0 引言

腫瘤微環(huán)境概念最早可追溯至1863年Virchow提出的“腫瘤起源于慢性炎癥”和1889年P(guān)aget提出的“種子和土壤”假說(shuō),作為“種子”的腫瘤細(xì)胞所處周邊環(huán)境被認(rèn)為是“土壤”

.2011年,Hanahan和Weinberg總結(jié)了腫瘤的十大惡性特征,明確了“微環(huán)境”因素在腫瘤發(fā)生發(fā)展中的重要作用

.腫瘤細(xì)胞與其所處的微環(huán)境是一個(gè)功能整體,腫瘤細(xì)胞能夠教育重塑腫瘤微環(huán)境(tumor microenvironment,TME),而TME通過不斷重塑改造以形成更利于腫瘤生存的生態(tài)條件.腫瘤微環(huán)境是一個(gè)復(fù)雜的綜合體,主要由腫瘤細(xì)胞、間質(zhì)細(xì)胞、浸潤(rùn)免疫細(xì)胞、細(xì)胞因子、趨化因子、組織蛋白酶、血管淋巴管和細(xì)胞外基質(zhì)等構(gòu)成,各組分與腫瘤細(xì)胞相互影響、共同進(jìn)化,驅(qū)動(dòng)腫瘤生長(zhǎng)和進(jìn)展,同時(shí)在調(diào)控腫瘤治療敏感性方面也發(fā)揮舉足輕重的作用

.消化系統(tǒng)腫瘤發(fā)病率和死亡率在全球均位居前列,放療和化療在消化系統(tǒng)腫瘤的非手術(shù)治療中占據(jù)主導(dǎo)地位,放化療抵抗則是腫瘤患者治療失敗的主要原因.因此,腫瘤放化療抵抗機(jī)制研究一直是消化系統(tǒng)腫瘤治療領(lǐng)域研究熱點(diǎn),以往研究多集中于腫瘤細(xì)胞自身突變積累與DNA損傷修復(fù)機(jī)制異常等方面探索

.近來(lái)癌癥治療整體概念的出現(xiàn),腫瘤不再被認(rèn)為僅僅是腫瘤細(xì)胞自身的病理改變,而是微環(huán)境甚至系統(tǒng)調(diào)控失常的病理表現(xiàn),其中微環(huán)境生化和力學(xué)特征改變導(dǎo)致的腫瘤惡性生物學(xué)特征增強(qiáng),成為腫瘤治療失敗的“幫兇”

.與生理狀態(tài)下的生化、病理和力學(xué)特征不同,實(shí)體腫瘤微環(huán)境具有缺氧、免疫抑制、代謝異常及基質(zhì)變硬四個(gè)顯著特征,本文從上述微環(huán)境四個(gè)特征出發(fā),歸納總結(jié)微環(huán)境參與消化系統(tǒng)腫瘤放化療抵抗新機(jī)制及靶向TME逆轉(zhuǎn)抵抗的治療新策略.

1 缺氧微環(huán)境參與消化系統(tǒng)腫瘤放化療抵抗的機(jī)制

缺氧是腫瘤微環(huán)境常見特征,造成腫瘤微環(huán)境缺氧的主要原因?yàn)?腫瘤細(xì)胞快速生長(zhǎng)而消耗大量營(yíng)養(yǎng)和氧氣,新生血管不能及時(shí)有效建立,腫瘤細(xì)胞通透性升高使液體外滲造成血液黏滯等,因此微環(huán)境內(nèi)存在供氧和耗氧不平衡

.缺氧常引發(fā)腫瘤細(xì)胞發(fā)生系列復(fù)雜病理改變以適應(yīng)低氧環(huán)境調(diào)節(jié),這種改變主要由缺氧誘導(dǎo)因子(hypoxia inducible factor,HIF)介導(dǎo)

.研究顯示缺氧微環(huán)境不僅顯著影響腫瘤細(xì)胞侵襲轉(zhuǎn)移

、干性

等惡性特征,而且可調(diào)控免疫抑制

、代謝重編程

及放化療抵抗

.

缺氧微環(huán)境導(dǎo)致的放化療抵抗主要包括以下幾種途徑:缺氧促進(jìn)腫瘤細(xì)胞DNA損傷修復(fù),導(dǎo)致腫瘤細(xì)胞耐藥基因表達(dá)增加以及抑制腫瘤細(xì)胞凋亡.腫瘤細(xì)胞DNA損傷是放射線治療和細(xì)胞毒性化療藥物殺傷腫瘤的共同作用機(jī)理,而缺氧可觸發(fā)腫瘤細(xì)胞DNA損傷修復(fù)

.將結(jié)直腸癌細(xì)胞在1%氧含量環(huán)境中培養(yǎng),測(cè)序發(fā)現(xiàn)其許多長(zhǎng)鏈非編碼RNA上調(diào),其中以LUCAT1上調(diào)最為顯著,體內(nèi)外實(shí)驗(yàn)顯示缺氧通過HIF-1α/LUCAT1/PTBP1軸抑制DNA損傷標(biāo)志物γ-H2AX表達(dá),使癌細(xì)胞對(duì)5-氟尿嘧啶和奧沙利鉑耐藥,此外,結(jié)直腸癌患者LUCAT1上調(diào)也提示化療療效不佳、預(yù)后不良,表明缺氧與化療療效存在一定的相關(guān)性

.也有研究顯示,將缺氧食管鱗癌細(xì)胞來(lái)源外泌體處理正常氧環(huán)境的癌細(xì)胞,能夠增強(qiáng)此細(xì)胞的DNA損傷修復(fù),誘導(dǎo)放射抗性,而敲減缺氧外泌體miRNA-340-5p,可逆轉(zhuǎn)正常氧癌細(xì)胞的放療抵抗

,提示缺氧癌細(xì)胞不僅自身對(duì)放療產(chǎn)生抵抗,還可通過外泌體等細(xì)胞間通訊方式,誘導(dǎo)周圍正常氧癌細(xì)胞的放射抗性.多藥耐藥基因1(multidrug resistance 1,MDR1)編碼的P-糖蛋白是藥物代謝過程中關(guān)鍵轉(zhuǎn)運(yùn)體,MDR1基因激活是腫瘤產(chǎn)生耐藥的重要原因

.有報(bào)道在氯化鈷模擬的缺氧環(huán)境中,肝癌細(xì)胞HIF-1α蛋白水平升高、對(duì)缺氧耐受增加,同時(shí)MDR1表達(dá)上調(diào),導(dǎo)致肝癌對(duì)曲古抑菌素A、索拉菲尼和5-氟尿嘧啶等多藥耐藥

,提示缺氧可調(diào)控耐藥相關(guān)基因、導(dǎo)致腫瘤耐藥.凋亡抵抗也是腫瘤耐藥的重要途徑,缺氧信號(hào)顯示可強(qiáng)化腫瘤細(xì)胞的抗凋亡通路

.研究發(fā)現(xiàn)

,HIF-1α可調(diào)控p53和NF-κB而減少細(xì)胞凋亡、降低胃癌細(xì)胞的化療敏感性.細(xì)胞膜碳酸酐酶Ⅸ(carbonic anhydrase Ⅸ,CAⅨ)在缺氧環(huán)境中可被異常激活而導(dǎo)致HIF-1α上調(diào),使癌細(xì)胞產(chǎn)生放療抵抗,抑制CAIX表達(dá)則能夠下調(diào)HIF-1α、促進(jìn)食管癌細(xì)胞凋亡及增加其放療敏感性

.以上證據(jù)表明,缺氧可通過誘導(dǎo)腫瘤細(xì)胞DNA損傷修復(fù)、調(diào)控耐藥相關(guān)基因和抑制凋亡等適應(yīng)性生存方式,抵抗放療和化療藥物損傷,從而使腫瘤產(chǎn)生對(duì)治療的耐受性.

以上通過兩種方法對(duì)南方某市某日電動(dòng)汽車充電負(fù)荷進(jìn)行預(yù)測(cè)，根據(jù)預(yù)測(cè)的結(jié)果，計(jì)算了絕對(duì)誤差、平均絕對(duì)誤差、相對(duì)誤差、平均相對(duì)誤差等數(shù)據(jù)。由這些指標(biāo)可以發(fā)現(xiàn)，基于BP神經(jīng)網(wǎng)絡(luò)算法和指數(shù)平滑法的滾動(dòng)預(yù)測(cè)精度要高于BP神經(jīng)網(wǎng)絡(luò)算法的電動(dòng)汽車充電負(fù)荷的日預(yù)測(cè)。

2 免疫抑制微環(huán)境參與消化系統(tǒng)腫瘤放化療抵抗的機(jī)制

腫瘤免疫抑制微環(huán)境主要由免疫抑制細(xì)胞和免疫抑制因子組成,是腫瘤發(fā)生、進(jìn)展及轉(zhuǎn)移的重要調(diào)控因素,免疫抑制微環(huán)境強(qiáng)弱不僅顯著影響免疫治療效果

,也調(diào)控腫瘤放化療敏感性.FoxP3

調(diào)節(jié)性T細(xì)胞(regulatory T cell,Treg)是經(jīng)典免疫抑制細(xì)胞,研究顯示結(jié)直腸癌對(duì)奧沙利鉑的耐藥與Treg細(xì)胞擴(kuò)增相關(guān),其機(jī)制為結(jié)直腸癌細(xì)胞來(lái)源外泌體miR-208b作用于Treg細(xì)胞,促進(jìn)其增殖及免疫抑制功能增強(qiáng)

.也有研究發(fā)現(xiàn)進(jìn)展期直腸癌患者術(shù)前新輔助放療療效與外周血中Treg細(xì)胞比例相關(guān),PD-1陽(yáng)性Treg細(xì)胞比例較高者放療效果不佳

.微環(huán)境中腫瘤相關(guān)巨噬細(xì)胞(tumor-related macrophage,TAM)包括M1型和M2型,其中M2型巨噬細(xì)胞主要發(fā)揮免疫抑制功能,M2型巨噬細(xì)胞免疫抑制功能強(qiáng)化可增強(qiáng)胃癌和結(jié)直腸化療耐藥

.除了抑制腫瘤免疫,該類細(xì)胞可釋放外泌體傳遞非編碼RNA和嘧啶類物質(zhì)至腫瘤細(xì)胞,導(dǎo)致腫瘤細(xì)胞惡性生物特征改變

.研究發(fā)現(xiàn)M2型巨噬細(xì)胞來(lái)源外泌體能夠促進(jìn)胃癌

和胰腺癌

化療耐藥;并且通過釋放嘧啶類物質(zhì)在藥物攝取和代謝水平競(jìng)爭(zhēng)性抑制化療藥物,降低胰腺癌吉西他濱治療敏感性

.髓源性抑制細(xì)胞(myeloid-derived suppressor cell,MDSC)是另一類重要的免疫抑制細(xì)胞,不僅抑制T細(xì)胞特異性免疫反應(yīng)、促進(jìn)微環(huán)境內(nèi)炎癥反應(yīng)和血管生成

,而且參與消化系統(tǒng)腫瘤肝、肺預(yù)轉(zhuǎn)移龕形成

.小鼠結(jié)腸癌組織和直腸癌患者外周血均存在MDSC細(xì)胞擴(kuò)增,并伴隨精氨酸酶1(arginase 1,Arg1)活性增加和L-精氨酸耗竭;Arg1陽(yáng)性MDSC細(xì)胞在削弱T細(xì)胞和M1型巨噬細(xì)胞抗腫瘤免疫的同時(shí),可強(qiáng)化M2型巨噬細(xì)胞免疫抑制功能,導(dǎo)致腫瘤免疫狀態(tài)失衡、放射敏感性受損

.MDSC細(xì)胞向M1型巨噬細(xì)胞分化抑制狀態(tài)也導(dǎo)致化療耐藥,使用Toll樣受體激動(dòng)劑R848上調(diào)M1型巨噬細(xì)胞的分化比例,能夠顯著增加結(jié)直腸癌對(duì)奧沙利鉑的敏感性

.除調(diào)控免疫功能,MDSC細(xì)胞也通過旁分泌信號(hào)增強(qiáng)腫瘤細(xì)胞干性.有報(bào)道MDSC細(xì)胞對(duì)肝內(nèi)膽管癌干性的增強(qiáng)并不依賴于其免疫抑制功能,而是由MDSC細(xì)胞分泌LTB4蛋白作用于癌細(xì)胞膜BLT2受體所致,干擾LTB4-BLT2通路則減弱肝內(nèi)膽管癌細(xì)胞干性、并逆轉(zhuǎn)吉西他濱耐藥

.可見,微環(huán)境免疫特征能夠影響消化系統(tǒng)腫瘤放化療敏感性,除強(qiáng)化免疫抑制功能的因素外,免疫抑制細(xì)胞與癌細(xì)胞互作所致腫瘤增殖、轉(zhuǎn)移和干性增加,也進(jìn)一步阻礙了治療效果.

3 代謝微環(huán)境參與消化系統(tǒng)腫瘤放化療抵抗的機(jī)制

“對(duì)了，你還記得小學(xué)一年級(jí)教你的那個(gè)班主任嗎？”我媽在整理完我的書桌之后，突然提到一個(gè)我一時(shí)半會(huì)兒都無(wú)法回憶起面容的人，“她今年帶完最后一個(gè)小學(xué)六年級(jí)就要退休，回家?guī)ё约旱膶O子了。”

代謝重編程是腫瘤標(biāo)志特征之一,腫瘤細(xì)胞常表現(xiàn)為葡萄糖、谷氨酰胺、脂質(zhì)、氨基酸代謝增加和乳酸累積

.正常細(xì)胞一般傾向于通過氧化磷酸化獲得能量,而癌細(xì)胞即使在有氧條件下,也以糖酵解為主要代謝途徑,即Warburg效應(yīng)

.與腫瘤細(xì)胞代謝特征相似,TME中免疫細(xì)胞亦表現(xiàn)為糖酵解水平升高,腫瘤細(xì)胞和免疫細(xì)胞糖酵解所致乳酸累積共同促進(jìn)腫瘤增殖、轉(zhuǎn)移、血管生成及免疫逃逸

.結(jié)直腸癌組織糖酵解相關(guān)基因表達(dá)與患者預(yù)后相關(guān)性分析顯示,組織水平糖酵解速率與晚期轉(zhuǎn)移性結(jié)直腸癌患者化療療效呈負(fù)相關(guān)

.已有大量研究表明,腫瘤細(xì)胞糖酵解活性增強(qiáng)參與消化系統(tǒng)腫瘤化療抵抗

.MDSC細(xì)胞在分化和激活過程中糖酵解活性增強(qiáng)

,所致乳酸累積進(jìn)一步促進(jìn)MDSC細(xì)胞浸潤(rùn)和免疫抑制功能強(qiáng)化,從而導(dǎo)致胰腺癌放療抵抗

.腫瘤糖酵解活性增強(qiáng)常伴隨谷氨酰胺分解增加,谷氨酰胺分解能夠在表觀遺傳水平調(diào)控結(jié)直腸細(xì)胞對(duì)化療藥物的敏感性

,其機(jī)制為提高腫瘤細(xì)胞DNA甲基化水平以促進(jìn)WNT信號(hào)通路活化和腫瘤干性增加.除葡萄糖和谷氨酰胺代謝,脂代謝重編程也是腫瘤細(xì)胞能量代謝失控的重要特征

.胃癌間充質(zhì)干細(xì)胞(mesenchymal stem cell,MSC)通過促進(jìn)脂肪酸氧化(fatty acid oxidation,FAO)增加胃癌細(xì)胞干性和化療抵抗

,揭示了脂代謝對(duì)腫瘤治療敏感性的調(diào)控.鐵死亡是近年來(lái)新發(fā)現(xiàn)的細(xì)胞程序性死亡方式,主要由細(xì)胞膜脂質(zhì)過氧化誘導(dǎo)

.食管鱗癌組織中Nrf2與SLC7A11表達(dá)上調(diào)與患者TNM分期及放療療效呈負(fù)相關(guān),體外實(shí)驗(yàn)進(jìn)一步證實(shí)其介導(dǎo)的放療抵抗機(jī)制與其抑制細(xì)胞鐵死亡有關(guān)

.氨基酸代謝亦影響腫瘤治療敏感性,胰腺癌細(xì)胞中長(zhǎng)鏈非編碼RNA(long noncoding RNA,lncRNA)能夠通過上調(diào)L型氨基酸轉(zhuǎn)運(yùn)蛋白(L-type amino acid transporter 2,LAT2),促進(jìn)胰腺癌對(duì)吉西他濱耐藥

.金屬離子代謝參與調(diào)控惡性腫瘤進(jìn)展是代謝微環(huán)境研究新方向,有報(bào)道細(xì)胞內(nèi)銅離子蓄積可加重肝癌放療抵抗

,而銅螯合劑可靶向銅代謝而促進(jìn)細(xì)胞鐵死亡,逆轉(zhuǎn)肝癌放療抵抗.以上證據(jù)表明,微環(huán)境糖、脂質(zhì)、氨基酸和金屬離子代謝紊亂參與腫瘤治療抵抗,代謝微環(huán)境重編程是限制消化系統(tǒng)放化療療效的關(guān)鍵因素.

4 力學(xué)微環(huán)境參與消化系統(tǒng)腫瘤放化療抵抗的機(jī)制

在消化系腫瘤中,硬度力學(xué)信號(hào)參與腫瘤放化療敏感性的研究以肝癌為主.研究表明基質(zhì)硬度增加可削弱肝癌細(xì)胞奧沙利鉑治療敏感性,可能與高基質(zhì)硬度激活integrin β1/Akt/mTOR/SOX2信號(hào)通路增強(qiáng)肝癌細(xì)胞干性有關(guān)

.也有報(bào)道顯示,基質(zhì)硬度上調(diào)integrin β1、局部粘著斑激酶(focal adhesion kinase,FAK)、ERK和STAT3等,降低肝癌細(xì)胞對(duì)順鉑敏感性

.硬度力學(xué)信號(hào)同樣可激活肝癌細(xì)胞miR-17-5p/PTEN/PI3K/Akt/MMPs通路,削弱二甲雙胍對(duì)肝癌細(xì)胞侵襲轉(zhuǎn)移的抑制作用

.機(jī)械硬度增加也可促進(jìn)EMT和Yes相關(guān)蛋白(Yes-associated protein,YAP)/轉(zhuǎn)錄共激活因子PDZ結(jié)合基序(transcriptional coactivator with PDZ-binding motif,TAZ)活化,介導(dǎo)胰腺癌對(duì)紫杉醇治療抵抗

.利用海藻酸鈉凝膠微球建立不同硬度包圍的肝癌細(xì)胞微球模型,分別用順鉑、5-氟尿嘧啶和紫杉醇處理,結(jié)果顯示高硬度環(huán)境(105 kPa)中肝癌細(xì)胞存活率明顯高于低硬度(21 kPa)和中硬度(70 kPa)環(huán)境,提示高硬度環(huán)境明顯增強(qiáng)肝癌化療耐藥,可能與硬度誘導(dǎo)的內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)有關(guān)

.將結(jié)直腸癌細(xì)胞與成纖維細(xì)胞三維共培養(yǎng)形成腫瘤球體以模擬體內(nèi)腫瘤微環(huán)境,發(fā)現(xiàn)其硬度水平較對(duì)照基底顯著升高,對(duì)5-氟尿嘧啶和瑞格菲尼的耐受性也增加

,提示力學(xué)微環(huán)境參與調(diào)控結(jié)直腸癌化療耐藥.近期,有研究從DNA損傷修復(fù)角度揭示了基質(zhì)硬度介導(dǎo)細(xì)胞放化療抵抗新機(jī)制.研究顯示

,相較于低硬度基底生長(zhǎng)的對(duì)照細(xì)胞,高硬度基底生長(zhǎng)的正常細(xì)胞和腫瘤細(xì)胞對(duì)基因毒性化療藥物和放射線抗性明顯增強(qiáng),對(duì)其機(jī)制解析發(fā)現(xiàn)基質(zhì)硬度可促進(jìn)DNA損傷因子RNF8泛素化修飾、招募BRCA1和53BP1至損傷結(jié)合位點(diǎn),而加速DNA損傷修復(fù),提示調(diào)控DNA損傷修復(fù)可能是硬度力學(xué)參與消化系統(tǒng)腫瘤放化療抵抗的關(guān)鍵因素.盡管力學(xué)微環(huán)境在腫瘤進(jìn)展中扮演的角色被逐漸重視,但其驅(qū)動(dòng)的放化療抵抗目前仍處起步階段,其相關(guān)機(jī)制的闡明尚需研究的進(jìn)一步積累.

腫瘤的發(fā)生進(jìn)展不僅伴隨微環(huán)境生化特征的改變,也影響微環(huán)境力學(xué)特征的改變,包括胞外基質(zhì)硬度增加

、機(jī)械擠壓周邊組織

及增加組織滲透壓和靜水壓

等.作為實(shí)體瘤最顯著力學(xué)特征,基質(zhì)硬度增加顯示可正向調(diào)控腫瘤生長(zhǎng)、侵襲、轉(zhuǎn)移、上皮間充質(zhì)轉(zhuǎn)化(epithelialmesenchymal transition,EMT)和干性增強(qiáng)等惡性特征

.此外,基質(zhì)硬度增加也促進(jìn)微環(huán)境內(nèi)血管新生

及免疫細(xì)胞浸潤(rùn)、極化和功能改變

.基質(zhì)硬度不僅可驅(qū)動(dòng)腫瘤發(fā)展轉(zhuǎn)移,也可削弱腫瘤放化療的敏感性

,但硬度力學(xué)信號(hào)誘導(dǎo)腫瘤放化療抵抗及相關(guān)調(diào)控機(jī)制研究目前報(bào)道十分有限.

財(cái)務(wù)報(bào)告分析指反映一個(gè)企業(yè)在一段時(shí)間內(nèi)經(jīng)營(yíng)成果并形成的書面文件，主要包括現(xiàn)金流量表、資產(chǎn)負(fù)債表、利潤(rùn)表等。一般財(cái)務(wù)報(bào)告主要為投資者以及債權(quán)人等外部使用者服務(wù)，充分展現(xiàn)企業(yè)財(cái)務(wù)整體情況。與此同時(shí)財(cái)務(wù)報(bào)告還作為總結(jié)判斷過程，用于發(fā)現(xiàn)財(cái)務(wù)報(bào)告項(xiàng)目比率、數(shù)量、重要事項(xiàng)的發(fā)生變化以及發(fā)展趨勢(shì)，為預(yù)測(cè)企業(yè)未來(lái)發(fā)展提供重要參考依據(jù)。但目前很多中小企業(yè)決策層在財(cái)務(wù)報(bào)告分析方面普遍存在不到位和不及時(shí)情況，難以發(fā)現(xiàn)管理中存在問題。例如近年來(lái)發(fā)生的銀廣夏、世通、安然等都出現(xiàn)的嚴(yán)重后果都和企業(yè)財(cái)務(wù)內(nèi)控缺乏健全和缺失有著緊密聯(lián)系，企業(yè)無(wú)法準(zhǔn)確到位分析財(cái)務(wù)報(bào)告信息，十分容易形成財(cái)務(wù)風(fēng)險(xiǎn)，影響企業(yè)安全運(yùn)營(yíng)。

5 靶向TME提高腫瘤放化療療效的新策略—調(diào)控力學(xué)微環(huán)境

越來(lái)越多的證據(jù)顯示

,將治療策略擴(kuò)展到腫瘤微環(huán)境,而不僅僅是腫瘤細(xì)胞本身,能夠?qū)崿F(xiàn)更強(qiáng)的抗腫瘤效率.已有實(shí)驗(yàn)和臨床研究證實(shí)

,改善微環(huán)境缺氧、抑制血管生成、調(diào)控腫瘤代謝和腫瘤免疫在治療腫瘤和增加放化療敏感性中意義重大,許多抗血管生成藥物和免疫藥物也已被批準(zhǔn)而廣泛應(yīng)用于臨床,在此不再贅述.而改善腫瘤力學(xué)微環(huán)境是近年提高腫瘤放化療療效的新角度,盡管研究報(bào)道有限,但其臨床應(yīng)用前景廣闊.

賴氨酰氧化酶(lysyl oxidase,LOX)和賴氨酰氧化酶樣蛋白(LOX-like,LOXL)是促微環(huán)境基質(zhì)膠原交聯(lián)、組織硬度增加的關(guān)鍵分子

,LOX家族蛋白在增強(qiáng)胃癌

、肝癌

、結(jié)直腸癌

和胰腺癌

等腫瘤惡性特征中的研究已較為深入.抑制LOX家族蛋白靶向基質(zhì)硬度在腫瘤治療領(lǐng)域也取得一定進(jìn)展.研究顯示,LOX表達(dá)增加與腫瘤化療耐藥有關(guān),小鼠胰腺癌

移植瘤模型中,LOX上調(diào)可減弱吉西他濱治療敏感性,將LOX活性抑制劑β-氨基丙腈(BAPN)與化療藥物聯(lián)用,可通過促進(jìn)藥物滲透、改善藥物分布均勻性而提高化療療效.新型小分子抑制劑如LOX/LOXL2雙重抑制劑PXS-S1A,LOXL2特異抑制劑PXS-S2A及LOXL2/LOXL3雙重抑制劑PXS-5153A,顯示可減弱腫瘤細(xì)胞增殖、遷移和血管新生能力,提示可能成為放化療增敏劑

.干擾腫瘤細(xì)胞對(duì)硬度力學(xué)信號(hào)的感知應(yīng)答是調(diào)控力學(xué)微環(huán)境的另一途徑,通過抑制integrin整合素家族、FAK、Rho相關(guān)激酶(Rho-associated kinase,ROCK)和YAP/TAZ介導(dǎo)的硬度傳導(dǎo)信號(hào)可能逆轉(zhuǎn)腫瘤耐藥

.目前一些靶向整合素的單抗藥物如單英妥木單抗(Intetumumab)、阿比妥珠單抗(Abituzumab)和小分子抑制劑如E-7820、ATN-161等已進(jìn)入臨床試驗(yàn)階段

.值得注意的是,阿比妥珠單抗聯(lián)合化療在治療轉(zhuǎn)移性結(jié)直腸癌Ⅰ期臨床試驗(yàn)中展示出良好安全性和耐受性,盡管Ⅱ期臨床試驗(yàn)結(jié)果證實(shí)其總體療效并未優(yōu)于標(biāo)準(zhǔn)化療方案,但integrin αvβ6高表達(dá)患者可明顯獲益

.提示基于integrin αvβ6表達(dá)對(duì)結(jié)直腸癌患者分層,可能使靶向整合素藥物在應(yīng)用中獲得更好的臨床效果.作為FAK抑制劑,地法替尼(Defactinib)與RAF/MEK抑制劑VS-6766聯(lián)用在RAS/RAF突變的實(shí)體瘤臨床試驗(yàn)中取得突破性進(jìn)展

.消化系腫瘤臨床前研究表明,地法替尼與紫杉醇聯(lián)用在治療胰腺癌細(xì)胞和原位胰腺癌小鼠模型中具有協(xié)同作用

,提示抑制FAK可能增加化療敏感性.法舒地爾(Fasudil)能夠改善腦血管痙攣,近期研究發(fā)現(xiàn)法舒地爾能夠抑制ROCK信號(hào)通路,并提高小鼠胰腺癌吉西他濱和白蛋白紫杉醇化療療效

.此外,通過干預(yù)細(xì)胞骨架動(dòng)力

、選擇性剪切機(jī)制

和核剛度

等來(lái)減弱硬度力學(xué)信號(hào),可能也有益于提高實(shí)體腫瘤治療療效.因此,靶向力學(xué)微環(huán)境逆轉(zhuǎn)腫瘤放化療抵抗新策略無(wú)疑為腫瘤放化療增敏臨床應(yīng)用提供新希望.

6 展望

本文從腫瘤微環(huán)境缺氧、免疫抑制、代謝異常和基質(zhì)硬度四個(gè)角度,對(duì)其參與消化系統(tǒng)腫瘤放化療抵抗及相關(guān)機(jī)制進(jìn)行了歸納總結(jié),同時(shí)對(duì)靶向力學(xué)微環(huán)境逆轉(zhuǎn)腫瘤放化療抵抗臨床前景進(jìn)行了探討,顯示基質(zhì)硬度在腫瘤進(jìn)展和放化療抵抗中的重要作用.然而,微環(huán)境力學(xué)物理特征的研究目前較為有限,尚有許多問題亟待解決,如力學(xué)信號(hào)與微環(huán)境生化信號(hào)如何協(xié)同參與放化療抵抗？不同癌種力學(xué)信號(hào)調(diào)控放化療抵抗機(jī)制是否存在共性？關(guān)鍵力學(xué)感應(yīng)分子篩查及干預(yù)對(duì)腫瘤放化療抵抗的逆轉(zhuǎn)效果？力學(xué)信號(hào)主要通過改變何種腫瘤惡性特征而影響治療療效？此外,硬度關(guān)聯(lián)體內(nèi)外理想模型的匱乏同樣制約相關(guān)機(jī)制的深入開展,隨著三維類器官模型,激光捕獲微切割,單細(xì)胞多組學(xué)測(cè)序及人工智能等前沿技術(shù)的進(jìn)展,鑒定相同癌種不同局部微環(huán)境特征,及不同癌種共性微環(huán)境特征成為可能,有望對(duì)臨床腫瘤放化療抵抗逆轉(zhuǎn)帶來(lái)突破性改變.

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