Neureiter Daniel, Zopf Steffen, Dimmler Arno, Stintzing Sebastian, Hahn Eckhart G, Kirchner Thomas, Herold Christoph, Ocker Matthias
Department of Pathology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Pancreatology. 2005;5(4-5):387-97. doi: 10.1159/000086539. Epub 2005 Jun 23.
New concepts of tumorigenesis favor an unregulated process recapitulating different stages of embryogenic development with dysregulation of transition states. The aim of our study was to investigate the possibility of differentiation pathways of human pancreatic cancer cell lines in vivo.
Different human pancreatic cancer cell lines (YAPC, DAN-G, CAPAN-1, PANC-1 and MIA PaCa-2) were implanted subcutaneously (3 x 10(6) cells) for 28 days in nude mice. Xenotransplants were characterized with histochemistry (HE, PAS), immunohistochemistry (cytokeratin (CK)7, CK8, CK18, CK19, CK20, vimentin, chromogranin A (Chr-A), alpha1-antichymotrypsin (alpha1-chym), beta-catenin, laminin-5, pancreatic and duodenal homeobox gene 1 (pdx-1), sonic hedgehog protein (shh), Patched (ptc)), Western blotting and real-time PCR (CK7, CK8, CK20, Chr-A, pdx-1, shh, ptc).
Depending on three major morphologic phenotypes of tumor cell xenotransplants (ductal (YAPC), ductal/solid (DAN-G, CAPAN-1), solid (PANC-1, MIA PaCa-2)), a decrease of CK7/CK19 was found, accompanied by an increase of CK8/18 and vimentin. Predominantly the CK7-positive ductal phenotype (YAPC and DAN-G) was associated with pdx-1 expression, whereas the CK8-positive solid phenotype was associated with shh/ptc expression on protein and mRNA level. Additionally, CK-20 expression was mainly linked to the ductal phenotype, co-localized with nuclear beta-catenin. The endocrine-exocrine transdifferentiation, as assessed by Chr-A and alpha1-chym, was on a constant low to moderate level in all xenotransplants. Finally, an intensive epithelial-mesenchymal interaction was observed by overexpression of laminin-5 at the invasion front.
The observed patterns of morphology and molecular differentiation in human pancreatic cancer xenografts indicate that these cancer cell lines have different capabilities of pattern formation in vivo associated with molecular differentiation markers, especially of embryonic pancreatic development.
肿瘤发生的新概念倾向于一种不受调控的过程，该过程重现胚胎发育的不同阶段，同时伴有过渡状态的失调。我们研究的目的是探讨人胰腺癌细胞系在体内分化途径的可能性。
将不同的人胰腺癌细胞系（YAPC、DAN - G、CAPAN - 1、PANC - 1和MIA PaCa - 2）皮下接种（3×10⁶个细胞）于裸鼠体内，持续28天。通过组织化学（苏木精 - 伊红染色、过碘酸 - 雪夫染色）、免疫组织化学（细胞角蛋白（CK）7、CK8、CK18、CK19、CK20、波形蛋白、嗜铬粒蛋白A（Chr - A）、α1 - 抗胰凝乳蛋白酶（α1 - chym）、β - 连环蛋白、层粘连蛋白 - 5、胰腺和十二指肠同源盒基因1（pdx - 1）、音猬因子蛋白（shh）、patched（ptc））、蛋白质印迹法和实时聚合酶链反应（CK7、CK8、CK20、Chr - A、pdx - 1、shh、ptc）对异种移植瘤进行特征分析。
根据肿瘤细胞异种移植瘤的三种主要形态学表型（导管型（YAPC）、导管/实体型（DAN - G、CAPAN - 1）、实体型（PANC - 1、MIA PaCa - 2）），发现CK7/CK19减少，同时CK8/18和波形蛋白增加。主要是CK7阳性的导管型表型（YAPC和DAN - G）与pdx - 1表达相关，而CK8阳性的实体型表型在蛋白质和mRNA水平上与shh/ptc表达相关。此外，CK - 20表达主要与导管型表型相关，与核β - 连环蛋白共定位。通过Chr - A和α1 - chym评估的内分泌 - 外分泌转分化在所有异种移植瘤中处于持续的低到中等水平。最后，在侵袭前沿观察到层粘连蛋白 - 5的过表达导致强烈的上皮 - 间质相互作用。
在人胰腺癌异种移植瘤中观察到的形态和分子分化模式表明，这些癌细胞系在体内具有与分子分化标志物相关的不同模式形成能力，尤其是胚胎胰腺发育相关的标志物。
