A clinically relevant model of human pancreatic adenocarcinoma identifies patterns of metastasis associated with alterations of the TGF-beta/Smad4 signaling pathway.
Genetic alterations impacting the TGF-beta/Smad4 pathway are found in nearly all pancreatic adenocarcinomas, and recent reports have identified a relationship between DPC4/Smad4 expression and patient survival. In this study we use a clinically relevant animal model of pancreatic cancer to examine the impact of these genetic changes on the biology of pancreatic cancer.


METHODS
Using high-density oligonucleotide DNA microarray technology, a comprehensive examination of the components of the TGF-beta/Smad4 pathway was performed on three human pancreatic adenocarcinoma cell lines. The in vitro and in vivo growth characteristics of these cell lines was then compared. Finally, using a clinically relevant orthotopic xenograft model of pancreatic cancer, primary tumor growth and metastases were measured for pancreatic tumors derived from each cell line.


RESULTS
Examination of the TGF-beta/Smad4 pathway components identified that these three cell lines possess molecular profiles consistent with approximately 90% of pancreatic adenocarcinoma tumors in patients. A significant discrepancy between in vitro and in vivo growth characteristics of each cell line was identified. When tumors from each cell line were established in nu/nu mice, each cell line exhibited distinct metastatic profiles. Data from these studies is consistent, with clinical observations concerning DPC4/Smad4 and patient outcome.


CONCLUSIONS
Using an orthotopic model of tumor growth and metastasis identifies distinct metastatic profiles associated with molecular alterations of the TGF-beta/Smad4 pathway and provides insight with regard to the biologic consequences of these changes.
Holloway
Shane
S
Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-9155, USA.
Davis
Mishel
M
Jaber
Raffat
R
Fleming
Jason
J
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators