Cancer stem cell marker phenotypes are reversible and functionally homogeneous in a preclinical model of pancreatic cancer.
Cancer stem cell marker phenotypes are reversible and functionally homogeneous in a preclinical model of pancreatic cancer.
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DOI：
10.1158/0008-5472.can-14-2793
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发表时间：
2015-11-01
期刊：
影响因子：
11.2
通讯作者：
Sebolt-Leopold JS
中科院分区：
文献类型：
--
作者：
Dosch JS;Ziemke EK;Shettigar A;Rehemtulla A;Sebolt-Leopold JS
尽管在检测和治疗策略方面取得了进展，但与胰腺癌相关的生存率仍然令人沮丧。胰腺肿瘤发生的基因工程小鼠模型基于其概括人类疾病的关键临床特征（包括化疗抗性和纤维化）的能力而获得了相当大的关注。然而，目前尚不清楚以KrasG 12 D/Trp 53 R172 H/Pdx-1-Cre（KPC）小鼠模型为例的转基因系统是否重现了人类胰腺肿瘤的功能异质性，所述人类胰腺肿瘤含有具有致瘤特性的不同细胞。为了便于追踪异质肿瘤细胞群体，我们将基于荧光素酶的标签整合到KPC小鼠模型的遗传背景中。我们从多个独立的肿瘤细胞系中分离出胰腺癌细胞，发现大约87个细胞中有1个表现出致瘤能力。值得注意的是，该频率显著高于人类胰腺癌的报告频率。癌症干细胞（CSC）标志物，包括CD 133，CD 24，Sca-1，和功能性Aldefluor活性不能区分同基因移植物中的致瘤性和非致瘤性细胞。此外，源自KPC肿瘤的三维球状体培养物并不富集具有干细胞样特征的细胞，并且与单层培养的细胞相比并没有显著更高的致瘤性。此外，我们在几个孤立的亚群中未观察到对吉西他滨或盐霉素的反应的显著差异。总之，这些研究表明，人类疾病中CSC的分层组织在常用的胰腺癌小鼠模型中没有重现，因此提供了肿瘤细胞表型和功能异质性的新观点。
Survival rates associated with pancreatic cancer remain dismal despite advancements in detection and treatment strategies. Genetically engineered mouse models of pancreatic tumorigenesis have gained considerable attention based on their ability to recapitulate key clinical features of human disease including chemotherapeutic resistance and fibrosis. However, it is unclear if transgenic systems exemplified by the KrasG12D/Trp53R172H/Pdx-1-Cre (KPC) mouse model recapitulate the functional heterogeneity of human pancreatic tumors harboring distinct cells with tumorigenic properties. To facilitate tracking of heterogeneous tumor cell populations, we incorporated a luciferase-based tag into the genetic background of the KPC mouse model. We isolated pancreatic cancer cells from multiple independent tumor lines and found that roughly 1 out of 87 cells exhibited tumorigenic capability. Notably, this frequency is significantly higher than reported for human pancreatic adenocarcinomas. Cancer stem cell (CSC) markers including CD133, CD24, Sca-1, and functional Aldefluor activity were unable to discriminate tumorigenic from nontumorigenic cells in syngeneic transplants. Furthermore, three-dimensional spheroid cultures originating from KPC tumors did not enrich for cells with stem-like characteristics, and were not significantly more tumorigenic than cells cultured as monolayers. Additionally, we did not observe significant differences in response to gemcitabine or salinomycin in several isolated sub-populations. Taken together, these studies show that the hierarchical organization of CSCs in human disease is not recapitulated in a commonly used mouse model of pancreatic cancer, and therefore provide a new view of the phenotypic and functional heterogeneity of tumor cells.