Epigenetic/Genetic Mismatch: Using Transdifferentiation as a Potential Cancer Therapy to Exploit the Cell Type Specificity of Cancer

Abstract

Every cell type capable of proliferation can be malignantly transformed. However, there appears to be no naturally occurring universal set of genetic mutations capable of converting every cell type to a malignant state. Any specific cell type is generally resistant to transformation by the cancer mutations accumulated by cells of different lineages, presumably due to epigenetic differences. Evidence for this idea derives from experiments in which the developmental fates of cancer cells are altered to reduce malignancy. Reprogramming cancer cells to more primitive developmental states using pluripotency factors (IPS) or somatic nuclear transfer suppresses the malignant phenotype, as does subsequent directed differentiation to mature cells of lineages distinct from the originating cell. Direct transdifferentiation to an alternative cell fate also reduces tumorigenicity. In contrast, after reprogramming, cells induced to redifferentiate toward the original tumor cell type are tumorigenic. In these types of experiments an epigenetic/genetic mismatch often results in suppression of malignancy or cell death. Elucidating the specific transcription and cell signaling network incompatibilities will identify new targets for cancer therapy. Moreover, novel strategies to induce an incompatible transdifferentiated state, in which expression of thousands of genes are altered, will prove useful in controlling malignancies that otherwise easily evolve resistance to single target-based therapeutics. Engineering small molecules, genetic vectors, cytokines, growth factors, targeted extracellular vesicles, and cell fusion will help realize transdifferentiation-based therapeutics for cancer.