Is conversion of solid into more anoxic ascites tumors associated with p53 inactivation?
Most solid tumors are unable to grow in the ascites form, unless selected by prolonged serial transfer of peritoneal fluid (Klein, 1955). Established ascites tumor cells grow under highly crowded, virtually anoxic conditions (Warburg and Hiepler, 1953). Hypoxia was recently identified as a powerful inducer of p53 dependent apoptosis (Graeber et al., 1996). We wished to examine whether the conversion of relatively well-vascularized solid mouse tumors into freely growing ascitic cell variants favors cell with mutated or deleted p53. We have sequenced exons 4-9 of p53 cDNA from two serially transplanted methylcholanthrene induced sarcomas (MCIM and MSWBS) that were available in the original solid and the gradually converted ascites form. We have also examined five additional solid tumors, four carcinomas and one sarcoma and six additional ascites tumors, five carcinomas and one sarcoma. Sequence analysis showed that all solid tumors carried exclusively wild type p53. Among the eight ascites tumors, five carried mutant p53 and three had only the wild type gene. In one of the two isogenic pairs, the original solid tumor line had only wild type, whereas the derived ascites line had only mutant p53. In the second pair, the solid tumor was wild type whereas the ascitic variant was heterozygous. The naturally occurring alternatively spliced p53 (p53as) mRNA was detected in all solid tumors, but not in five of the eight ascites tumors. Our findings indicate that conversion of solid into ascites tumors favors the selection of cell variants with mutated p53 and of cells that lack the alternatively spliced form of p53.
Magnusson
K P
KP
Microbiology and Tumor Biology Center (MTC), Karolinska Institute, Stockholm, Sweden.
Satalino
R
R
Qian
W
W
Klein
G
G
Wiman
K G
KG
D000818:Animals; D001201:Ascites / Q000235:genetics* / Q000473:pathology*; D015687:Cell Hypoxia; D017353:Gene Deletion; D016158:Genes, p53 / Q000235:genetics*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D012513:Sarcoma, Experimental / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53