Tumor reversion: correction of malignant behavior by microenvironmental cues

Cancer is characterized by unrestrained proliferation and loss of organization, a process that is intimately linked to, and controlled by, reciprocal signaling between the genetically altered tumor epithelium, the stroma, the components of the basement membrane and inflammatory mediators. Much work has been done to characterize the genetics of cancer cells. In this review, we describe the experiments that have been performed, which point to the significant role of the tissue microenvironment in the developmental regulation of normal and neoplastic cells. Using a variety of model systems, the works of a number of laboratories have converged on a hypothesis where the correction of 1 or 2 signaling defects can revert tumor cells to a normal phenotype, both in vivo and in culture, even when the tumor cells possess multiple genetic and epigenetic lesions. This paradigm has been successfully used to treat acute promyelocytic leukemia, and it remains the task of biomedical researchers to identify additional targets for the reversion of other human malignancies.