細胞特性
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細胞進行間葉細胞-上皮細胞轉化而成，同時表達上皮細胞和間葉細胞的標志，從中可分離獲得表達早期胚胎發(fā)育標志SSEA-4、Oct-4、Nanog、Sox-2及C-kit的細胞，提示卵巢OSE中存在多能干細胞。2005年首次分離鑒定了卵巢癌腫瘤干細胞：他們從進展期卵巢漿液性腺癌患者的腹水中分離得到19個能夠不斷自我更新的細胞克隆，其中2個克隆可以在懸浮培養(yǎng)體系中形成細胞球，細胞球內有上皮細胞、顆粒細胞、生殖細胞特異性表面蛋白的腫瘤細胞。這兩個克隆表達了Nestin、Oct-4、Nanog等干細胞標記，并且在小鼠體內實驗中可以形成與原發(fā)腫瘤相同的新生腫瘤。
EOCSCs的表面標記至今尚存爭議：側群細胞（side population, SP）中存在EOCSCs的富集，SP細胞較非SP細胞具有更強的增殖分化能力；卵巢癌CD133細胞亞群增殖性和克隆源性明顯強于CD133細胞亞群；CD44 CD117細胞亞群符合之前報道的所有CSCs的特性；CD44MYD88細胞亞群能夠產生細胞因子和趨化因子，修復能力強，對傳統(tǒng)的化療方案耐藥，能抵抗由TNFα介導的細胞凋亡，懸浮培養(yǎng)能夠形成細胞球，體內試驗可以形成原發(fā)腫瘤等。經對比多種標記，最近由Silva等提出ALDHCD133可以作為卵巢癌干細胞的標志。
相關研究發(fā)現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miRNAs的研究發(fā)現，EOCSCs的特點為低水平的miR-199a和miR-214，而成熟EOC細胞存在高水平的miR-199a和miR-214。且這些調控IKKβ/NF-κB和PTEN/AKT通路的miRNA由Twist1調控，并與EOCSCs的分化相關。
與腫瘤關系
EOCSCs已被證實與卵巢癌化療耐藥相關，使用含鉑類藥物化療造成了治療介導的選擇作用和耐藥性EOCSCs的富集，且CSCs的靜止為腫瘤細胞提供了保護機制，是臨床上腫瘤復發(fā)尤其是多重藥物耐藥的重要因素之一。EOCSC介導的化療耐藥可能由于特異性表達了藥物的膜轉運體。最近Ma等研究發(fā)現在含鉑類化療藥物的干細胞培養(yǎng)體系中培養(yǎng)人EOC細胞系SKOV3，獲得了成球細胞并且該細胞亞群同時具有腫瘤干細胞特性和化療耐藥特性。該細胞群具有自我更新和高成瘤能力，并且過表達Nanog、Oct-4、Sox-2及CD133等干細胞相關標記。不但對選擇過程中應用的化療藥物耐藥，對其他藥物如氨甲喋呤等亦耐藥。
擴展閱讀：
[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.
