Identification of pancreatic cancer stem cells
Identification of pancreatic cancer stem cells
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DOI：
10.1158/0008-5472.can-06-2030
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Simeone, Diane M.
中科院分区：
文献类型：
--
作者：
Li, Chenwei;Heidt, David G.;Simeone, Diane M.
新出现的证据表明，肿瘤的生长和繁殖能力依赖于肿瘤内的一小部分细胞，称为癌症干细胞。尽管在人类血液、脑和乳腺癌中已经提供了支持这一理论的数据，但胰腺癌干细胞的身份还没有确定。利用人胰腺癌在免疫缺陷小鼠体内生长的异种移植模型，我们鉴定了一个高致瘤性的胰腺癌细胞亚群，表达细胞表面标志CD44、CD24和上皮特异性抗原(ESA)。具有CD44(+)CD24(+)ESA(+)表型的胰腺癌细胞(0.2-0.8%的胰腺癌细胞)与非致瘤性癌细胞相比，其致瘤潜力增加了100倍，其中50%的动物注射了少至100个CD44(+)CD24(+)ESA(+)细胞形成的肿瘤在组织学上与其起源的人类肿瘤无法区分。在原位胰尾注射模型中，CD44(+)CD24(+)ESA(+)胰腺癌细胞成瘤能力增强。CD44(+)CD24(+)ESA(+)胰腺癌细胞表现出自我更新的干细胞特性，能够产生分化的后代，并增加发育信号分子Sonic Hedgehog的表达。胰腺癌干细胞的鉴定和调控其生长和存活的信号通路的进一步阐明可能为治疗胰腺癌提供新的治疗方法。众所周知，胰腺癌对标准化疗和放射耐药。
Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.