Genetic redundancy in human cervical carcinoma cells: identification of cells with "normal" properties.
Although it is generally assumed that cancer arises from a singular cell, a tumor must be considered as a dynamic and emergent biological structure, whose organizing principle is determined by genetic and epigenetic modifications, occurring variably in response to microenvironmental selection conditions. As previously shown, HPV-positive cervical carcinoma cells have lost their ability to induce IFN-beta upon TNF-alpha treatment. However, regarding cancer as a non-linear system, which may, even in the absence of an apparent selection pressure, fluctuate between different "metastable" phenotypes, we demonstrate that TNF-alpha mediated IFN-beta induction is not irreversibly disturbed in all cells. Using the IFN-beta sensitive Encephalomyocarditis virus (EMCV) as a tool to monitor antiviral activity in long-term established malignant HeLa cells, rare IFN-beta expressing clones were rescued from a population of non-responsive and EMCV-sensitive cells. Antiviral activity was mediated by the re-expression of IRF-1 and p48 (IRF-9), both key regulatory molecules normally found to be suppressed in cervical carcinoma cells. Upon inoculating of selected clones into immunocompromised animals, a reduced or even an absence of tumorigenicity of initially highly malignant cells could be discerned. These data indicate that both the absence of interferon signaling and the ability to form tumors were reversed in a minority of cells. We provide a paradigm for the existence of innate genetic redundancy mechanisms, where a particular phenotype persists and can be isolated without application of drugs generally changing the epigenetic context.
Bachmann
Anastasia
A
Forschungsschwerpunkt Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120 Heidelberg, Federal Republic of Germany.
Zawatzky
Rainer
R
Rösl
Frank
F
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D018188:Cardiovirus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004686:Encephalomyocarditis virus / Q000254:growth & development / Q000276:immunology; D005260:Female; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D052161:Human papillomavirus 18 / Q000276:immunology; D006801:Humans; D016867:Immunocompromised Host; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D030361:Papillomavirus Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000821:virology
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; C494227:IRF9 protein, human; D050856:Interferon Regulatory Factor-1; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D000077209:Decitabine; D001374:Azacitidine