Investigators Pinpoint Gene That Suppresses Spread of Melanoma

A new gene, designated KiSS-1, has been isolated from cells of malignantmelanoma, in which metastatic potential was suppressed by the introductionof normal human chromosome 6. According to the research report in the December4th Journal of the National Cancer Institute, KiSS-1 substantiallysuppresses the metastasis of melanoma in laboratory animals and may proveuseful in the clinical setting for distinguishing metastatic from nonmetastaticmelanomas.

In the report, Jeong-Hyung Lee, PhD, The Pennsylvania State UniversityCollege of Medicine, and colleagues explain that tumor metastasis is nowunderstood to be a multistep process involving complex interactions betweentumor cells and host cells. To metastasize, say the authors, tumor cellsmust dissociate from the tumor mass, be transported to another site inthe body, and establish themselves at that site, invading the surroundingtissue and responding to growth signals at the secondary site. Unless eachstep in this pathway is successfully accomplished, they state, metastaseswill not develop. Both positive and negative regulators exist for eachstep in this cascade of events, add Lee and coworkers, implicating theinvolvement of dozens of different genes.

In previous studies, Lee and colleagues found that introducing a normalhuman chromosome 6 into the highly metastatic human melanoma cell lineC8161 almost entirely suppressed its metastatic properties, although thecells still were tumor-producing. This finding suggested that metastaticcapability was the result of genetic changes occurring after the cellsbecame tumorigenic, that at least some of these later mutations occurredon chromosome 6, and that one or more metastasis-suppressor genes mightbe located on chromosome 6 or regulated by genes on that chromosome.

Tumor-Suppressor Gene Isolated and Tested

In the current study, the researchers used a process known as subtractivehybridization to attempt to isolate the gene(s) in nonmalignant clonesof C8161 cells responsible for suppressing metastasis. A previously unidentifiedgene, designated KiSS-1, was isolated and then introduced into unaltered(parental) malignant C8161 cells. Resulting clones expressing differentlevels of KiSS-1 were selected and each type was injected into separategroups of immune-deficient mice by two methods (either into the skin ordirectly into the circulatory system) designed to elicit spontaneous andinduced (experimental) metastases, respectively. As controls, additionalgroups of mice were similarly injected with C8161 cells into which onlythe vector used to carry KiSS-1 was introduced.

In the test of spontaneous metastasis (measuring the ability of intradermallyinjected cells to metastasize to distant sites), the KiSS-1 clones wereconsistently less able to colonize lung or regional lymph nodes than thecontrol C8161 cells. Parental C8161 cells resulted in an average of 50lung metastases per mouse, and all mice had lymph node metastases. By contrast,the KiSS-1-expressing clones resulted in as few as one and no more thansix lung metastases per animal and few instances of regional lymph nodeinvolvement.

In addition, the researchers tested various body tissues for the expressionof messenger RNA (mRNA) by the KiSS-1 gene. KiSS-1 mRNA was abundant inplacental tissue, and weak expression was found in the kidney. The authorsnote that KiSS-1 expression was also detected in normal human melanocytes,suggesting that it functions in normal melanoma precursor cells and thatloss of the gene's expression may indicate greater potential for melanomametastasis. Although the predicted protein product of KiSS-1 resemblesprotein products involved in certain cell signaling processes and/or cytoskeletalorganization, the researchers caution that further study of the role ofKiSS-1 in melanoma progression is needed. Additional experiments are alsoneeded, they conclude, to determine whether KiSS-1 has a role in othercancers and whether it may be a useful marker for assessing melanoma progressionin the clinical setting.

Translation of Findings to the Clinic Called Challenging

In an editorial accompanying this report, Isaiah J. Fidler, DVM, PhD,and Robert Radinsky, PhD, The University of Texas M. D. Anderson CancerCenter, Houston, observe that the identification of metastasis-suppressinggenes can be expected to have far-reaching implications for diagnosingand treating disseminated cancer. But, say Fidler and Radinsky, the translationof these findings to clinical reality still faces serious challenges.

By the time of diagnosis, they say, many human tumors contain differenttypes of cells with varying metastatic potential, which may limit the abilityto predict a given tumor's metastatic potential using the expression levelof metastasis-suppressing genes. Since metastasis can be produced froma small subpopulation of cells within the primary tumor, they add, thehigh expression level of metastasis-suppressing genes by the majority ofthe nonmetastatic cells in a primary tumor could mask a clinically relevantpopulation of metastatic cells.

Moreover, say Fidler and Radinsky, detailed understanding of the functionand regulation of metastasis-suppressing genes is needed to direct thedevelopment of therapeutic approaches designed to increase their expression.Despite these challenges, they maintain, a growing understanding of themolecular biology of cancer metastasis and the advent of new technologiesoffer unprecedented opportunities for inhibiting and treating cancer metastasis.