(yī)院普外科　上海　200040; 2復(fù)旦大學(xué)腫瘤轉(zhuǎn)移研究所　上?！?00040;3復(fù)旦大學(xué)生物醫(yī)學(xué)研究院　上?！?00032)

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腫瘤代謝與腫瘤轉(zhuǎn)移

王祥宇1,2鄭燕1,2,3魯明1,2(綜述)欽倫秀1,2,3△(審校)

(1復(fù)旦大學(xué)附屬華山醫(yī)院普外科上海200040;2復(fù)旦大學(xué)腫瘤轉(zhuǎn)移研究所上海200040;3復(fù)旦大學(xué)生物醫(yī)學(xué)研究院上海200032)

【摘要】在腫瘤的發(fā)生、發(fā)展過程中,腫瘤細(xì)胞的代謝會改變?yōu)樘囟ǖ淖V式以適應(yīng)腫瘤的快速生長。近年來的研究表明,腫瘤的代謝與腫瘤的轉(zhuǎn)移也存在密切聯(lián)系。本文主要從腫瘤細(xì)胞代謝及腫瘤微環(huán)境中的代謝兩方面綜述腫瘤代謝在腫瘤轉(zhuǎn)移中的作用及機(jī)制的研究進(jìn)展。

【關(guān)鍵詞】糖類;氨基酸;膽固醇;脂肪酸;腫瘤微環(huán)境;腫瘤轉(zhuǎn)移

*This work was supported by the National Natural Science Foundation of China,Program of International Cooperation and Exchanges (81120108016).

近年來,腫瘤代謝領(lǐng)域的研究受到了越來越多的關(guān)注。異常的代謝變化是惡性腫瘤的重要特征,在腫瘤的發(fā)生、發(fā)展過程中發(fā)揮非常重要的作用,腫瘤代謝的研究可為腫瘤的診療提供新的指標(biāo)和干預(yù)靶點。轉(zhuǎn)移是惡性腫瘤另一重要的生物學(xué)表型,是影響惡性腫瘤預(yù)后的首要因素[1]?，F(xiàn)在認(rèn)為,腫瘤轉(zhuǎn)移是一個多因素參與、多階段發(fā)展的動態(tài)過程,涉及腫瘤細(xì)胞本身、腫瘤與微環(huán)境之間相互作用等多方面因素[2]。

有關(guān)腫瘤的代謝已有許多相關(guān)綜述,其中大部份側(cè)重于描述腫瘤的代謝異常及其與腫瘤發(fā)生的密切聯(lián)系[3-5],而對于代謝酶及代謝途徑在腫瘤轉(zhuǎn)移的作用及其機(jī)制的綜述還很少。近年來已有許多研究報道顯示,腫瘤本身以及微環(huán)境的代謝異常與腫瘤轉(zhuǎn)移存在密切的聯(lián)系。基于目前的研究現(xiàn)狀,本文將主要從腫瘤細(xì)胞的關(guān)鍵物質(zhì)代謝及微環(huán)境的異常代謝等方面對腫瘤代謝在腫瘤轉(zhuǎn)移中的作用及其機(jī)制的研究進(jìn)展作一綜述。

糖代謝與腫瘤轉(zhuǎn)移葡萄糖是生物體進(jìn)行糖類代謝的主要原料。與正常組織相比,即使在有氧條件下,腫瘤組織仍然主要以糖酵解方式進(jìn)行葡萄糖代謝,產(chǎn)生大量乳酸,德國生化學(xué)家Otto Warburg發(fā)現(xiàn)的這種現(xiàn)象即“Warburg效應(yīng)”,也稱有氧糖酵解[6-7]。該研究還發(fā)現(xiàn),高度惡性或者轉(zhuǎn)移性的腫瘤細(xì)胞比低度惡性的腫瘤細(xì)胞的糖酵解能力更強(qiáng),提示了腫瘤異常代謝與其侵襲轉(zhuǎn)移特性可能存在潛在的聯(lián)系[7]。近年來,人們利用同位素示蹤技術(shù)證實了“Warburg效應(yīng)”在腫瘤中普遍存在[8-9],并逐漸揭示了其調(diào)控機(jī)制。腫瘤特殊的微環(huán)境刺激以及癌基因和抑癌基因異常調(diào)控,是“Warburg效應(yīng)”產(chǎn)生的根本原因[5,10-11]。近年來的研究顯示,異常的葡萄糖代謝在腫瘤轉(zhuǎn)移過程中也發(fā)揮了重要作用。

葡萄糖攝取與腫瘤轉(zhuǎn)移在正常細(xì)胞中,葡萄糖是進(jìn)行能量代謝最主要的原料,而腫瘤細(xì)胞攝取大量的葡萄糖進(jìn)行糖酵解,其中間代謝產(chǎn)物可以通過磷酸戊糖、氨基酸及脂質(zhì)合成等途徑,進(jìn)行旺盛的生物合成代謝,為腫瘤快速生長提供蛋白質(zhì)、脂肪及核酸[8]。臨床上以此為原理發(fā)明的PET-CT,可以利用葡萄糖類似物18-氟脫氧葡萄糖 (2-18F-fluoro-2-deoxy-D-glucose,18FFDG)等為標(biāo)志物,通過檢測轉(zhuǎn)移灶攝取的FDG來診斷腫瘤的遠(yuǎn)處轉(zhuǎn)移和治療效果[12-14]。近年來研究發(fā)現(xiàn),在微環(huán)境刺激以及癌基因和抑癌基因異常調(diào)控下,腫瘤細(xì)胞通過異常表達(dá)一型葡萄糖轉(zhuǎn)運蛋白 (glucose transporter 1,GLUT1)和二型己糖激酶 (hexokinase 2,HK2)大量攝取葡萄糖[15-20]。而且GLUT1和HK2的異常表達(dá)與多種腫瘤的轉(zhuǎn)移呈正相關(guān)[21-22],而通過干擾GLUT1和HK2的表達(dá)或抑制其活性,可顯著降低葡萄糖的攝取而減弱糖酵解作用,進(jìn)而抑制腫瘤的生長及侵襲轉(zhuǎn)移能力[23-26]。

丙酮酸代謝與腫瘤轉(zhuǎn)移在糖酵解過程中,中間產(chǎn)物磷酸烯醇式丙酮酸 (phosphoenolpyruvate,PEP)在丙酮酸激酶催化下產(chǎn)生丙酮酸 (pyruvate)是非常關(guān)鍵的環(huán)節(jié)。Christofk等[27]發(fā)現(xiàn),正常組織中主要表達(dá)M1型丙酮酸激酶 (pyruvate kinase,muscle 1,PKM1),而腫瘤組織異常表達(dá)M2型丙酮酸激酶 (pyruvate kinase,muscle 2,PKM2)。后續(xù)研究發(fā)現(xiàn),c-Myc基因所介導(dǎo)的選擇性剪切是腫瘤特異性表達(dá)PKM2的主要原因[28]。PKM2在腫瘤中主要以二聚體形式存在,一方面,可促進(jìn)糖酵解中間產(chǎn)物進(jìn)行生物合成代謝,另一方面,二聚體形式的PKM2以磷酸激酶活性的形式參與信號轉(zhuǎn)導(dǎo)[29-30],通過轉(zhuǎn)運進(jìn)入細(xì)胞核與β-catenin、缺氧誘導(dǎo)因子 (hypoxia-inducible factor,HIF)等轉(zhuǎn)錄因子共同參與基因的轉(zhuǎn)錄調(diào)控[31-32]。PKM2的異常表達(dá)與多種腫瘤的轉(zhuǎn)移呈正相關(guān)[33-35],而干擾PKM2的表達(dá),可顯著抑制腫瘤的生長及侵襲轉(zhuǎn)移能力[36]。

乳酸代謝與腫瘤轉(zhuǎn)移丙酮酸激酶催化產(chǎn)生的丙酮酸主要通過A型乳酸脫氫酶 (lactate dehydrogenase A,LDH-A)催化生成終產(chǎn)物乳酸 (lactate),乳酸脫氫酶的表達(dá)與肝癌、結(jié)直腸癌、前列腺癌、多發(fā)性骨髓瘤、腎癌和胰腺癌的侵襲轉(zhuǎn)移密切相關(guān)[37-40]。研究表明,LDH-A在腫瘤中的異常激活與癌基因c-Myc以及LDH-A的異常乙酰化修飾密切相關(guān)[41-42],而下調(diào)LDH-A的表達(dá)可以顯著逆轉(zhuǎn)腫瘤的“Warburg效應(yīng)”,并且抑制腫瘤的侵襲轉(zhuǎn)移能力[43-45]。乳酸作為LDH-A的催化產(chǎn)物,可能介導(dǎo)了腫瘤侵襲轉(zhuǎn)移的調(diào)控。臨床研究發(fā)現(xiàn),腫瘤組織中的乳酸含量也與其轉(zhuǎn)移正相關(guān)[46-47],實驗研究也證實了乳酸可以促進(jìn)乳腺癌的侵襲轉(zhuǎn)移潛能[48]。一方面,乳酸可能參與了腫瘤干細(xì)胞特性的維持[49],另一方面,最新研究顯示乳酸可能參與腫瘤細(xì)胞與微環(huán)境的相互作用,腫瘤細(xì)胞分泌的乳酸可促進(jìn)微環(huán)境中的巨噬細(xì)胞向M2型轉(zhuǎn)化,進(jìn)而促進(jìn)腫瘤的侵襲轉(zhuǎn)移[50];而微環(huán)境中的乳酸也可以通過激活HIF,引起某些類型腫瘤的發(fā)生與轉(zhuǎn)移[51]。

氨基酸代謝與腫瘤轉(zhuǎn)移除糖類外,氨基酸類營養(yǎng)物質(zhì)也是細(xì)胞進(jìn)行合成代謝的重要原料。近年來研究發(fā)現(xiàn),谷氨酰胺、絲氨酸及天冬氨酸等氨基酸的異常代謝對腫瘤的生長及侵襲轉(zhuǎn)移有重要的意義[52-53]。下面主要探討谷氨酰胺的分解代謝在腫瘤轉(zhuǎn)移中的作用機(jī)制。

Roberts等[54-55]很早就發(fā)現(xiàn)部分腫瘤中存在異常活躍的谷氨酰胺代謝,這些腫瘤細(xì)胞不一定依賴葡萄糖的攝取,卻表現(xiàn)出谷氨酰胺依賴性生長,這種現(xiàn)象稱為“谷氨酰胺成癮”[56-57]。谷氨酰胺主要在線粒體內(nèi)生成α-酮戊二酸 (α-ketoglutarate,α-KG),通過三羧酸循環(huán)途徑為氧化磷酸化以及脂質(zhì)合成提供原料。研究表明,在癌基因c-Myc的調(diào)控下[58],谷氨酰胺代謝的關(guān)鍵酶谷氨酰胺酶 (glutaminase,GLS)和一型谷氨酸脫氫酶 (glutamate dehydrogenase 1,GDH1)在多種腫瘤中高表達(dá),并且與腫瘤的分級及預(yù)后密切相關(guān),而通過降低GLS或GDH1的表達(dá),可以通過抑制脂質(zhì)合成或者引起細(xì)胞內(nèi)氧化還原壓力,引起腫瘤細(xì)胞的凋亡[59-61]。最新的研究顯示,在腫瘤進(jìn)展過程中,周圍環(huán)境變化引起的氧化壓力是抑制腫瘤細(xì)胞遠(yuǎn)處轉(zhuǎn)移的重要因素[62-64],而谷氨酰胺代謝的中間產(chǎn)物延胡索酸 (fumarate)可以通過激活谷胱甘肽過氧化物酶 (glutathione peroxidase,GPx),來降低腫瘤細(xì)胞內(nèi)部的活性氧化物 (reactive oxygen species,ROS)水平,維持氧化還原平衡[60],進(jìn)而可能促進(jìn)了腫瘤的轉(zhuǎn)移。關(guān)于谷氨酰胺代謝在腫瘤侵襲轉(zhuǎn)移中的作用及其具體機(jī)制,還有待進(jìn)一步研究。

脂質(zhì)代謝與腫瘤轉(zhuǎn)移除了糖類和氨基酸代謝的變化外,脂質(zhì)代謝的改變也是腫瘤代謝的一個重要特征。脂質(zhì)是一類不溶于水的分子,主要包括三酰甘油、磷脂、鞘脂和固醇等。脂質(zhì)代謝中還有一種重要的代謝物脂肪酸,脂肪酸是一類由一個末端羧基和一條烴鏈構(gòu)成的分子,是包括三酰甘油、磷脂和膽固醇脂在內(nèi)的脂質(zhì)分子的重要組分。脂質(zhì)分子是生物膜的重要結(jié)構(gòu)組分,同時它們在信號轉(zhuǎn)導(dǎo)和激素合成過程中也發(fā)揮重要作用[65]。下面著重綜述膽固醇代謝和脂肪酸代謝在腫瘤轉(zhuǎn)移中的作用及機(jī)制。

膽固醇代謝與腫瘤轉(zhuǎn)移膽固醇 (cholesterol)是細(xì)胞膜尤其是細(xì)胞質(zhì)膜的關(guān)鍵成分[66],并且是甾醇類激素、膽汁酸、維生素等的合成前體[67]。已有的研究顯示,膽固醇代謝與腫瘤轉(zhuǎn)移存在密切聯(lián)系。一方面,血漿膽固醇水平與多種腫瘤的發(fā)生和發(fā)展密切相關(guān)[68-69],Alikhani等[70]在乳腺癌動物模型中證實,血漿膽固醇水平異常可促進(jìn)乳腺癌的轉(zhuǎn)移。另一方面,利用他汀類藥物抑制膽固醇合成,可抑制多種腫瘤的侵襲轉(zhuǎn)移[71-74]。

膽固醇代謝影響腫瘤侵襲轉(zhuǎn)移的具體分子機(jī)制目前尚不明確。已有的研究工作提示可能有以下幾種機(jī)制: (1)脂筏 (lipid raft)是細(xì)胞質(zhì)膜上富含膽固醇和鞘脂 (sphingolipid)的微結(jié)構(gòu)域,在細(xì)胞信號轉(zhuǎn)導(dǎo)和細(xì)胞質(zhì)膜蛋白質(zhì)分選等生物學(xué)過程中發(fā)揮重要作用[75]。作為脂筏的關(guān)鍵組分,膽固醇水平變化可影響脂筏的結(jié)構(gòu)和功能[76]。最近的研究顯示,脂筏與多種腫瘤侵襲轉(zhuǎn)移相關(guān)的信號轉(zhuǎn)導(dǎo)過程密切相關(guān):骨橋蛋白 (osteopontin,OPN)是重要的促腫瘤轉(zhuǎn)移分子,OPN通過其受體蛋白整合素 (integrin)和CD44激活MAPK、PI3K/AKT以及NF-等信號通路,上調(diào)尿激酶型纖維蛋白溶酶原激活物 (urinary plasminogen activator,uPA)、基質(zhì)金屬蛋白酶-2 (matrix metallopeptidase 2,MMP-2)和基質(zhì)金屬蛋白酶-9 (matrix metallopeptidase 9,MMP-9)等基因的表達(dá),促進(jìn)腫瘤侵襲轉(zhuǎn)移[77]。而Integrin和CD44都定位于脂筏中,其下游信號通路的激活依賴于脂筏[78-79]。Murai等[80]研究發(fā)現(xiàn),降低細(xì)胞質(zhì)膜膽固醇水平破壞脂筏結(jié)構(gòu),可促進(jìn)CD44蛋白從細(xì)胞質(zhì)膜上脫落,進(jìn)而抑制腫瘤細(xì)胞的遷移。此外,脂筏在EGFR信號通路的激活過程中也發(fā)揮重要作用,而EGFR通路是腫瘤侵襲轉(zhuǎn)移中重要的信號通路[81]。已有的研究顯示,EGFR的脂筏定位可促進(jìn)其配體依賴的磷酸化以及下游AKT的磷酸化[82]。而Irwin等[83]在乳腺癌中研究發(fā)現(xiàn),當(dāng)EGFR定位于脂筏時,乳腺癌細(xì)胞株對EGFR酪氨酸激酶抑制劑表現(xiàn)出耐藥性;而利用甲基-β-環(huán)糊精或他汀類藥物降低膽固醇破壞脂筏,可降低這種抵抗效應(yīng)。 (2)膽固醇合成代謝的旁路代謝途徑中存在兩種重要代謝產(chǎn)物焦磷酸法尼酯 (farnesyl pyrophosphate,FPP)和焦磷酸牛兒基牛兒酯 (geranylgeranyl pyrophosphate,GGPP),這兩種代謝產(chǎn)物參與了Ras和Rho蛋白的異戊烯化,而異戊烯化修飾是Ras和Rho蛋白與細(xì)胞膜結(jié)合和激活所必需的[74]。在神經(jīng)膠質(zhì)瘤中的研究顯示,抑制膽固醇合成會引起FPP和GGPP這兩種代謝產(chǎn)物水平的下降,進(jìn)而抑制Ras-Raf-MEK-ERK信號途徑,最終導(dǎo)致神經(jīng)膠質(zhì)瘤細(xì)胞生長遷移和侵襲能力的下降[84]。 (3)最新研究表明,在乳腺癌中,膽固醇代謝異常引起其代謝產(chǎn)物27-羥膽固醇 (27-HC)的累積,累積的27-HC通過激活雌激素受體 (estrogen receptor,ER)和肝X受體 (liver X receptor,LXR)促進(jìn)乳腺癌的生長和侵襲轉(zhuǎn)移[85-86]。

脂肪酸代謝與腫瘤轉(zhuǎn)移脂肪酸參與了腫瘤細(xì)胞的多個生物學(xué)過程: (1)脂肪酸是細(xì)胞膜重要結(jié)構(gòu)分子磷脂的基本合成組分,因此,腫瘤細(xì)胞快速增殖需要大量的脂肪酸[87]; (2)某些類型的腫瘤 (如前列腺癌)主要依賴脂肪酸β-氧化作為能量的主要來源,而并不依賴于葡萄糖攝取的增加[88]; (3)脂肪酸還參與許多重要的促癌脂質(zhì)信號分子包括磷酸肌醇、溶血磷脂酸和前列腺素的合成[89]。已有的研究顯示,在多種腫瘤中觀察到脂肪酸代謝途徑中的關(guān)鍵基因ATP-檸檬酸裂解酶 (ATP citrate lyase,ACLY)、乙酰輔酶A羧化酶 (Acetyl-CoA carboxylase,ACC)、脂肪酸合成酶 (Fatty acid synthase,FASN)和?；?輔酶A去飽和酶 (stearoyl-coenzyme A desaturase,SCD)的表達(dá)和活性的提高,并且與不良預(yù)后密切相關(guān)[90-92],通過下調(diào)這些代謝酶的表達(dá)或利用特異性抑制劑抑制代謝酶活性可抑制腫瘤的生長[93-95]。

近年來的研究表明,脂肪酸代謝在腫瘤轉(zhuǎn)移過程中也發(fā)揮重要作用。Budhu等[96]利用配對的肝癌組織和癌旁組織進(jìn)行代謝組學(xué)研究和差異表達(dá)基因的篩選,鑒定出與肝癌進(jìn)展相關(guān)的28種代謝物和169個差異表達(dá)基因,進(jìn)一步研究發(fā)現(xiàn),在這些代謝產(chǎn)物和基因中,SCD代謝途徑相關(guān)代謝物和基因與肝癌進(jìn)展表現(xiàn)出顯著的相關(guān)性,進(jìn)一步研究顯示干擾SCD的表達(dá)可抑制肝癌細(xì)胞的遷移和侵襲能力。Li等[97]的研究顯示,在多種腫瘤中高表達(dá)的跨膜糖蛋白CD147,也是腫瘤細(xì)胞脂肪酸代謝的重要調(diào)控因子,其調(diào)控的脂肪酸代謝在腫瘤侵襲轉(zhuǎn)移過程中發(fā)揮了重要作用。這些研究表明,脂肪酸代謝也在腫瘤細(xì)胞遷移和侵襲的過程發(fā)揮重要作用,然而其影響腫瘤轉(zhuǎn)移的具體分子機(jī)制還需要更深入的研究。

腫瘤微環(huán)境異常代謝與腫瘤轉(zhuǎn)移近年來,腫瘤微環(huán)境對腫瘤轉(zhuǎn)移的調(diào)控作用引起越來越多的關(guān)注[98]。腫瘤的快速增殖和異常的血管生成,使腫瘤細(xì)胞處于氧和營養(yǎng)物質(zhì)缺乏的代謝環(huán)境,進(jìn)一步改變了腫瘤細(xì)胞的代謝方式。一方面,缺氧的外界信號可以通過激活HIF,使腫瘤細(xì)胞的糖酵解能力進(jìn)一步加強(qiáng)[99];另一方面,惡劣的微環(huán)境可以直接刺激腫瘤細(xì)胞表達(dá)熱休克蛋白90 (heat shock protein 90,HSP90),重塑細(xì)胞骨架,增強(qiáng)細(xì)胞的運動遷移能力,從而促進(jìn)細(xì)胞侵襲轉(zhuǎn)移[100]。

在腫瘤轉(zhuǎn)移過程中,腫瘤細(xì)胞可以通過直接攝取轉(zhuǎn)移微環(huán)境中的次級代謝產(chǎn)物來實現(xiàn)快速的能量供應(yīng),并實現(xiàn)在轉(zhuǎn)移灶的定植。Loo等[101]發(fā)現(xiàn),轉(zhuǎn)移性的結(jié)直腸癌細(xì)胞可以直接分泌B型肌酸激酶 (creatine kinase,brain,CKB)進(jìn)入肝臟微環(huán)境,將微環(huán)境中的肌酸磷酸化為磷酸肌酸,腫瘤細(xì)胞又可以通過攝取磷酸肌酸來快速產(chǎn)生ATP,進(jìn)而增強(qiáng)其侵襲轉(zhuǎn)移的能力。

微環(huán)境中的間質(zhì)細(xì)胞同樣可以通過異常代謝促進(jìn)腫瘤的侵襲轉(zhuǎn)移。一方面,腫瘤相關(guān)成纖維細(xì)胞 (cancer-associated-fibroblast,CAF)可以通過快速的脂肪分解及葡萄糖酵解產(chǎn)生酮體及乳酸等物質(zhì),并將其分泌到微環(huán)境中,而腫瘤細(xì)胞可以大量攝取這類營養(yǎng)物質(zhì)[102-103]。同樣,微環(huán)境中的脂肪細(xì)胞也可直接將脂質(zhì)等物質(zhì)傳遞給腫瘤細(xì)胞[104]。這些物質(zhì)都可以為腫瘤細(xì)胞快速提供能量,并促進(jìn)癌細(xì)胞的增殖及侵襲轉(zhuǎn)移能力。除此之外,最新研究發(fā)現(xiàn),腫瘤細(xì)胞通過外泌小體攜帶的miR-122抑制轉(zhuǎn)移灶間質(zhì)細(xì)胞 (主要是成纖維細(xì)胞)的葡萄糖攝取能力,間接地改造轉(zhuǎn)移灶微環(huán)境的代謝狀態(tài)來促進(jìn)其在轉(zhuǎn)移灶中的生存以及定植能力[105]。

另一方面,微環(huán)境中的免疫細(xì)胞的代謝異常則介導(dǎo)了腫瘤的免疫逃逸。樹突狀細(xì)胞是機(jī)體內(nèi)重要的抗原呈遞細(xì)胞,其在抗腫瘤免疫中扮演了重要角色,Herber等[106]發(fā)現(xiàn),腫瘤微環(huán)境中的樹突狀細(xì)胞存在大量脂肪的累積,減弱了其抗原呈遞的能力,進(jìn)而使其抗腫瘤免疫的作用受到抑制,通過清除樹突狀細(xì)胞內(nèi)累積的脂肪可以明顯增強(qiáng)其對腫瘤的免疫反應(yīng)。而正常的葡萄糖代謝也是效應(yīng)T細(xì)胞發(fā)揮功能的前提條件[107],最新研究發(fā)現(xiàn),腫瘤細(xì)胞通過競爭性攝取葡萄糖,限制了T淋巴細(xì)胞對葡萄糖的吸收,使其腫瘤殺傷作用受到抑制,引起了腫瘤的免疫逃逸,進(jìn)而促進(jìn)了腫瘤的侵襲轉(zhuǎn)移[108-109]。

綜上所述,從“Warburg效應(yīng)”的提出開始,腫瘤代謝領(lǐng)域的研究已歷經(jīng)多年的發(fā)展。近十年來,隨著代謝組學(xué)以及腫瘤基因組學(xué)的發(fā)展,人們對代謝調(diào)控在腫瘤發(fā)生發(fā)展過程中的作用機(jī)制正逐步加深了解?，F(xiàn)在觀點認(rèn)為,外部環(huán)境的刺激以及癌基因和抑癌基因的異常調(diào)控,是腫瘤細(xì)胞采取異常的物質(zhì)及能量代謝方式的根本原因,這一方面滿足了腫瘤快速生長的需求,另一方面對于腫瘤的侵襲轉(zhuǎn)移也有深遠(yuǎn)的影響。此外,腫瘤微環(huán)境中間質(zhì)細(xì)胞及免疫細(xì)胞的代謝改變,也參與了腫瘤轉(zhuǎn)移的調(diào)控過程。所有這些發(fā)現(xiàn),都為腫瘤代謝以及腫瘤轉(zhuǎn)移研究提供了新的研究方向。此外,由于腫瘤代謝與正常代謝的顯著差異,腫瘤細(xì)胞及其微環(huán)境特異性的異常代謝途徑有望成為抗腫瘤轉(zhuǎn)移的新靶點,通過篩選針對這些代謝途徑中的代謝酶的抑制劑或小分子化合物,可能為抗腫瘤轉(zhuǎn)移的治療帶來根本性的變革。

參考文獻(xiàn)

[1]HANAHAN D,WEINBERG RA.Hallmarks of cancer:the next generation[J].Cell,2011,144 (5):646-674.

[2]CHAFFER CL,WEINBERG RA.A perspective on cancer cell metastasis[J].Science,2011,331 (6024):1559-1564.

[3]FINLEY L W,ZHANG J,YE J,etal.SnapShot:cancer metabolism pathways[J].CellMetab,2013,17 (3):466.

[4]CAIRNS RA,MAK TW.Oncogenic isocitrate dehydrogenase mutations:mechanisms,models,and clinical opportunities[J].CancerDiscov,2013,3 (7):730-741.

[5]CAIRNS RA,HARRIS IS,MAK TW.Regulation of cancer cell metabolism[J].NatRevCancer,2011,11 (2):85-95.

[6]WARBURG O,WIND F,NEGELEIN E.The metabolism of tumors in the body[J].JGenPhysiol,1927,8 (6):519-530.

[7]WARBURG O.On the origin of cancer cells[J].Science,1956,123 (3191):309-314.

[8]DEBERARDINIS RJ,MANCUSO A,DAIKHIN E,etal.Beyond aerobic glycolysis:transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis[J].ProcNatlAcadSciUSA,2007,104 (49):19345-19350.

[9]ALTENBERG B,GREULICH KO.Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes[J].Genomics,2004,84 (6):1014-1020.

[10]LEVINE AJ,PUZIO-KUTER AM.The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes[J].Science,2010,330 (6009):1340-1344.

[11]SCHULZE A,HARRIS AL.How cancer metabolism is tuned for proliferation and vulnerable to disruption[J].Nature,2012,491 (7424):364-373.

[12]RIEDL CC,AKHURST T,LARSON S,etal.18F-FDG PET scanning correlates with tissue markers of poor prognosis and predicts mortality for patients after liver resection for colorectal metastases[J].JNuclMed,2007,48 (5):771-775.

[13]KAIRA K,ENDO M,ABE M,etal.Biologic correlation of 2-[18F]-fluoro-2-deoxy-D-glucose uptake on positron emission tomography in thymic epithelial tumors[J].JClinOncol,2010,28 (23):3746-3753.

[14]VANDER HM,CANTLEY LC,THOMPSON CB.Understanding the Warburg effect:the metabolic requirements of cell proliferation[J].Science,2009,324 (5930):1029-1033.

[15]SHINOHARA Y,YAMAMOTO K,KOGURE K,etal.Steady state transcript levels of the type II hexokinase and type 1 glucose transporter in human tumor cell lines[J].CancerLett,1994,82 (1):27-32.

[16]YOUNES M,LECHAGO LV,SOMOANO JR,etal.Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers[J].CancerRes,1996,56 (5):1164-1167.

[17]SCHWARTZENBERG-BAR-YOSEPH F,ARMONI M,KARNIELI E.The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression[J].CancerRes,2004,64 (7):2627-2633.

[18]WU N,ZHENG B,SHAYWITZ A,etal.AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1[J].MolCell,2013,49 (6):1167-1175.

[19]VITICCHIE G,AGOSTINI M,LENA AM,etal. p63 supports aerobic respiration through hexokinase II[J].ProcNatlAcadSciUSA,2015,112 (37):11577-11582.

[20]GUO W,QIU Z,WANG Z,etal.MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer[J].Hepatology,2015,62 (4):1132-1144.

[21]AIRLEY R,LONCASTER J,DAVIDSON S,etal.Glucose transporter glut-1 expression correlates with tumor hypoxia and predicts metastasis-free survival in advanced carcinoma of the cervix[J].ClinCancerRes,2001,7 (4):928-934.

[22]PALMIERI D,FITZGERALD D,SHREEVE SM,etal.Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis[J].MolCancerRes,2009,7 (9):1438-1445.

[23]CHAN DA,SUTPHIN PD,NGUYEN P,etal.Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality[J].SciTranslMed,2011,3 (94):70r-94r.

[24]PATRA KC,WANG Q,BHASKAR PT,etal.Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer[J].CancerCell,2013,24 (2):213-228.

[25]MARINI C,SALANI B,MASSOLLO M,etal.Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer[J].CellCycle,2013,12 (22):3490-3499.

[26]WANG L,XIONG H,WU F,etal.Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth[J].CellRep,2014,8 (5):1461-1474.

[27]CHRISTOFK HR,VANDER HM,HARRIS MH,etal.The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumourgrowth[J].Nature,2008,452 (7184):230-233.

[28]DAVID CJ,CHEN M,ASSANAH M,etal.HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer[J].Nature,2010,463 (7279):364-368.

[29]Christofk HR,Vander HM,Wu N,etal.Pyruvate kinase M2 is a phosphotyrosine-binding protein[J].Nature,2008,452 (7184):181-186.

[30]HITOSUGI T,KANG S,VANDER HM,etal.Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth[J].SciSignal,2009,2 (97):a73.

[31]LUO W,HU H,CHANG R,etal.Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1[J].Cell,2011,145 (5):732-744.

[32]YANG W,XIA Y,JI H,etal.Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation[J].Nature,2011,480 (7375):118-122.

[33]ZHAN C,SHI Y,LU C,etal.Pyruvate kinase M2 is highly correlated with the differentiation and the prognosis of esophageal squamous cell cancer[J].DisEsophagus,2013,26 (7):746-753.

[34]LI J,YANG Z,ZOU Q,etal.PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer[J].ClinTranslOncol,2014,16 (2):200-207.

[35]FENG C,GAO Y,WANG C,etal.Aberrant overexpression of pyruvate kinase M2 is associated with aggressive tumor features and the BRAF mutation in papillary thyroid cancer[J].JClinEndocrinolMetab,2013,98 (9):E1524-E1533.

[36]GOLDBERG MS,SHARP PA.Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression[J].JExpMed,2012,209 (2):217-224.

[37]FARINATI F,SALVAGNINI M,DE MARIA N,etal.Unresectable hepatocellular carcinoma:a prospective controlled trial with tamoxifen[J].JHepatol,1990,11 (3):297-301.

[38]KOUKOURAKIS MI,GIATROMANOLAKI A,SIVRIDIS E,etal.Lactate dehydrogenase 5 expression in operable colorectal cancer:strong association with survival and activated vascular endothelial growth factor pathway-a report of the Tumour Angiogenesis Research Group[J].JClinOncol,2006,24 (26):4301-4308.

[39]MOREAU P,CAVO M,SONNEVELD P,etal.Combination of international scoring system 3,high lactate dehydrogenase,and t (4;14) and/or del (17p) identifies patients with multiple myeloma (MM) treated with front-line autologous stem-cell transplantation at high risk of early MM progression-related death[J].JClinOncol,2014,32 (20):2173-2180.

[40]SCHER HI,HELLER G,MOLINA A,etal.Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer[J].JClinOncol,2015,33 (12):1348-1355.

[41]ZHAO D,ZOU S W,LIU Y,etal.Lysine-5 acetylation negatively regulates lactate dehydrogenase A and is decreased in pancreatic cancer[J].CancerCell,2013,23 (4):464-476.

[42]LEWIS BC,PRESCOTT JE,CAMPBELL SE,etal.Tumor induction by the c-Myc target genes rcl and lactate dehydrogenase A[J].CancerRes,2000,60 (21):6178-6183.

[43]FANTIN VR,ST-PIERRE J,LEDER P.Attenuation of LDH-A expression uncovers a link between glycolysis,mitochondrial physiology,and tumor maintenance[J].CancerCell,2006,9 (6):425-434.

[44]XIE H,HANAI J,REN JG,etal.Targeting lactate dehydrogenase-a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells[J].CellMetab,2014,19 (5):795-809.

[45]RIZWAN A,SERGANOVA I,KHANIN R,etal. Relationships between LDH-A,lactate,and metastases in 4T1 breast tumors[J].ClinCancerRes,2013,19 (18):5158-5169.

[46]SCHWICKERT G,WALENTA S,SUNDFOR K,etal.Correlation of high lactate levels in human cervical cancer with incidence of metastasis[J].CancerRes,1995,55 (21):4757-4759.

[47]WALENTA S,SALAMEH A,LYNG H,etal.Correlation of high lactate levels in head and neck tumors with incidence of metastasis[J].AmJPathol,1997,150 (2):409-415.

[48]BONUCCELLI G,TSIRIGOS A,WHITAKER-MENEZES D,etal.Ketones and lactate "fuel" tumor growth and metastasis:Evidence that epithelial cancer cells use oxidative mitochondrial metabolism[J].CellCycle,2010,9 (17):3506-3514.

[49]MARTINEZ-OUTSCHOORN UE,PRISCO M,ERTEL A,etal.Ketones and lactate increase cancer cell "stemness," driving recurrence,metastasis and poor clinical outcome in breast cancer:achieving personalized medicine via Metabolo-Genomics[J].CellCycle,2011,10 (8):1271-1286.

[50]COLEGIO OR,CHU NQ,SZABO AL,etal.Functional polarization of tumour-associated macrophages by tumour-derived lactic acid[J].Nature,2014,513 (7519):559-563.

[51]GOODWIN ML,JIN H,STRAESSLER K,etal.Modeling alveolar soft part sarcomagenesis in the mouse:a role for lactate in the tumor microenvironment[J].CancerCell,2014,26 (6):851-862.

[52]HENSLEY CT,WASTI AT,DEBERARDINIS RJ.Glutamine and cancer:cell biology,physiology,and clinical opportunities[J].JClinInvest,2013,123 (9):3678-3684.

[53]KIM D,FISKE B P,BIRSOY K,etal.SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance[J].Nature,2015,520 (7547):363-367.

[54]ROBERTS E,FRANKEL S.Free amino acids in normal and neoplastic tissues of mice as studied by paper chromatography[J].CancerRes,1949,9 (11):645-648,3.

[55]ROBERTS E,BORGES PR.Patterns of free amino acids in growing and regressing tumors[J].CancerRes,1955,15 (10):697-699.

[56]YUNEVA M,ZAMBONI N,OEFNER P,etal.Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells[J].JCellBiol,2007,178 (1):93-105.

[57]WISE DR,DEBERARDINIS RJ,MANCUSO A,etal.Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction[J].ProcNatlAcadSciUSA,2008,105 (48):18782-18787.

[58]GAO P,TCHERNYSHYOV I,CHANG TC,etal.c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism[J].Nature,2009,458 (7239):762-765.

[59]WANG J B,ERICKSON J W,FUJI R,etal.Targeting mitochondrial glutaminase activity inhibits oncogenic transformation[J].CancerCell,2010,18 (3):207-219.

[60]JIN L,LI D,ALESI GN,etal.Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth[J].CancerCell,2015,27 (2):257-270.

[61]SELTZER MJ,BENNETT BD,JOSHI AD,etal.Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1[J].CancerRes,2010,70 (22):8981-8987.

[62]PISKOUNOVA E,AGATHOCLEOUS M,MURPHY MM,etal.Oxidative stress inhibits distant metastasis by human melanoma cells[J].Nature,2015,527 (7577):186-191.

[63]LE GAL K,IBRAHIM MX,WIEL C,etal.Antioxidants can increase melanoma metastasis in mice[J].SciTranslMed,2015,7 (308):308re8.

[64]SAYIN VI,IBRAHIM MX,LARSSON E,etal.Antioxidants accelerate lung cancer progression in mice[J].SciTranslMed,2014,6 (221):215r-221r.

[65]SANTOS CR,SCHULZE A.Lipid metabolism in cancer[J].FEBSJ,2012,279 (15):2610-2623.

[66]IKONEN E.Roles of lipid rafts in membrane transport[J].CurrOpinCellBiol,2001,13 (4):470-477.

[67]RUSSELL DW.The enzymes,regulation,and genetics of bile acid synthesis[J].AnnuRevBiochem,2003,72:137-174.

[68]PELTON K,FREEMAN MR,SOLOMON KR.Cholesterol and prostate cancer[J].CurrOpinPharmacol,2012,12 (6):751-759.

[69]KITAHARA CM,BERRINGTON DGA,FREEDMAN ND,etal.Total cholesterol and cancer risk in a large prospective study in Korea[J].JClinOncol,2011,29 (12):1592-1598.

[70]ALIKHANI N,FERGUSON RD,NOVOSYADLYY R,etal.Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model[J].Oncogene,2013,32 (8):961-967.

[71]NIELSEN SF,NORDESTGAARD BG,BOJESEN SE.Statin use and reduced cancer-related mortality[J].NEnglJMed,2012,367 (19):1792-1802.

[72]TARAS D,BLANC JF,RULLIER A,etal.Pravastatin reduces lung metastasis of rat hepatocellular carcinoma via a coordinated decrease of MMP expression and activity[J].JHepatol,2007,46 (1):69-76.

[73]ZHANG J,YANG Z,XIE L,etal.Statins,autophagy and cancer metastasis[J].IntJBiochemCellBiol,2013,45 (3):745-752.

[74]ROY M,KUNG HJ,GHOSH PM.Statins and prostate cancer:role of cholesterol inhibition vs.prevention of small GTP-binding proteins[J].AmJCancerRes,2011,1 (4):542-561.

[75]SIMONS K,IKONEN E.Functional rafts in cell membranes[J].Nature,1997,387 (6633):569-572.

[76]FREEMAN MR,DI VIZIO D,SOLOMON KR.The Rafts of the Medusa:cholesterol targeting in cancer therapy[J].Oncogene,2010,29 (26):3745-3747.

[77]RANGASWAMI H,BULBULE A,KUNDU GC.Osteopontin:role in cell signaling and cancer progression[J].TrendsCellBiol,2006,16 (2):79-87.

[78]PATRA SK.Dissecting lipid raft facilitated cell signaling pathways incancer[J].BiochimBiophysActa,2008,1785 (2):182-206.

[79]MURAI T.The role of lipid rafts in cancer cell adhesion and migration[J].IntJCellBiol,2012,2012:763283.

[80]MURAI T,MARUYAMA Y,MIO K,etal.Low cholesterol triggers membrane microdomain-dependent CD44 shedding and suppresses tumor cell migration[J].JBiolChem,2011,286 (3):1999-2007.

[81]NICHOLSON RI,GEE JM,HARPER ME.EGFR and cancer prognosis[J].EurJCancer,2001,37 (Suppl 4):S9-S15.

[82]HRYNIEWICZ-JANKOWSKA A,AUGOFF K,BIERNATOWSKA A,etal.Membrane rafts as a novel target in cancer therapy[J].BiochimBiophysActa,2014,1845 (2):155-165.

[83]IRWIN ME,MUELLER KL,BOHIN N,etal.Lipid raft localization of EGFR alters the response of cancer cells to the EGFR tyrosine kinase inhibitor gefitinib[J].JCellPhysiol,2011,226 (9):2316-2328.

[84]AFSHORDEL S,KERN B,CLASOHM J,etal.Lovastatin and perillyl alcohol inhibit glioma cell invasion,migration,and proliferation-impact of Ras-/Rho-prenylation[J].PharmacolRes,2015,91:69-77.

[85]NELSON ER,WARDELL SE,JASPER JS,etal.27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology[J].Science,2013,342 (6162):1094-1098.

[86]WU Q,ISHIKAWA T,SIRIANNI R,etal.27-Hydroxycholesterol promotes cell-autonomous,ER-positive breast cancer growth[J].CellRep,2013,5 (3):637-645.

[87]ZAIDI N,LUPIEN L,KUEMMERLE NB,etal.Lipogenesis and lipolysis:the pathways exploited by the cancer cells to acquire fatty acids[J].ProgLipidRes,2013,52 (4):585-589.

[88]LIU Y,ZUCKIER LS,GHESANI NV.Dominant uptake of fatty acid over glucose by prostate cells:a potential new diagnostic and therapeutic approach[J].AnticancerRes,2010,30 (2):369-374.

[89]ZHANG F,DU G.Dysregulated lipid metabolism in cancer[J].WorldJBiolChem,2012,3 (8):167-174.

[90]MIGITA T,NARITA T,NOMURA K,etal.ATP citrate lyase:activation and therapeutic implications in non-small cell lung cancer[J].CancerRes,2008,68 (20):8547-8554.

[91]OGINO S,NOSHO K,MEYERHARDT JA,etal. Cohort study of fatty acid synthase expression and patient survival in colon cancer[J].JClinOncol,2008,26 (35):5713-5720.

[92]NGUYEN PL,MA J,CHAVARRO JE,etal.Fatty acid synthase polymorphisms,tumor expression,body mass index,prostate cancer risk,and survival[J].JClinOncol,2010,28 (25):3958-3964.

[93]HATZIVASSILIOU G,ZHAO F,BAUER DE,etal.ATP citrate lyase inhibition can suppress tumor cell growth[J].CancerCell,2005,8 (4):311-321.

[94]BRUSSELMANS K,DE SCHRIJVER E,VERHOEVEN G,etal.RNA interference-mediated silencing of the acetyl-CoA-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells[J].CancerRes,2005,65 (15):6719-6725.

[95]SOUNNI NE,CIMINO J,BLACHER S,etal.Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal[J].CellMetab,2014,20 (2):280-294.

[96]BUDHU A,ROESSLER S,ZHAO X,etal.Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes[J].Gastroenterology, 2013,144 (5):1066-1075.

[97]LI J,HUANG Q,LONG X,etal.CD147 reprograms fatty acid metabolism in hepatocellularcarcinoma cells through Akt/mTOR/SREBP1c and P38/PPARalpha pathways[J].JHepatol, 2015,63(6):1378-1389.

[98]QUAIL DF,JOYCE JA.Microenvironmental regulation of tumor progression and metastasis[J].NatMed,2013,19 (11):1423-1437.

[99]KIM JW,GAO P,DANG CV.Effects of hypoxia on tumor metabolism[J].CancerMetastasisRev,2007,26 (2):291-298.

[100]CAINO MC,CHAE YC,VAIRA V,etal.Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells[J].JClinInvest,2013,123 (7):2907-2920.

[101]LOO JM,SCHERL A,NGUYEN A,etal. Extracellular metabolic energetics can promote cancer progression[J].Cell,2015,160 (3):393-406.

[102]SOTGIA F,MARTINEZ-OUTSCHOORN UE,HOWELL A,etal.Caveolin-1 and cancer metabolism in the tumor microenvironment:markers,models,and mechanisms[J].AnnuRevPathol,2012,7:423-467.

[103]MARTINEZ-OUTSCHOORN UE,LISANTI MP,SOTGIA F.Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells,fueling tumor growth[J].SeminCancerBiol,2014,25:47-60.

[104]NIEMAN KM,KENNY HA,PENICKA CV,etal.Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth[J].NatMed,2011,17 (11):1498-1503.

[105]FONG MY,ZHOU W,LIU L,etal.Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis[J].NatCellBiol,2015,17 (2):183-194.

[106]HERBER DL,CAO W,NEFEDOVA Y,etal.Lipid accumulation and dendritic cell dysfunction in cancer[J].NatMed,2010,16 (8):880-886.

[107]CHANG CH,CURTIS JD,MAGGI LJ,etal.Posttranscriptional control of T cell effector function by aerobic glycolysis[J].Cell,2013,153 (6):1239-1251.

[108]CHANG CH,QIU J,O′SULLIVAN D,etal.Metabolic competition in the tumor microenvironment is a driver of cancer progression[J].Cell,2015,162 (6):1229-1241.

[109]HO PC,BIHUNIAK JD,MACINTYRE AN,etal.Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses[J].Cell,2015,162 (6):1217-1228.

Cancer metabolism and metastasis

WANG Xiang-yu1,2,ZHENG Yan1,2,3,LU Ming1,2,QIN Lun-xiu1,2,3△

(1DepartmentofGeneralSurgery,HuashanHospital,FudanUniversity,Shanghai200040,China;2CancerMetastasisInstitute,FudanUniversity,Shanghai200040,China;3InstituteofBiomedicalSciences,FudanUniversity,Shanghai200032,China)

【Abstract】Metastasis and metabolic deregulation are two of the major essential hallmarks of cancer.In the initiation and development of cancer,tumor cells are known to undergo metabolic alterations to sustain faster proliferation.Recent studies indicated that metabolic changes of tumors are also closely related to tumor metastasis.In this review,we summarize the research progress about the roles and related mechanism of tumor metabolism in tumor metastasis from the aspects of both the tumor cell and microenvironment.

【Key words】carbohydrate;amino acid;cholesterol;fatty acid;tumor microenvironment;cancer metastasis

【中圖分類號】R730

【文獻(xiàn)標(biāo)識碼】B

doi:10.3969/j.issn.1672-8467.2016.01.016

(收稿日期:2015-11-06;編輯:張秀峰)

國家自然科學(xué)基金國際(地區(qū))合作與交流項目(8112108016)

△Corresponding authorE-mail:qinlx@fudan.edu.cn