KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model
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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.
KeywordsKISS1 Metastasis suppressor Pancreatic adenocarcinoma
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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