Dosch Joseph S, Ziemke Elizabeth K, Shettigar Amrith, Rehemtulla Alnawaz, Sebolt-Leopold Judith S
Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan.
Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan.
Cancer Res. 2015 Nov 1;75(21):4582-92. doi: 10.1158/0008-5472.CAN-14-2793. Epub 2015 Sep 10.
Survival rates associated with pancreatic cancer remain dismal despite advancements in detection and experimental 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 Kras(G12D)/Trp53(R172H)/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 subpopulations. 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.
尽管在检测和实验性治疗策略方面取得了进展，但胰腺癌的生存率仍然很低。基于其能够重现人类疾病的关键临床特征，包括化疗耐药性和纤维化，胰腺肿瘤发生的基因工程小鼠模型受到了广泛关注。然而，尚不清楚以Kras(G12D)/Trp53(R172H)/Pdx-1-Cre (KPC)小鼠模型为代表的转基因系统是否能重现具有不同致瘤特性细胞的人类胰腺肿瘤的功能异质性。为了便于追踪异质性肿瘤细胞群体，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系中分离出胰腺癌细胞，发现大约87个细胞中有1个具有致瘤能力。值得注意的是，这个频率明显高于人类胰腺腺癌的报道频率。癌症干细胞(CSC)标志物，包括CD133、CD24、Sca-1和功能性醛脱氢酶活性，在同基因移植中无法区分致瘤细胞和非致瘤细胞。此外，源自KPC肿瘤的三维球体培养物并未富集具有干细胞样特征的细胞，其致瘤性并不比单层培养的细胞显著更高。此外，我们在几个分离的亚群中未观察到对吉西他滨或沙利霉素反应的显著差异。综上所述，这些研究表明，在常用的胰腺癌小鼠模型中，人类疾病中癌症干细胞的层次组织并未得到重现，因此为肿瘤细胞的表型和功能异质性提供了新的视角。
