趙鋮龍,楊 誠(chéng) 綜述 肖建如 審校
?
黑色素瘤特異性抗原在腫瘤中的表達(dá)及其對(duì)免疫治療的作用
趙鋮龍,楊誠(chéng)綜述肖建如審校
黑色素瘤特異性抗原;腫瘤睪丸抗原;腫瘤;免疫治療
黑色素瘤特異性抗原(preferentially expressed antigen of melanoma, PRAME)是腫瘤睪丸抗原家族的一員,最初在黑色素瘤患者中被發(fā)現(xiàn),是一種能夠被細(xì)胞毒性T淋巴細(xì)胞特異性識(shí)別并引起腫瘤溶解的表面抗原[1],其表達(dá)可受調(diào)控區(qū)域的甲基化調(diào)節(jié)[2]。腫瘤睪丸抗原(cancer-testis antigens, CTAs)家族在男性性細(xì)胞及胚胎組織中保守表達(dá),并在正常組織中幾乎不表達(dá),廣泛存在于多種腫瘤組織中[3]。目前,已有大量關(guān)于CTAs的相關(guān)研究,尤其是PRAME的,認(rèn)為其與腫瘤預(yù)后相關(guān),可作為新的腫瘤標(biāo)志物監(jiān)測(cè)及評(píng)估腫瘤發(fā)生及發(fā)展,并可作為腫瘤免疫治療的靶點(diǎn)。因此,筆者對(duì)PRAME在常見(jiàn)腫瘤中的表達(dá)情況及其作用進(jìn)行綜述。
PRAME在急、慢性白血病,淋巴瘤,骨髓增生異常綜合征等多種血液系統(tǒng)腫瘤或腫瘤相關(guān)疾病中廣泛表達(dá),并引起廣泛重視。PRAME在急性髓細(xì)胞白血病(AML)中的表達(dá)率為30%~64%,而在急性粒細(xì)胞白血病(ALL)中為17%~42%,兩者表達(dá)量之間的差異有統(tǒng)計(jì)學(xué)意義;而在慢性髓細(xì)胞白血病(CML)中的表達(dá)水平為22%~60%[4, 5]。
相關(guān)研究發(fā)現(xiàn),PRAME的表達(dá)水平與腫瘤預(yù)后相關(guān),可作為預(yù)后判斷的獨(dú)立因素。Oehler 等[6]認(rèn)為,隨著CML的疾病進(jìn)展,PRAME的表達(dá)逐漸增多,并認(rèn)為晚期CML患者酪氨酸激酶抑制治療效果較差。同時(shí)發(fā)現(xiàn)PRAME在特定類(lèi)型的CML中可以抑制腫瘤細(xì)胞分化,并可作為腫瘤預(yù)后判斷的指標(biāo)及治療靶點(diǎn);Luetkens T等[7]的研究結(jié)果也表明PRAME陽(yáng)性的CML患者其總體預(yù)后較差。然而,在兒童AML患者中,PRAME高表達(dá)則提示預(yù)后較好[8];Abdelmalak等[9]在45例ALL患者中也發(fā)現(xiàn)類(lèi)似結(jié)果,認(rèn)為PRAME陽(yáng)性提示預(yù)后較好,可將PRAME用于免疫治療適應(yīng)癥的篩選,并且可作為少量殘留腫瘤的檢測(cè)指標(biāo)。
PRAME可以參與細(xì)胞周期及細(xì)胞增殖凋亡的調(diào)控過(guò)程,并在此基礎(chǔ)上進(jìn)一步影響腫瘤的發(fā)生及發(fā)展。Tanaka等[10]通過(guò)siRNA技術(shù)在CML細(xì)胞系K562中抑制PRAME的表達(dá),結(jié)果發(fā)現(xiàn)腫瘤細(xì)胞周期停滯與G0/G1期,并導(dǎo)致細(xì)胞凋亡,認(rèn)為PRAME可能是BCR-ABL相關(guān)的靶點(diǎn),調(diào)節(jié)細(xì)胞生長(zhǎng)信號(hào);筆者同時(shí)對(duì)32例急性白血病患者進(jìn)行檢測(cè)分析,結(jié)果發(fā)現(xiàn)患者疾病復(fù)發(fā)時(shí)其腫瘤細(xì)胞周期S期的比例及PRAME的表達(dá)均明顯增高。Nicolas等[11]發(fā)現(xiàn),PRAME高表達(dá)可導(dǎo)致細(xì)胞增殖率減低,基礎(chǔ)死亡率增高;而通過(guò)siRNA下調(diào)PRAME表達(dá)后的K562細(xì)胞種植于裸鼠體內(nèi),其致瘤性明顯增強(qiáng)。
PRAME在其他血液系統(tǒng)腫瘤中也有所表達(dá)。Kewitz等[12]發(fā)現(xiàn),抑制PRAME表達(dá)可增強(qiáng)霍奇金淋巴瘤對(duì)維甲酸及細(xì)胞毒性藥物的敏感性,該過(guò)程包括BCL-2在內(nèi)的多種基因參與;而PRAME基因在骨髓增生異常綜合征晚期可發(fā)生低甲基化,從而使PRAME過(guò)表達(dá),這種變化可使病情進(jìn)展,預(yù)后較差[13]。
2.1PRAME與乳腺癌可用于預(yù)后評(píng)估及病情監(jiān)測(cè)的腫瘤標(biāo)志物的相關(guān)研究一直是乳腺癌研究的熱點(diǎn)。在目前發(fā)現(xiàn)的眾多腫瘤分子標(biāo)志物中,PRAME被認(rèn)為是最為理想的標(biāo)志物之一[14, 15]。Doolan等[16]對(duì)103例乳腺癌活檢標(biāo)本進(jìn)行分析,認(rèn)為PRAME可獨(dú)立用于乳腺癌預(yù)后的判斷,PRAME高表達(dá)的患者其總體預(yù)后及無(wú)瘤生存期均較差;Epping等[17]分析PRAME與乳腺癌預(yù)后的關(guān)系,發(fā)現(xiàn)PRAME高表達(dá)的患者更易發(fā)生腫瘤轉(zhuǎn)移且總體生存期較差。
2.2PRAME與肺癌有關(guān)PRAME在肺癌中表達(dá)的相關(guān)研究較少。Bankovic等[18]對(duì)30例非小細(xì)胞肺癌患者的腫瘤及瘤旁對(duì)照標(biāo)本進(jìn)行檢測(cè)并做生存分析,其中22例檢測(cè)到PRAME表達(dá),且PRAME表達(dá)組患者的生存率及生存時(shí)間有高于非表達(dá)組患者的趨勢(shì)。該研究樣本量較小,其結(jié)果雖無(wú)明顯統(tǒng)計(jì)學(xué)意義,但仍提示PRAME在肺癌發(fā)生發(fā)展及免疫治療中的潛在意義。Babiak等[19]應(yīng)用不同類(lèi)型的腫瘤相關(guān)抗原蛋白刺激肺癌患者外周血細(xì)胞樣本并檢測(cè)其特異性細(xì)胞毒性T細(xì)胞反應(yīng)情況,結(jié)果發(fā)現(xiàn)包括PRAME在內(nèi)的多種腫瘤相關(guān)抗原可導(dǎo)致反應(yīng),證實(shí)了PRAME用于免疫治療的可行性。GSK 2302032是PRAME脂質(zhì)體試劑,目前已經(jīng)完成Ⅰ期劑量遞增臨床試驗(yàn),試驗(yàn)招募ⅠB,Ⅱ及ⅢA期PRAME陽(yáng)性的肺癌術(shù)后患者各15例以證實(shí)藥物的療效及安全性,但尚無(wú)統(tǒng)計(jì)結(jié)果報(bào)道[20]。
2.3PRAME與骨肉瘤PRAME及其他多種CTAs在骨肉瘤中的表達(dá)已被證實(shí)。Tan等[21]在多株骨肉瘤細(xì)胞系中同樣證實(shí)了PRAME的表達(dá),并證實(shí)PRAME對(duì)骨肉瘤細(xì)胞增殖及凋亡存在調(diào)控作用,下調(diào)PRAME的表達(dá)可使細(xì)胞周期停滯于G1期并促進(jìn)細(xì)胞凋亡;筆者同時(shí)對(duì)36例骨肉瘤穿刺活檢標(biāo)本進(jìn)行檢測(cè),約70%的腫瘤標(biāo)本有PRAME表達(dá),隨訪結(jié)果顯示該部分患者預(yù)后較差。在另外一項(xiàng)研究中,筆者對(duì)48例骨肉瘤患者的腫瘤標(biāo)本進(jìn)行檢測(cè),PRAME表達(dá)率為68%;筆者還在PRAME陽(yáng)性的標(biāo)本中,檢測(cè)出包括細(xì)胞增殖及凋亡相關(guān)的EAF2及CASP5在內(nèi)的40種基因過(guò)表達(dá),并認(rèn)為PRAME在腫瘤發(fā)生過(guò)程中起重要作用[22]。
2.4PRAME與頭頸部鱗狀細(xì)胞癌PRAME在頭頸部鱗狀細(xì)胞癌中的表達(dá)水平較高。Cuffel等[23]對(duì)57例原發(fā)性頭頸部鱗狀細(xì)胞癌標(biāo)本進(jìn)行檢測(cè),PRAME的陽(yáng)性率約為49%,且PRAME陽(yáng)性患者的總體生存時(shí)間更長(zhǎng)。Szczepanski等[24]通過(guò)對(duì)53例患者研究發(fā)現(xiàn)PRAME的陽(yáng)性率高達(dá)100%;進(jìn)一步的隨訪分析更揭示了PRAME與腫瘤惡性程度,大小,臨近淋巴結(jié)轉(zhuǎn)移及腫瘤整體預(yù)后明顯相關(guān)。同時(shí),PRAME在不同程度的癌前病變中也有所表達(dá)。
2.5PRAME與泌尿系統(tǒng)腫瘤PRAME在腎透明細(xì)胞癌中的陽(yáng)性率約為40%,其他CTAs在腎透明細(xì)胞癌中的表達(dá)率也較高[25, 26];以PRAME等為靶點(diǎn)的免疫治療在腎癌治療中有很好的應(yīng)用前景,相關(guān)研究結(jié)果認(rèn)為,單一靶點(diǎn)的免疫治療適應(yīng)人群在30%以上,而多靶點(diǎn)治療的適應(yīng)人群則超過(guò)40%[27]。在尿路上皮癌中表達(dá)的陽(yáng)性率為20%,其中惡性程度較低的無(wú)肌肉組織浸潤(rùn)的患者中PRAME陽(yáng)性率僅為8%;PRAME表達(dá)與腫瘤整體預(yù)后無(wú)明顯相關(guān)性,但與腫瘤大小,分期及分級(jí)相關(guān),且PRAME陽(yáng)性患者對(duì)化療敏感性較差[28]。
2.6PRAME與其他實(shí)體腫瘤PRAME在Ewing肉瘤、脂肪肉瘤、間皮瘤、視網(wǎng)膜母細(xì)胞瘤及神經(jīng)管母細(xì)胞瘤等多種間葉組織來(lái)源腫瘤中亦均有不同程度的表達(dá)[29-34],作為腫瘤靶向治療的潛在靶點(diǎn),吸引著研究人員的注意。
PRAME在白血病細(xì)胞中的作用機(jī)制可能與維甲酸受體(retinoic acid receptor, RAR)介導(dǎo)的信號(hào)通路相關(guān)[35],如維甲酸(retinoic acid, RA)通過(guò)與RAR結(jié)合可參與機(jī)體細(xì)胞增殖、分化、凋亡及椎體發(fā)育等諸多生理過(guò)程的調(diào)節(jié)[36-38]。PRAME抑制RA/RAR信號(hào)通路后,不僅能抑制腫瘤細(xì)胞分化及凋亡,促進(jìn)細(xì)胞增殖,更能夠促進(jìn)干細(xì)胞惡性變[39]。相反,若抑制PRAME表達(dá)則可恢復(fù)RA/RAR信號(hào)通路的功能,促時(shí)腫瘤細(xì)胞周期停滯,細(xì)胞凋亡[10]。PRAME可在RA存在的情況下與RAR結(jié)合,招募EZH2,共同下調(diào)腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體(tumor necrosis factor-related apoptosis-inducing ligand, TRAIL)的表達(dá),從而導(dǎo)致細(xì)胞凋亡[40]。體外實(shí)驗(yàn)證實(shí),PRAME是E3泛素連接酶的亞單位之一,可以參與NFY介導(dǎo)的基因表達(dá)的調(diào)控[10]。
PRAME的表達(dá)水平受很多因素的調(diào)節(jié),AML1-ETO及BCR-ABL可上調(diào)PRAME表達(dá),而SOX9則可抑制其表達(dá)[1, 41, 42]。與其他CTAs相類(lèi)似,PRAME在正常組織中通常處于高甲基化狀態(tài),而在腫瘤組織中處于低甲基化狀態(tài)[2, 7, 43];microRNA-211也可能參與PRAME表達(dá)的調(diào)控,在黑色素瘤細(xì)胞中,下調(diào)miR-211可能是PRAME明顯表達(dá)的因素之一[44]。
腫瘤免疫治療即利用免疫系統(tǒng)對(duì)腫瘤的殺傷作用進(jìn)行治療。免疫系統(tǒng)在腫瘤發(fā)生發(fā)展中起重要作用,相關(guān)文獻(xiàn)表明,慢性炎癥反應(yīng)可參與腫瘤發(fā)生[45, 46]。另外,免疫系統(tǒng)可識(shí)別腫瘤相關(guān)抗原,通過(guò)樹(shù)突狀細(xì)胞(dendritic cell, DC)經(jīng)交叉提呈(cross-presentation)激活T細(xì)胞產(chǎn)生抗腫瘤作用[47, 48]。然而,腫瘤細(xì)胞可通過(guò)免疫逃逸機(jī)制抑制T細(xì)胞對(duì)其的殺傷作用[49, 50]。
免疫治療可分為主動(dòng)免疫及被動(dòng)免疫,前者主要通過(guò)收集患者外周血中的自體DC,在體與相關(guān)抗原接觸反應(yīng)后回輸至患者體內(nèi),進(jìn)而刺激自體T細(xì)胞產(chǎn)生抗腫瘤活性;被動(dòng)免疫則是指將體外制備的相應(yīng)抗體直接輸入體內(nèi)進(jìn)行抗腫瘤治療。兩者各有優(yōu)缺點(diǎn),在臨床治療中根據(jù)患者病情需要進(jìn)行選擇。
PRAME最初在黑色素瘤患者中被發(fā)現(xiàn),是一種能夠被細(xì)胞毒性T淋巴細(xì)胞特異性識(shí)別并引起腫瘤溶解的表面抗原,隨后的研究發(fā)現(xiàn),PRAME可廣泛表達(dá)于多種腫瘤細(xì)胞中,而在正常組織中幾乎不表達(dá)或表達(dá)量極低,因此與其他CTAs一同被認(rèn)為是腫瘤免疫治療重要的潛在靶點(diǎn)。
關(guān)于PRAME用于主動(dòng)免疫治療的可能性已有較多研究[29-31, 51, 52],結(jié)果不盡相同。然而,需要指出的是,施行主動(dòng)免疫治療的時(shí)機(jī)非常重要。免疫治療用于控制術(shù)后殘留微小病灶及預(yù)防腫瘤復(fù)發(fā)效果優(yōu)于術(shù)前患者或不適合手術(shù)治療的患者,這可能與由腫瘤產(chǎn)生的對(duì)免疫系統(tǒng)的抑制及免疫逃逸相關(guān)[31]。另外一個(gè)不能忽略的問(wèn)題是腫瘤免疫治療的不良反應(yīng)。Saldanha-Araujo等[53]在不同組織中分離的干細(xì)胞中檢測(cè)包括PRAME在內(nèi)的CTAs表達(dá)情況,并指出在腫瘤免疫治療的同時(shí)需要考慮到其對(duì)間充質(zhì)干細(xì)胞的不良反應(yīng)。目前尚無(wú)成熟的腫瘤免疫方式,包括以PRAME為靶點(diǎn)在內(nèi)的眾多相關(guān)治療仍需進(jìn)一步研究。
綜上所述,PRAME作為腫瘤睪丸抗原家族中的一員,廣泛表達(dá)于多種惡性腫瘤細(xì)胞及癌前病變組織中,在正常組織中的表達(dá)量較少。目前,PRAME在多種腫瘤中被認(rèn)為是重要的腫瘤標(biāo)志物,可用于判斷腫瘤發(fā)生發(fā)展及其預(yù)后,并可作為病情監(jiān)測(cè),尤其是微小殘留病灶監(jiān)測(cè)的重要指標(biāo)。同時(shí)PRAME作為腫瘤免疫治療的靶點(diǎn),相關(guān)研究已取得一定進(jìn)展。然而,PRAME在腫瘤發(fā)生發(fā)展中的作用機(jī)制尚不明確,仍需進(jìn)一步研究;以其為靶點(diǎn)的免疫治療的臨床應(yīng)用亦需深入探索。
[1]van Baren N, Chambost H, Ferrant A,etal. PRAME, a gene encoding an antigen recognized on a human melanoma by cytolytic T cells, is expressed in acute leukaemia cells[J]. Br J Haematol, 1998,102(5):1376-1379.
[2]Schenk T, Stengel S, Goellner S,etal. Hypomethylation of PRAME is responsible for its aberrant overexpression in human malignancies[J]. Genes Chromosomes Cancer, 2007,46(9):796-804.
[3]Goodison S, Urquidi V. The cancer testis antigen PRAME as a biomarker for solid tumor cancer management[J]. Biomark Med, 2012,6(5):629-632.
[4]Ding K, Wang XM, Fu R,etal. PRAME Gene Expression in Acute Leukemia and Its Clinical Significance[J]. Cancer Biol Med, 2012,9(1):73-76.
[5]Zhang W, Chi K, Zhang Y,etal. Correlation between preferentially expressed antigen of melanoma and tumour necrosis factor-related apoptosis-inducing ligand gene expression in different types of leukaemia patients[J]. Acta Haematol, 2013,130(4):297-304.
[6]Oehler V G, Guthrie K A, Cummings C L,etal. The preferentially expressed antigen in melanoma (PRAME) inhibits myeloid differentiation in normal hematopoietic and leukemic progenitor cells[J]. Blood, 2009,114(15):3299-3308.
[7]Luetkens T, Schafhausen P, Uhlich F,etal. Expression, epigenetic regulation, and humoral immunogenicity of cancer-testis antigens in chronic myeloid leukemia[J]. Leuk Res, 2010,34(12):1647-1655.
[8]Steinbach D, Hermann J, Viehmann S,etal. Clinical implications of PRAME gene expression in childhood acute myeloid leukemia[J]. Cancer Genet Cytogenet, 2002,133(2):118-123.
[9]Abdelmalak C A, Yahya R S, Elghannam D M,etal. PRAME gene expression in childhood acute lymphoblastic leukemia: impact on prognosis[J]. Clin Lab, 2014,60(1):55-61.
[10]Tanaka N, Wang Y H, Shiseki M,etal. Inhibition of PRAME expression causes cell cycle arrest and apoptosis in leukemic cells[J]. Leuk Res, 2011,35(9):1219-1225.
[11]Tajeddine N, Gala JL, Louis M,etal. Tumor-associated antigen preferentially expressed antigen of melanoma (PRAME) induces caspase-independent cell death in vitro and reduces tumorigenicity in vivo[J]. Cancer Res, 2005,65(16):7348-7355.
[12]Kewitz S, Staege M S. Knock-down of PRAME increases retinoic acid signaling and cytotoxic drug sensitivity of Hodgkin lymphoma cells[J]. PLoS One, 2013,8(2):e55897.
[13]Qian J, Zhu ZH, Lin J,etal. Hypomethylation of PRAME promoter is associated with poor prognosis in myelodysplastic syndrome[J]. Br J Haematol, 2011,154(1):153-155.
[14]Sun Y, Urquidi V, Goodison S. Derivation of molecular signatures for breast cancer recurrence prediction using a two-way validation approach[J]. Breast Cancer Res Treat, 2010,119(3):593-599.
[15]Sun Y, Todorovic S, Goodison S. Local-learning-based feature selection for high-dimensional data analysis[J]. IEEE Trans Pattern Anal Mach Intell, 2010,32(9):1610-1626.
[16]Doolan P, Clynes M, Kennedy S,etal. Prevalence and prognostic and predictive relevance of PRAME in breast cancer[J]. Breast Cancer Res Treat, 2008,109(2):359-365.
[17]Epping M T, Hart A A, Glas A M,etal. PRAME expression and clinical outcome of breast cancer[J]. Br J Cancer, 2008,99(3):398-403.
[18]Bankovic J, Stojsic J, Jovanovic D,etal. Identification of genes associated with non-small-cell lung cancer promotion and progression[J]. Lung cancer (Amsterdam, Netherlands), 2010,67(2):151-159.
[19]Babiak A, Steinhauser M, Gotz M,etal. Frequent T cell responses against immunogenic targets in lung cancer patients for targeted immunotherapy[J]. Oncol Rep, 2014,31(1):384-390.
[20]De Pas T, Giovannini M, Rescigno M,etal. Vaccines in non-small cell lung cancer: rationale, combination strategies and update on clinical trials[J]. Crit Rev Oncol Hematol, 2012,83(3):432-443.
[21]Jin S, Shen J N, Guo Q C,etal. 2-D DIGE and MALDI-TOF-MS analysis of the serum proteome in human osteosarcoma[J]. Proteomics Clin Appl, 2007,1(3):272-285.
[22]Toledo S R, Zago M A, Oliveira I D,etal. Insights on PRAME and osteosarcoma by means of gene expression profiling[J]. J Orthop Sci, 2011,16(4):458-466.
[23]Cuffel C, Rivals J P, Zaugg Y,etal. Pattern and clinical significance of cancer-testis gene expression in head and neck squamous cell carcinoma[J]. Int J Cancer, 2011,128(11):2625-2634.
[24]Szczepanski M J, DeLeo A B, Luczak M,etal. PRAME expression in head and neck cancer correlates with markers of poor prognosis and might help in selecting candidates for retinoid chemoprevention in pre-malignant lesions[J]. Oral Oncol, 2013,49(2):144-151.
[25]Neumann E, Engelsberg A, Decker J,etal. Heterogeneous expression of the tumor-associated antigens RAGE-1, PRAME, and glycoprotein 75 in human renal cell carcinoma: candidates for T-cell-based immunotherapies[J]. Cancer Res, 1998,58(18):4090-4095.
[26]Dannenmann S R, Hermanns T, Bransi A,etal. Spontaneous peripheral T-cell responses toward the tumor-associated antigen cyclin D1 in patients with clear cell renal cell carcinoma[J]. Cancer Immunol Res, 2013,1(5):288-295.
[27]Ringhoffer M, Muller C R, Schenk A,etal. Simultaneous expression of T-cell activating antigens in renal cell carcinoma: implications for specific immunotherapy[J]. J Urol, 2004,171(6 Pt 1):2456-2460.
[28]Dyrskjot L, Zieger K, Kissow L T,etal. Expression of MAGE-A3, NY-ESO-1, LAGE-1 and PRAME in urothelial carcinoma[J]. Br J Cancer, 2012,107(1):116-122.
[29]Altvater B, Kailayangiri S, Theimann N,etal. Common Ewing sarcoma-associated antigens fail to induce natural T cell responses in both patients and healthy individuals[J].Cancer Immunol Immunother, 2014,63(10):1047-1060.
[30]Mahlendorf D E, Staege M S. Characterization of Ewing sarcoma associated cancer/testis antigens[J]. Cancer Biol Ther, 2013,14(3):254-261.
[31]Hemminger J A, Toland A E, 0000000202711792 A O,etal. Expression of cancer-testis antigens MAGEA1, MAGEA3, ACRBP, PRAME, SSX2, and CTAG2 in myxoid and round cell liposarcoma[J]. Mod Pathol, 2014,27(9):1238-1245.
[32]Brenne K, Nymoen D A, Reich R,etal. PRAME (preferentially expressed antigen of melanoma) is a novel marker for differentiating serous carcinoma from malignant mesothelioma[J]. Am J Clin Pathol, 2012,137(2):240-247.
[33]Nalini V, Segu R, Deepa P R,etal. Molecular Insights on Post-chemotherapy Retinoblastoma by Microarray Gene Expression Analysis[J]. Bioinform Biol Insights, 2013,7:289-306.
[34]Vulcani-Freitas T M, Saba-Silva N, Cappellano A,etal. PRAME gene expression profile in medulloblastoma[J]. Arq Neuropsiquiatr, 2011,69(1):9-12.
[35]Epping M T, Wang L, Edel M J,etal. The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling[J]. Cell, 2005,122(6):835-847.
[36]Gudas L J, Wagner JA. Retinoids regulate stem cell differentiation[J]. J Cell Physiol, 2011,226(2):322-330.
[37]Dolle P. Developmental expression of retinoic acid receptors (RARs) [J]. Nucl Recept Signal, 2009,7:e006.
[38]Mark M, Ghyselinck N B, Chambon P. Function of retinoic acid receptors during embryonic development[J]. Nucl Recept Signal, 2009,7:e002.
[39]Argiris A, Lee SC, Feinstein T,etal. Serum biomarkers as potential predictors of antitumor activity of cetuximab-containing therapy for locally advanced head and neck cancer[J]. Oral Oncol, 2011,47(10):961-966.
[40]De Carvalho D D, Mello B P, Pereira W O,etal. PRAME/EZH2-mediated regulation of TRAIL: a new target for cancer therapy[J]. Curr Mol Med, 2013,13(2):296-304.
[41]Steinbach D, Viehmann S, Zintl F,etal. PRAME gene expression in childhood acute lymphoblastic leukemia[J]. Cancer Genet Cytogenet, 2002,138(1):89-91.
[42]Passeron T, Valencia J C, Namiki T,etal. Upregulation of SOX9 inhibits the growth of human and mouse melanomas and restores their sensitivity to retinoic acid[J]. J Clin Invest, 2009,119(4):954-963.
[43]Ortmann C A, Eisele L, Nuckel H,etal. Aberrant hypomethylation of the cancer-testis antigen PRAME correlates with PRAME expression in acute myeloid leukemia[J]. Ann Hematol, 2008,87(10):809-818.
[44]Sakurai E, Maesawa C, Shibazaki M,etal. Downregulation of microRNA-211 is involved in expression of preferentially expressed antigen of melanoma in melanoma cells[J]. Int J Oncol, 2011,39(3):665-672.
[45]Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer[J]. Cell, 2006,124(4):823-835.
[46]Balkwill F, Charles K A, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease[J]. Cancer Cell, 2005,7(3):211-217.
[47]Ueno H, Klechevsky E, Morita R,etal. Dendritic cell subsets in health and disease[J]. Immunol Rev, 2007,219:118-142.
[48]Groothuis T A, Neefjes J. The many roads to cross-presentation[J]. J Exp Med, 2005,202(10):1313-1318.
[49]Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors[J].Adv Immunol, 2006,90:51-81.
[50]Campoli M, Ferrone S, Zea A H,etal. Mechanisms of tumor evasion[J].Cancer Treat Res, 2005,123:61-88.
[51]Yao J, Caballero O L, Yung W K,etal. Tumor subtype-specific cancer-testis antigens as potential biomarkers and immunotherapeutic targets for cancers[J]. Cancer Immunol Res, 2014,2(4):371-379.
[52]Beard R E, Abate-Daga D, Rosati S F,etal. Gene expression profiling using nanostring digital RNA counting to identify potential target antigens for melanoma immunotherapy[J].Clin Cancer Res, 2013,19(18):4941-4950.
[53]Saldanha-Araujo F, Haddad R, Zanette D L,etal. Cancer/Testis antigen expression on mesenchymal stem cells isolated from different tissues[J]. Anticancer Res, 2010,30(12):5023-5027.
(2015-03-10收稿2015-09-18修回)
(責(zé)任編輯岳建華)
趙鋮龍,博士研究生,醫(yī)師。
200003,上海長(zhǎng)征醫(yī)院骨腫瘤科
肖建如,E-mail:jianruxiao83@163.com
R730.5