細(xì)胞特性
上皮性卵巢癌發(fā)生于卵巢表面上皮(ovarian surface epithelium, OSE)。OSE由位于卵巢白膜的間充質(zhì)細(xì)胞進(jìn)行間葉細(xì)胞-上皮細(xì)胞轉(zhuǎn)化而成，同時(shí)表達(dá)上皮細(xì)胞和間葉細(xì)胞的標(biāo)志，從中可分離獲得表達(dá)早期胚胎發(fā)育標(biāo)志SSEA-4、Oct-4、Nanog、Sox-2及C-kit的細(xì)胞，提示卵巢OSE中存在多能干細(xì)胞。2005年首次分離鑒定了卵巢癌腫瘤干細(xì)胞：他們從進(jìn)展期卵巢漿液性腺癌患者的腹水中分離得到19個(gè)能夠不斷自我更新的細(xì)胞克隆，其中2個(gè)克隆可以在懸浮培養(yǎng)體系中形成細(xì)胞球，細(xì)胞球內(nèi)有上皮細(xì)胞、顆粒細(xì)胞、生殖細(xì)胞特異性表面蛋白的腫瘤細(xì)胞。這兩個(gè)克隆表達(dá)了Nestin、Oct-4、Nanog等干細(xì)胞標(biāo)記，并且在小鼠體內(nèi)實(shí)驗(yàn)中可以形成與原發(fā)腫瘤相同的新生腫瘤。
EOCSCs的表面標(biāo)記至今尚存爭(zhēng)議：側(cè)群細(xì)胞（side population, SP）中存在EOCSCs的富集，SP細(xì)胞較非SP細(xì)胞具有更強(qiáng)的增殖分化能力；卵巢癌CD133細(xì)胞亞群增殖性和克隆源性明顯強(qiáng)于CD133細(xì)胞亞群；CD44 CD117細(xì)胞亞群符合之前報(bào)道的所有CSCs的特性；CD44MYD88細(xì)胞亞群能夠產(chǎn)生細(xì)胞因子和趨化因子，修復(fù)能力強(qiáng)，對(duì)傳統(tǒng)的化療方案耐藥，能抵抗由TNFα介導(dǎo)的細(xì)胞凋亡，懸浮培養(yǎng)能夠形成細(xì)胞球，體內(nèi)試驗(yàn)可以形成原發(fā)腫瘤等。經(jīng)對(duì)比多種標(biāo)記，最近由Silva等提出ALDHCD133可以作為卵巢癌干細(xì)胞的標(biāo)志。
相關(guān)研究發(fā)現(xiàn)Wnt/β-Catenin通路、Hedhog通路、Notch通路、PTEN/AKT通路等可能參與了EOCSCs及卵巢癌的發(fā)生發(fā)展。對(duì)miRNAs的研究發(fā)現(xiàn)，EOCSCs的特點(diǎn)為低水平的miR-199a和miR-214，而成熟EOC細(xì)胞存在高水平的miR-199a和miR-214。且這些調(diào)控IKKβ/NF-κB和PTEN/AKT通路的miRNA由Twist1調(diào)控，并與EOCSCs的分化相關(guān)。
與腫瘤關(guān)系
EOCSCs已被證實(shí)與卵巢癌化療耐藥相關(guān)，使用含鉑類藥物化療造成了治療介導(dǎo)的選擇作用和耐藥性EOCSCs的富集，且CSCs的靜止為腫瘤細(xì)胞提供了保護(hù)機(jī)制，是臨床上腫瘤復(fù)發(fā)尤其是多重藥物耐藥的重要因素之一。EOCSC介導(dǎo)的化療耐藥可能由于特異性表達(dá)了藥物的膜轉(zhuǎn)運(yùn)體。最近Ma等研究發(fā)現(xiàn)在含鉑類化療藥物的干細(xì)胞培養(yǎng)體系中培養(yǎng)人EOC細(xì)胞系SKOV3，獲得了成球細(xì)胞并且該細(xì)胞亞群同時(shí)具有腫瘤干細(xì)胞特性和化療耐藥特性。該細(xì)胞群具有自我更新和高成瘤能力，并且過表達(dá)Nanog、Oct-4、Sox-2及CD133等干細(xì)胞相關(guān)標(biāo)記。不但對(duì)選擇過程中應(yīng)用的化療藥物耐藥，對(duì)其他藥物如氨甲喋呤等亦耐藥。
擴(kuò)展閱讀：
[1]Mimeault M, Batra SK. Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies [ J ]. Stem Cells, 2006, 24 (11) : 231922345.
[3]Viran, Zech N, Rozman P, et al. Putative stem cells with an embryonic character isolated from the ovarian surface ep ithelium of women with no naturally present follicles and oocytes [ J ]. Differentiation, 2008, 76 (8) : 8432856.
[4]Bapat SA, Mali AM, Koppikar CB, et al. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res,2005,65:3025-3029.
[5]Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness. PNAS. 2006,103,11154–11159.
[6]Ferrandina G, Bonanno G, Pierelli L, et al. Expression of CD133.1 and CD133.2 in ovarian cancer. Int J Gynecol Cancer, 2008,18:506-514.
[7]Zhang S, Balch C, Chan MW, et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res,2008, 68:4311-4320.
[8]Alvero AB, Chen R, Fu HH, et al. Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle, 2009, 8:158–166.
[9]Silva IA, Bai S, McLean K, et al. Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res. 2011 Jun 1;71(11):3991-4001.
[10]Irena Conic, Irena Dimov, Desanka Tasic-Dimov, et al. Ovarian Epithelial Cancer Stem Cells. The Scientific World JOURNAL,2011,11: 1243–1269.
[11]Yin, G., Chen, R., Alvero, A.B., et al. TWISTing stemness, inflammation and proliferation of epithelial ovarian cancer cells through MIR199A2/214. Oncogene, 2010,29:3545–3553.
[12]Ma, L., Lai, D., Liu, T., et al. Cancer stem-like cells can be isolated with drug selection in human ovarian cancer cell line SKOV3. Acta Biochim. Biophys. Sin. 2010,42: 593–602.
