Title: Kiss1 over-Expression Suppresses Metastasis of Pancreatic Adenocarcinoma in a Xenograft Mouse Model Authors
|Mcnally, Lacey -|
|Welch, Danny -|
|Stfford, Lewis -|
|Long, Joshua -|
|Sellers, Jeffery -|
|Haung, Zhi -|
|Grizzle, William -|
Submitted to: Clinical and Experimental Metastasis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 24, 2010
Publication Date: December 27, 2010
Citation: Mcnally, L.R., Welch, D.R., Beck, B.H., Stfford, L.J., Long, J.W., Sellers, J.C., Haung, Z.Q., Grizzle, W.E. 2010. KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model. Clinical and Experimental Metastasis. 27:591-600. Interpretive Summary: Pancreatic cancer is currently the fourth leading cause of cancer death in the United States. Pancreatic cancer patients have a median survival of <6 months and a dismal 5-year survival rate of 5%. The lethal nature of pancreatic cancer is strongly associated with its early spread (metastasis) from the pancreas to other organs. The aggressive, but largely asymptomatic, nature of this disease commonly leads to its late discovery in patients making it by and large incurable. Conventional therapies such as chemotherapy, radiation, and surgery, are largely ineffective in treating pancreatic cancer; therefore, novel treatment strategies are desperately needed. Since metastasis has usually occurred before the detection of cancer, preventing the growth of already spread cells offers promise for patients with pancreatic cancer. One potential therapeutic target is the KISS1 metastasis suppressor. KISS1 is a gene that has been shown to prevent the spread of melanoma, breast and ovarian cancers in animal models. Therefore, in this study we sought to determine if KISS1 could reduce or block the spread of pancreatic cancer in an animal model. Indeed, we found that when pancreatic cancer cells were engineered to express KISS1 that metastasis was effectively halted. These findings suggest that KISS1 may represent a potential treatment for pancreatic cancer.
Technical 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), KFM'SS (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-KFM'SS 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 KFM'SS and KISS1-expressing orthotopic tumors by immunohistochemistry. Metastases were not found in lungs of mice with S2VP10L-KISS1 tumors; whereas, KFM'SS 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.