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Overexpression of Tropomysin-Related Kinase B in Metastatic Human Pancreatic Cancer Cells

Departments of ¹ Surgical Oncology, ² Cancer Biology, ³ Gastrointestinal Medical Oncology, ⁴ Pathology, ⁵ Biostatistics, and ⁶ Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center and ⁷ The Program in Cancer Biology, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas

Requests for reprints: Paul J. Chiao, Departments of Surgical Oncology and Molecular and Cellular Oncology, Box 107, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1030; Fax: 713-794-4830; E-mail: pjchiao{at}mdanderson.org.

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.

Key Words: pancreatic cancer • metastasis • tropomysin-related kinase B • vascular endothelial growth factor • interleukin 8

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