Metastasis suppressed, but tumorigenicity and local invasiveness unaffected, in the human melanoma cell line MelJuSo after introduction of human chromosomes 1 or 6

Abstract

Progression of human melanoma toward increasing malignant behavior is associated with several nonrandom chromosomal aberrations, most commonly involving chromosomes 1, 6, 7, 9, and 10. We previously showed that introduction of human chromosome 6 into the highly metastatic human malignant melanoma cell line C8161 completely suppressed metastasis without altering tumorigenicity (Welch DR, Chen P, Miele ME, et al., Oncogene 9:255-262, 1994). Alterations of chromosome 1 are the most frequent chromosome abnormality observed in melanomas, and they frequently arise late in tumor progression. The purpose of the study presented here was to compare the effects of chromosomes 1 and 6 on malignant melanoma metastasis. By using microcell-mediated chromosome transfer, single copies of neo-tagged human chromosomes 1 or 6 were introduced into the human melanoma cell line MelJuSo. The presence of the added chromosome was verified by G banding of karyotypes, fluorescence in situ hybridization, and screening for polymorphic markers on each chromosome. The incidence and number of metastases per lung after intravenous or intradermal injection of parental MelJuSo cells was significantly (P<0.01) greater than those of hybrids containing either chromosome 1 or chromosome 6, although chromosome 1 was a less potent inhibitor of metastasis than chromosome 6. Cultures established from primary tumors and metastases remained neomycin resistant, suggesting that portions of the added chromosomes were retained. These results strengthen the evidence for the presence of a melanoma metastasis suppressor gene on chromosome 6. neo6/MelJuSo hybrids expressed 2.4- to 3.4-fold more of the melanoma differentiation-associated gene mda-6 (previously shown to be identical to WAF1/CIP1/Sdi1/CAP20) than parental metastatic cells. mda-6/WAF1 is among the candidate genes on chromosome 6. These results also demonstrate, for the first time, the existence of metastasis suppressor genes on human chromosome 1, although these genes appear to be less potent than the one encoded on chromosome 6.

Adenovirus-mediated p16/CDKN2 gene transfer suppresses glioma invasion in vitro

“…p21-treatment induced G 1 arrest, as expected, but did not interfere with the capability of glioma cells to invade. Interestingly, micro-cell mediated transfer of chromosome 6, where the p21 gene is located, to human melanoma cells did not modify their invasiveness in vitro or in vivo (Welch et al, 1993;Miele et al, 1996). These data are consistent with a previous study showing that transfer of the Rb cDNA to cancer cells decrease their invasiveness in a cell-cycle independent way (Li et al, 1996).…”

Suppression of the malignant phenotype of human glioma cells by overexpression of manganese superoxide dismutase

“…This fact was overlooked by some researchers. In a recent report, Miele et al (1995) claimed that transfection of MnSOD did not suppress tumorigenicity and metastasis of human melanoma C8161 cells. In this study, the authors showed an increase in MnSOD mRNA, but less than a 1.6-fold increase or a slight decrease in MnSOD protein in two transfectant clones and no increase in MnSOD activity using a native gel assay.…”

Rho proteins induce metastatic properties in vivo

“…Cell transformation is not always followed by the ability of the tumor cells to metastasize (Miele et al, 1996). In fact, not all the known oncogenes are able to induce the metastatic phenotype in addition to the tumorigenic phenotype.…”

“…Oncogenic transformation is the ®rst step for the generation of tumors, but it is not always associated with the metastatic phenotype suggesting that dierent proteins may be implicated in the induction of tumorigenic and metastatic behavior of the tumor cells (Miele et al, 1996). It has been suggested that Rho proteins, in addition to their ability to induce cell transformation may have a role in metastasis.…”