Faculty Collaboration Database

Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells. Clin Cancer Res 2005 Jan 15;11(2 Pt 1):440-9

Date

02/11/2005

Pubmed ID

15701826

Scopus ID

2-s2.0-19944429463 (requires institutional sign-in at Scopus site)   120 Citations

Abstract

PURPOSE: Pancreatic adenocarcinoma is currently the fourth leading cause of cancer death in the United States, and most pancreatic cancers develop locally advanced disease or metastasis at the time of diagnosis. The mechanisms by which it invades and metastasizes are not known.

EXPERIMENTAL DESIGN: To identify the genes involved in pancreatic cancer metastasis, we analyzed the gene expression profiles between highly metastatic Colo357L3.6pl and parental Colo357FG pancreatic cancer cell lines using cDNA microarrays and confirmed differential gene expression by reverse transcription-PCR, Western blotting, and immunologic analysis of 54 samples from pancreatic cancer patients. The correlation with clinical outcome was also examined. The possible signaling pathways involved with tropomyosin-related kinase B (TrkB) were analyzed.

RESULTS: Our findings showed that TrkB was overexpressed in the highly metastatic Colo357L3.6pl cells, which correlated with perineural invasion (P = 0.026), positive retroperitoneal margin (P = 0.0005), and shorter latency to development of liver metastasis (Cox proportional hazard ratio, 0.3; 95% confidence interval, 0.1-0.8; P = 0.01) in patient samples. Extracellular signal-regulated kinases 1 and 2 were activated and Elk-1 and AP-1 DNA binding activity was induced in Colo357L3.6pl cells. Furthermore, interleukin 8 and vascular endothelial growth factor were more strongly expressed in Colo357L3.6pl than Colo357FG cells, and these findings were confirmed in Colo357L3.6pl and Colo357FG orthotopic tumors.

CONCLUSION: These results suggest that overexpression of TrkB and activation of mitogen-activated protein kinase and AP-1, which may in turn induce the expression of vascular endothelial growth factor and interleukin 8, may mediate the cardinal clinical features of locally aggressive growth and metastasis of pancreatic cancer. Our results also imply that TrkB receptor may be a novel therapeutic target for pancreatic cancer.

Author List

Sclabas GM, Fujioka S, Schmidt C, Li Z, Frederick WA, Yang W, Yokoi K, Evans DB, Abbruzzese JL, Hess KR, Zhang W, Fidler IJ, Chiao PJ

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Aged
Animals
DNA-Binding Proteins
Electrophoretic Mobility Shift Assay
Enzyme Activation
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Interleukin-8
Lung Neoplasms
Lymphatic Metastasis
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinases
Neoplasm Invasiveness
Oligonucleotide Array Sequence Analysis
Pancreatic Neoplasms
Protein Kinases
Proto-Oncogene Proteins
Receptor, trkB
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factor AP-1
Transcription Factors
Tumor Cells, Cultured
Vascular Endothelial Growth Factor A
ets-Domain Protein Elk-1