Calle Anna Sanchez, Nair Neha, Oo Aung KoKo, Prieto-Vila Marta, Koga Megumi, Khayrani Apriliana Cahya, Hussein Maram, Hurley Laura, Vaidyanath Arun, Seno Akimasa, Iwasaki Yoshiaki, Calle Malu, Kasai Tomonari, Seno Masaharu
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
Department of Chemistry, Faculty of Science, Menoufia University Shebin El-Koam 32511, Egypt.
Am J Cancer Res. 2016 Dec 1;6(12):2799-2815. eCollection 2016.
Pancreatic ductal adenocarcinoma (PDAC) is the most representative form of pancreatic cancers. PDAC solid tumours are constituted of heterogeneous populations of cells including cancer stem cells (CSCs), differentiated cancer cells, desmoplastic stroma and immune cells. The identification and consequent isolation of pancreatic CSCs facilitated the generation of genetically engineered murine models. Nonetheless, the current models may not be representative for the spontaneous tumour occurrence. In the present study, we show the generation of a novel pancreatic iPSC-converted cancer stem cell lines (CSCcm) as a cutting-edge model for the study of PDAC. The CSCcm lines were achieved only by the influence of pancreatic cancer cell lines conditioned medium and were not subjected to any genetic manipulation. The xenografts tumours from CSCcm lines displayed histopathological features of ADM, PanIN and PDAC lesions. Further molecular characterization from RNA-sequencing analysis highlighted primary culture cell lines (1 CSCcm) as potential candidates to represent the pancreatic CSCs and indicated the establishment of the pancreatic cancer molecular pattern in their subsequent progenies 2 CSCcm and 3 CSCcm. In addition, preliminary RNA-seq SNPs analysis showed that the distinct CSCcm lines did not harbour single point mutations for the oncogene Kras codon 12 or 13. Therefore, PDAC-CSCcm model may provide new insights about the actual occurrence of the pancreatic cancer leading to develop different approaches to target CSCs and abrogate the progression of this fatidic disease.
胰腺导管腺癌（PDAC）是胰腺癌最具代表性的形式。PDAC实体瘤由包括癌症干细胞（CSCs）、分化癌细胞、促纤维增生性基质和免疫细胞在内的异质细胞群体组成。胰腺CSCs的鉴定及随后的分离促进了基因工程小鼠模型的产生。尽管如此，目前的模型可能无法代表自发性肿瘤的发生情况。在本研究中，我们展示了一种新型胰腺诱导多能干细胞转化的癌症干细胞系（CSCcm）的产生，作为研究PDAC的前沿模型。CSCcm系仅通过胰腺癌细胞系条件培养基的影响而获得，未进行任何基因操作。来自CSCcm系的异种移植肿瘤表现出腺泡内上皮黏液性化生（ADM）、胰腺上皮内瘤变（PanIN）和PDAC病变的组织病理学特征。RNA测序分析的进一步分子特征突出了原代培养细胞系（1 CSCcm）作为代表胰腺CSCs的潜在候选者，并表明在其后续子代2 CSCcm和3 CSCcm中建立了胰腺癌分子模式。此外，初步的RNA-seq单核苷酸多态性（SNP）分析表明，不同的CSCcm系在癌基因Kras密码子12或13处没有单点突变。因此，PDAC-CSCcm模型可能为胰腺癌的实际发生提供新的见解，从而开发出针对CSCs的不同方法并消除这种致命疾病的进展。
