Consensus transcriptome signature of perineural invasion in pancreatic carcinoma

被引:82
作者
Abiatari, Ivane [1 ]
DeOliveira, Tiago [1 ]
Kerkadze, Vachtang [3 ]
Schwager, Christian [5 ]
Esposito, Irene [2 ,6 ]
Giese, Nathalia A. [3 ]
Huber, Peter [5 ,7 ]
Bergman, Frank [4 ]
Abdollahi, Amir [5 ,7 ,8 ,9 ]
Friess, Helmut [1 ]
Kleeff, Joerg [1 ,7 ]
机构
[1] Tech Univ Munich, Dept Gen Surg, D-81675 Munich, Germany
[2] Tech Univ Munich, Inst Pathol, D-81675 Munich, Germany
[3] Univ Heidelberg, Dept Gen Surg, D-6900 Heidelberg, Germany
[4] Univ Heidelberg, Dept Pathol, D-6900 Heidelberg, Germany
[5] German Canc Res Ctr, Dept Radiat Oncol, D-6900 Heidelberg, Germany
[6] Helmholtz Zentrum Munchen, Inst Pathol, Oberschleissheim, Germany
[7] Tufts Univ, Caritas St Elizabeths Med Ctr, Ctr Canc Syst Biol, Dept Med,Sch Med, Medford, MA 02155 USA
[8] Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA
[9] Harvard Univ, Sch Med, Dept Surg, Karp Family Res Labs, Boston, MA 02115 USA
关键词
MESSENGER-RNA EXPRESSION; CANCER-CELLS; DUCTAL ADENOCARCINOMA; PLEXUS INVASION; BREAST-CANCER; KIF14; SURVIVAL; CYTOKINESIS; RESECTION; GROWTH;
D O I
10.1158/1535-7163.MCT-08-0755
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Perineural invasion, the growth of tumor cells along nerves, is a key feature of pancreatic cancer. The cardinal symptom of pancreatic cancer, abdominal pain often radiating to the back, as well as the high frequency of local tumor recurrence following resection are both attributed to the unique ability of pancreatic tumor cells to invade the neuronal system. The molecular mechanisms underlying the neuroaffinity of pancreatic tumors are not completely understood. In this study, we developed a novel method to monitor ex vivo perineural invasion into surgically resected rat vagal nerves by different human pancreatic tumor cell lines. Genome-wide transcriptional analyses were employed to identify the consensus set of genes differentially regulated in all highly nerve-invasive (nerve invasion passage 3) versus less invasive (nerve invasion passage 0) pancreatic tumor cells. The critical involvement of kinesin family member 14 (KIF14) and Rho-GDP dissociation inhibitor beta (ARHGDI beta) in perineural invasion was confirmed on RNA and protein levels in human pancreatic tumor specimens. We found significant up-regulation of KIF14 and ARHGDI beta mRNA levels in patients with pancreatic cancer, and both proteins were differentially expressed in tumor cells invading the perineural niche of pancreatic cancer patients as detected by immunohistochemistry. Moreover, functional knockdown of KIF14 and ARHGDI beta using small interfering RNA resulted in altered basal and/or perineural invasion of pancreatic tumor cells. Our work provides novel insights into the molecular determinants of perineural invasion in pancreatic cancer. The established nerve invasion model and the consensus signature of perineural invasion could be instrumental in the identification of novel therapeutic targets of pancreatic cancer as exemplified by KIF14 and ARHGDI beta. [Mol Cancer Ther 2009;8(6):1494-504]
引用
收藏
页码:1494 / 1504
页数:11
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