Characterization of two novel cell lines with distinct heterogeneity derived from a single human bile duct carcinoma.
Characterization of two novel cell lines with distinct heterogeneity derived from a single human bile duct carcinoma.
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DOI：
10.1371/journal.pone.0054377
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Qian Q
中科院分区：
文献类型：
--
作者：
Wang J;Li L;Zhang K;Yu Y;Li B;Li J;Yan Z;Hu Z;Yen Y;Wu M;Jiang X;Qian Q
肿瘤内异质性反映了亚克隆多样性，并解释了各种临床定义的表型，包括耐药性和复发的发展。然而，胆管癌（BDC）的瘤内异质性研究很少。两个高度异质性的细胞系命名为EH-CA 1a和EH-CA 1b从病理证实的BDC的原发肿瘤组织中建立。两种细胞系在核型、集落形成、致瘤性和放化疗敏感性方面的独特异质性和潜在机制被深入研究。两种细胞系均显示出典型的癌细胞形态。EH-CA 1a细胞以自由漂浮的聚集体生长，而EH-CA 1b细胞以单层贴壁生长。EH-CA 1a细胞克隆形成率较高，在低氧条件下仍能保持增殖。巧合的是，缺氧诱导因子1α（HIF 1 α）和血管内皮生长因子（VEGF）mRNA在EH-CA 1a细胞中显著高于EH-CA 1b细胞。两种细胞系在裸鼠体内均具有致瘤性，但EH-CA 1a细胞表现出更强的侵袭性。最重要的是，EH-CA 1a细胞对吉西他滨的放疗和化疗表现出更强的抵抗力。转移相关基因，包括基质金属蛋白酶2（MMP-2），MMP-9，上皮间质转化（EMT）标志物，如波形蛋白，蜗牛，和扭曲，更高的表达在EH-CA 1a细胞比EH-CA 1b细胞。此外，在EH-CA 1a细胞中表达癌干细胞样标志物CD 133的细胞的百分比远高于EH-CA 1b细胞。此外，EH-CA 1a和EH-CA 1b细胞中CD 133的敲低显著降低了它们的侵袭潜力，并增加了它们对辐射和吉西他滨的敏感性，这表明CD 133蛋白的差异表达可能部分地解释了这两种癌细胞之间恶性程度的差异。这两种细胞系的建立不仅将揭示肿瘤内BDC的异质性，而且可能有助于开发新的BDC治疗方法。
Intratumoral heterogeneity reflects subclonal diversity and accounts for a variety of clinically defined phenotypes including the development of drug resistance and recurrence. However, intratumoral heterogeneity of bile duct carcinoma (BDC) is rarely studied. Two highly heterogeneous cell lines named EH-CA1a and EH-CA1b were established from a primary tumor tissue of a pathologically proven BDC. Distinct heterogeneity and underlying mechanisms of two cell lines in karyotype, colony formation, tumorgenicity, and sensitivity to chemoradiotherapy were intensively studied. Both cell lines showed typical morphology of cancer cells. EH-CA1a cells grew as free-floating aggregates, while EH-CA1b cells grew adherently as a monolayer. EH-CA1a cells had higher cloning efficiencies and were able to keep proliferating under hypoxic condition. Coincidentally, hypoxia-induced factor-1α (HIF1α) and vascular endothelial growth factor (VEGF) mRNA were significantly higher in EH-CA1a cells than in EH-CA1b cells. Both cell lines were tumorigenic in nude mouse, however, EH-CA1a cells showed more aggressive characteristics. Most importantly, the EH-CA1a cells showed much more resistance against radiation and chemotherapy with gemcitabine. Metastasis-related genes including matrix metalloproteinase 2 (MMP-2), MMP-9, epithelial-mesenchymal transition (EMT) markers such as Vimentin, Snail, and Twist, are more highly expressed in EH-CA1a cells than in EH-CA1b cells. Moreover, the percentage of cells expressing cancer stem cell-like marker, CD133, in EH-CA1a cells is much higher than that in EH-CA1b cells. Moreover, knockdown of CD133 in both EH-CA1a and EH-CA1b cells significantly reduced their invasive potential and increased their sensitivities to radiation and gemcitabine, suggesting the differential expression of CD133 protein may partially account for the difference in malignancy between these two cancer cells. Establishment of these two cell lines will not only shed light on intratumoral heterogeneities of BDC, but also potentially facilitate the development of novel therapeutic approaches of BDC.
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