Regulation of Transdifferentiation and Retrodifferentiation by Inflammatory Cytokines in Hepatocellular Carcinoma

Liver cancers are typically inflammation-associated cancers characterized by close communication between the tumor cells and the tumor environment. This supportive inflammatory environment contributes to the establishment of a pathologic niche consisting of transformed epithelial cells, tumor-educated fibroblasts, endothelial cells, and immunosuppressive immature myeloid cells. Stromal and infiltrated immune cells help determine tumor fate, but the tumor cells themselves, including cancer stem cells, also influence the surrounding cells. This bidirectional communication generates an intricate network of signals that promotes tumor growth. Cell plasticity, which includes transdifferentiation and retrodifferentiation of differentiated cells, increases tumor heterogeneity. Plasticity allows non-cancer stem cells to replenish the cancer stem cell pool, initiate tumorigenesis, and escape the effects of therapeutic agents; it also promotes tumor aggressiveness. There is increasing evidence that an inflammatory environment promotes the retrodifferentiation of tumor cells into stem or progenitor cells; this could account for the low efficacies of some chemotherapies and the high rates of cancer recurrence. Increasing our understanding of the signaling network that connects inflammation with retrodifferentiation could identify new therapeutic targets, and lead to combined therapies that are effective against highly heterogeneous tumors.