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Ligand activation of alternatively spliced fibroblast growth factor receptor-1 modulates pancreatic adenocarcinoma cell malignancy

  • Published:
Journal of Gastrointestinal Surgery

Abstract

Pancreatic adenocarcinoma continues to be a devastating tumor (28,000 new cases per year in the United States; 10% 2-year survival). Pancreatic adenocarcinoma frequently (90% of the time) overexpresses fibroblast growth factor ligands (FGF-1 and FGF-2) and alternatively spliced high-affinity receptors (FGFR-lß) (FGFR-lct was previously found in normal pancreatic tissue). To study the significance of this observation in vitro, PANC-1 cells were stably transfected via the pMEXneo vector containing FGFR-la (PANC-la) or FGFR-lß (PANC-lß) isoforms. Cells were treated with 1 mg/ml of 5-fluorouracil. Cells were evaluated for growth inhibition, apoptosis (propidium iodide staining and flow cytometry, caspase 3 activation) and for Bcl-xL/BAX expression (by Western blot analysis). In vivo, 7 X 106 cells of each isoform were injected into nude Balb/c mice for xenograft formation (N = 10). Compared to PANC-lß (9%) in vitro, 5-fluorouracil-induced death was significantly (P < 0.05) increased in PANC-la (20%) at 24 hours. Increased cell death in PANC-la was mediated by activated caspase 3 and was correlated with decreased expression of Bcl-xL/BAX. In vivo, PANC-lß readily demonstrated formation of tumor xenograft at 2 weeks, whereas PANC-la did not form tumors. Alternative splicing of FGFR-1 to the ß isoform appears to correlate with pancreatic adenocarcinoma cell growth in vivo and resistance to chemotherapy. Inhibition of FGFR-1 splicing or overexpression of FGFR-la inhibits pancreatic adenocarcinoma cell growth in vivo and restores cytotoxic responses to chemotherapy, thereby suggesting the basis of rational interventional strategies for this devastating tumor.

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Authors and Affiliations

  1. Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama

    Selwyn M. Vickers M.D., Zhi-Qiang Huang M.D., LeeAnn MacMillan-Crow Ph.D., Jessica S. Greendorfer Ph.D. & John A. Thompson Ph.D.

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  1. Selwyn M. Vickers M.D.
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  2. Zhi-Qiang Huang M.D.
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Correspondence to Selwyn M. Vickers M.D..

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Supported by grants RWJ 66390, NIH DK51629, and HL45990.

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Vickers, S.M., Huang, ZQ., MacMillan-Crow, L. et al. Ligand activation of alternatively spliced fibroblast growth factor receptor-1 modulates pancreatic adenocarcinoma cell malignancy. J Gastrointest Surg 6, 546–553 (2002). https://doi.org/10.1016/S1091-255X(02)00036-7

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  • DOI: https://doi.org/10.1016/S1091-255X(02)00036-7

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