Kiss1 induction of metastatic dormancy

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA SY32-02 Since the vast majority of cancer morbidity and mortality are associated with the development of metastases, the development of strategies to control metastasis would represent a significant improvement. Metastasis is the culmination of a multi-step, sequential process in which tumor cells depart the primary tumor, enter a transport compartment (i.e., blood, lymphatic or body cavity), migrate to and colonize nearby or distant discontiguous sites. If a cell cannot complete any step of this so-called metastatic cascade, it cannot continue to subsequent steps. Therefore, early anti-metastasis therapies focused upon blocking essential steps, such as adhesion and invasion. Unfortunately, it was discovered that, by the time of diagnosis, millions of tumor cells have already been shed from primary tumors. Despite the inefficiency of the metastatic process, some disseminated tumor cells will have already had the opportunity to seed vital organs and begin proliferating (reviewed in (1,2)). Depending upon the size of the foci at the time of diagnosis, they may or may not be detected. But the inescapable conclusion is that targeting the steps in metastasis prior to seeding secondary sites was probably occurring before diagnosis. Other strategies would be required. It has long been recognized that patients can have disseminated cells present for many years or decades (3,4). The presence of single ectopic cells was not an issue until techniques capable of detecting them (or small emboli) were developed. Indeed, happenstance sections in tissues often detected disseminated neoplastic cells, but their clinical importance was negligible since they were not impacting function. This does not belittle the potential danger since those disseminated cells had already accomplished the majority of antecedent steps in metastasis. The potential for destructive behavior was present, but when tumor cells blended innocuously, they were difficult to detect and neutralize. The challenge has been to discriminate between those cells merely leaning toward destructive behavior from those truly committed to killing the host. While logic and evidence suggest that the presence of tumor cells in the peripheral circulation, lymph nodes or bone marrow are indicators of poor prognosis, the correlations are imperfect (reviewed in (3-5)). Recent staging criteria now incorporate parameters of single cells or microscopic masses (reviewed in (1,6)), but their ultimate importance is not yet fully defined. As a result, a unified definition of a "metastasis" is however still lacking and widely differs from a single disseminated cell to tumor cells that have seeded, but not yet proliferated (or minimally proliferated) at ectopic sites (so-called micrometastases) to a macroscopic mass that grows discontinuous from the primary tumor mass (1,6,7). We have advocated that disseminated cells can be called metastases only if they seed and proliferate at secondary sites. While the arrival of a tumor cell at the secondary site means that the cell has completed all prior steps in the metastatic cascade, seeding at ectopic sites is by no means a guarantee of growth. Thus, it is critical to distinguish between disseminated cells and overt, macroscopic metastasis. The distinction between a lodged or arrested cell in an organ and a metastasis is rooted in whether the tumor cell grows in the ectopic environment. In other words, disseminated cancer cells must also be able to respond to the microenvironment in order to survive and grow. Based upon their function (i.e., block metastasis without blocking primary tumor formation), metastasis suppressors appear to regulate cellular response to the microenvironment. It follows, then, that modulating the ability of cancer cells to respond to their microenvironment or modulating the secondary growth environment itself would be expected to alter the development of metastasis. Since one must assume that cancer cells escape, we need to focus therapeutic efforts on controlling their growth after they are away from the primary tumor. KISS1 is a metastasis suppressor first identified in melanoma (8), but also functional in breast (9 and ovarian cancers (10). Nascent KISS1 is secreted, proteolytically cleaved to make kisspeptins (KP) and binds a G-protein coupled receptor, GPR54 (11,12). In the absence of reliable antibodies to detect KISS1 and KP, an internal FLAG epitope was introduced before transfection into green fluorescent protein-expressing, C8161.9 human melanoma cells (13). Stably expressing clones were isolated, injected into athymic mice and metastases monitored. Macroscopic metastases in all organs was significantly suppressed, with corresponding increased survival. However, we found that KISS1-expressing cells seeded lungs, but did not form macroscopic metastases. The cells were capable of completing antecedent steps of the metastatic cascade, but not able to colonize lungs (13). Thus, the opportunity to control colonization may be close at hand. If disseminated cells could be maintained in a permanently dormant state, cancer then becomes a controllable disease rather than simply something that requires acute elimination. Unfortunately, dormancy generally confers resistance to proliferation-dependent therapies such as radiation and chemotherapy. Once cells break dormancy and proliferate, patient survival drops precipitously. Therefore, the identification of molecular targets that can selectively kill dormant cells or maintain them in a dormant state indefinitely, like KISS1, would have an immediate impact on patient survival. Since many patients have occult metastatic disease by the time of diagnosis, exogenous KISS1 therapy might be useful in patients as a prophylactic, adjuvant measure to keep metastatic cells dormant and prolong survival. References 1. Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatment strategies. Lancet 2007;369:1742-57. 2. Weiss L. Metastatic inefficiency. Adv Cancer Res 1990;54:159-211. 3. Pantel K, Woelfle U. Detection and molecular characterisation of disseminated tumour cells: Implications for anti-cancer therapy. Biochim Biophys Acta Rev Cancer 2005;1756:53-64. 4. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nature Rev Cancer 2004;4:448-56. 5. Christiano AP, Yoshida BA, Dubauskas Z et al. Development of markers of prostate cancer metastasis. Review and perspective. Urol Oncol 2000;5:217-23. 6. Welch DR. Defining a cancer metastasis. In: American Association for Cancer Research ed. AACR Education Book 2006. Philadelphia: AACR; 2006:111-5. 7. Welch DR. Do we need to redefine a cancer metastasis and staging definitions? Breast Disease 2007;26:3-12. 8. Lee J-H, Miele ME, Hicks DJ et al. KiSS-1 , a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 1996;88:1731-7. 9. Lee J-H, Welch DR. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res 1997;57:2384-7. 10. Jiang Y, Berk M, Singh LS et al. KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha. Clin Exptl Metastasis 2005;22:369-76. 11. Kauffman AS, Clifton DK, Steiner RA. Emerging ideas about kisspeptin-GPR54 signaling in the neuroendocrine regulation of reproduction. Trends Neurosci 2007;30:504-11. 12. Nash KT, Welch DR. The KISS1 metastasis suppressor: mechanistic insights and clinical utility. Front Biosci 2006;11:647-59. 13. Nash KT, Phadke PA, Navenot J-M et al. KISS1 metastasis suppressor secretion, multiple organ metastasis suppression, and maintenance of tumor dormancy. J Natl Cancer Inst 2007;99:309-21.