Different capabilities of morphological pattern formation and its association with the expression of differentiation markers in a xenograft model of human pancreatic cancer cell lines.
OBJECTIVE
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Neureiter
Daniel
D
Department of Pathology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany. d.neureiter@salk.at
Zopf
Steffen
S
Dimmler
Arno
A
Stintzing
Sebastian
S
Hahn
Eckhart G
EG
Kirchner
Thomas
T
Herold
Christoph
C
Ocker
Matthias
M
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D017931:DNA Primers; D012333:RNA, Messenger; D012334:RNA, Neoplasm