Advisory Committee Chair
Danny Welch
Advisory Committee Members
Louise Chow
Robert Hardy
Louis Justement
Richard Marchase
Joanne Murphy-Ullrich
Document Type
Dissertation
Date of Award
2006
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Failure to reduce the number of cancer deaths over the last 50 years is due to the inability to selectively target metastatic disease. Recently, the KISS1 metastasis suppressor has emerged as a promising molecular agent for the management of metastatic disease. Although KISS1 has been implicated in the regulation of the metastatic phenotype in human cancers and in in vivo mouse models, little is known about its mechanism. Recent evidence suggests that KISS1 is a neuropeptide that is processed and secreted to interact with its cognate receptor GPR54 in the hypothalamus to trigger puberty and maintain the reproductive state. However, whether KISS1 secretion is required for metastasis suppression is not clear. The goal of this study was to test the hypothesis that KISS1 secretion is required for multiple organ metastasis suppression using the highly metastatic human melanoma cell line C8161.9. To detect secretion, KISS1 was engineered with an internal FLAG epitope in order to identify processed forms in the absence of a suitable antibody. Green fluorescent C8161.9 cells were stably transfected with pcDNA3-FLAG KISS1 (KFM) or pcDNA3-FLAG KISS1 lacking the putative secretion signal (KFM)SS). Secretion and processing of KISS1 proteins could only be detected in C8161.9KFM cells despite equal KISS1 protein expression in whole cell lysate for both constructs. Only C8161.9KFM cells suppressed the incidence and frequency of metastases in the lung, kidney, eye and bone by 56%-100% when compared to C8161.9vector or C8161.9KFM)SS cells. In the lung, C8161.9KFM cells remained dormant while C8161.9KFM)SS and C8161.9vector cells formed iii overt metastatic lesions. These results suggest that KISS1 secretion is necessary to prevent colonization at the secondary site. More importantly, the dormancy of C8161.9KFM cells was sustained providing a significant survival advantage in these mice when compared to mice receiving C8161.9vector controls. These data indicate that KISS1 secretion is required for multiple organ metastasis suppression and for the maintenance of metastatic cells in a dormant state. Soluble Kisspeptin (mimetics) could potentially be used to maintain tumor dormancy, rendering disseminated micrometastasis a legitimate treatment target.
Recommended Citation
Nash, Kevin T., "Kiss1 Metastasis Suppressor Secretion Is Required For Metastasis Suppression" (2006). All ETDs from UAB. 3771.
https://digitalcommons.library.uab.edu/etd-collection/3771