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KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model

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Abstract

Identifying molecular targets for treatment of pancreatic cancer metastasis is critical due to the high frequency of dissemination prior to diagnosis of this lethal disease. Because the KISS1 metastasis suppressor is expressed at reduced levels in advanced pancreatic cancer, we hypothesized that re-expression of KISS1 would reduce metastases. Highly metastatic S2VP10 cells expressing luciferase (S2VP10L) were transfected with a FLAG-tagged version of KISS1 (KFM), KFMΔSS (with deleted secretion signal sequence), or pcDNA3 control plasmid (CP) and expression was confirmed by RTQ-PCR. SCID mice were implanted orthotopically with S2VP10L cells or transfectants and tumor growth and metastases were monitored using bioluminescence imaging. Mice with S2VP10L-KISS1 tumors developed fewer liver (98%) and lung (99%) metastases than S2VP10L. Unexpectedly, mice with S2VP10L-KFMΔSS tumors also had reduced liver and lung metastases, but had more metastases than mice with S2VP10L-KISS. KISS1 protein was found in the cytoplasm of both KFMΔSS and KISS1-expressing orthotopic tumors by immunohistochemistry. Metastases were not found in lungs of mice with S2VP10L-KISS1 tumors; whereas, KFMΔSS lung sections had regions of concentrated KISS1 staining, suggesting that secretion of KISS1 is needed to reduce metastasis significantly. These data suggest induction of KISS1 expression has potential as an adjuvant treatment for pancreatic cancer.

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Acknowledgments

This study funded by the NIH Spore in Pancreatic Cancer P20CA101955 (DJB), NIH-1K99CA139050 (LRM), NIH-CA134981 (DRW) and CA87728 (DRW), and National Foundation for Cancer Research Center for Metastasis Research (DRW). This study was supported by UAB’s Small Animal Imaging Shared Facility (P30CA013148), Mass Spectrometry and Proteomics Shared Facilities, and Tissue Characterization and Immunoreagent Resource. We would also like to thank S. Lagan for assistance in manuscript preparation.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Alabama at Birmingham, 1825 University Blvd, Shelby 701, Birmingham, AL, 35294-2182, USA

    Lacey R. McNally, Jeffery C. Sellers, Zhi Q. Huang & Donald J. Buchsbaum

  2. Department of Pathology, University of Alabama at Birmingham, 1670 University Blvd. VH-G019, Birmingham, AL, 35294-0019, USA

    Danny R. Welch, Benjamin H. Beck, Lewis J. Stafford, William E. Grizzle, Cecil R. Stockard, Kevin T. Nash & Donald J. Buchsbaum

  3. Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch

  4. Department of Pharmacology & Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch & Donald J. Buchsbaum

  5. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Joshua W. Long & Donald J. Buchsbaum

  6. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Donald J. Buchsbaum

  7. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch, William E. Grizzle & Donald J. Buchsbaum

  8. Center for Aging, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    William E. Grizzle

  9. Metabolic Bone Disease Research Center, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch & William E. Grizzle

  10. Gene Therapy Center, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch & Donald J. Buchsbaum

  11. National Foundation for Cancer Research-Center for Metastasis Research, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch

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  1. Lacey R. McNally
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  2. Danny R. Welch
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  3. Benjamin H. Beck
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  4. Lewis J. Stafford
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  5. Joshua W. Long
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  6. Jeffery C. Sellers
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  7. Zhi Q. Huang
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  8. William E. Grizzle
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  9. Cecil R. Stockard
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  10. Kevin T. Nash
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  11. Donald J. Buchsbaum
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Corresponding authors

Correspondence to Danny R. Welch or Donald J. Buchsbaum.

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McNally, L.R., Welch, D.R., Beck, B.H. et al. KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model. Clin Exp Metastasis 27, 591–600 (2010). https://doi.org/10.1007/s10585-010-9349-5

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  • DOI: https://doi.org/10.1007/s10585-010-9349-5

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