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Cell transformation arises from activation of oncoproteins and/or inactivation of tumor suppressor proteins. During the initial stage of carcinogenesis, transformation occurs in a single cell within an epithelial monolayer. However, it is not known what happens at the interface between normal and transformed cells once the initial transformation has occurred. Using elaborate cell culture systems, recent reports have shown that interactions between normal and transformed epithelial cells can induce various phenomena. For example, when Ras- or Src-transformed cells are surrounded by normal epithelial cells, multiple signaling pathways are activated and the transformed cells are apically extruded from the epithelium. In addition, normal and certain types of transformed cells compete with each other for cell survival, and the transformed cells undergo apoptosis. Importantly, when transformed cells alone are present, neither apoptosis nor elimination from epithelia occurs, indicating that the presence of surrounding normal cells influences the signaling pathways and fate of transformed cells. Comparable phenomena are also observed in zebrafish and mice in vivo model systems. In this review, I will introduce this newly emerging research field and discuss how these studies can potentially lead to establishment of novel types of cancer prevention and treatment. (Cancer Sci 2011; 102: 1749–1755)