Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

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Abstract
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‐β upon TNF‐α 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‐α mediated IFN‐β induction is not irreversibly disturbed in all cells. Using the IFN‐β sensitive Encephalomyocarditis virus (EMCV) as a tool to monitor antiviral activity in long‐term established malignant HeLa cells, rare IFN‐β 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.