Conversion of premalignant human cells to tumorigenic cells by methylmethane sulfonate and methylnitronitrosoguanidine

Abstract

Nine human tumor cell lines derived from both epithelial and mesenchymal tumors exhibited either an anchorage-independent growth non-tumorigenic phenotype or an anchorage-independent tumorigenic phenotype. Transformed epithelial cell lines with the non-tumorigenic phenotype could be converted to a progressively growing tumor phenotype following treatment with either methylmethane sulfonate (MMS) or N-methyl-N'-nitro-N-nitro-soguanidine (MNNG). In contrast, sarcoma derived cell lines with a non-tumorigenic phenotype could be converted to a progressively growing tumor phenotype only with MNNG. SV40 immortalized HET-1A non-tumorigenic phenotype cells could be converted to a progressively growing tumorigenic phenotype, infrequently, when treated with MNNG, but not MMS. Progressively growing tumors produced by either MMS or MNNG treated non-tumorigenic phenotypes exhibited metastatic potential in nude mice. Chemically treated HET-1A cells acquired the ability to produce tumor in mice but the tumor did not exhibit metastatic potential. In contrast, populations of tumorigenic cells were not rendered more biologically aggressive after treatment with either MMS or MNNG; i.e., the latency period for tumor development was not accelerated and the tumors did not exhibit metastatic potential. These results suggest that the biological effects of MMS and MNNG on non-tumorigenic, tumorigenic and immortalized cell lines are phenotype specific.

Epstein–Barr virus growth-transformed cells are converted to malignancy following transfection of a 1.3-kb CATR1 antisense construct independent of a change in the level of c- myc expression followed by a 8;14 chromosomal translocation

“…When these cells were examined by semi-quantitative RT-PCR, the tumors induced by the AGLCL-TR cells showed greater than 90% reduction in the level of CATR1 expression (Fig. 5) when compared with either the parental AGLCL cells or normal human fibroblasts (15). The RT-PCR data gathered for the c-myc gene confirmed the Northern blot analysis data, where we observed no detectable change in the level of c-myc expression by this procedure either.…”

“…We have previously demonstrated that cells derived from human SCC, that were nontumorigenic in nude mice, could be converted to a tumorigenic phenotype by treatment with MMS or MNNG (15,16). From tumors induced by these treated cells, we isolated a putative tumor suppressor gene, CATR1, and demonstrated that transfection of SCC or chemically transformed human foreskin cells (with either a nondirectional cDNA expression library and͞or subsequently with a 1.3-kb CATR1 antisense cDNA construct) will convert these cells to a malignant phenotype (20).…”

“…The AGLCL-TR cells were injected into 3-to 4-weekold male nude mice as described (15)(16)(17). Briefly, 5 ϫ 10 6 cells were injected s.c. into the flank of the mice.…”

“…In previous studies from our laboratory, we reported on the conversion of human cells, which were derived from squamous cell carcinomas (SCC) (unable to induce tumors in nude mice), to malignant cells following methyl methanesulfonate (MMS) or N-methyl-N-nitro-N-nitrosoguanidine (MNNG) treatment (15,16). The conversion did not appear to be related to either the frequency or location of mutations in c-myc, H-ras, Ki-ras (17), or p53 genes (18).…”

Malignant conversion of chemically transformed normal human cells.

“…We have previously isolated and characterized an AIG population of cells from human head and neck tumors that is similar in characteristics to the carcinogen-transformed normal human cells described above (9)(10)(11)(12). In cells from some of these head and neck malignancies, the tumor-associated genes, c-myc and H-ras, exhibited an increased expression (9,11,12), and the presence of a mutation in the 12th/13th codon of H-ras was detected (ref.…”