Overexpression of Tropomysin-Related Kinase B in Metastatic Human Pancreatic Cancer Cells
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:...
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Published in | Clinical cancer research Vol. 11; no. 2; pp. 440 - 449 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
15.01.2005
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.440.11.2 |