The central concept of this chapter is that derangement of microenvironment, which takes place in tumor progression, leads to the partial or full dedifferentiation of epithelial tumors. The review considers the role of intercellular communications and interaction of cells with extracellular matrix (ECM) in differentiation and tumor progression. To illustrate this point, we consider the main characteristics of normal hepatocyte differentiation and its alterations in the course of hepatocellular carcinoma progression and epithelial-to-mesenchymal transition. The control of liver differentiation is mainly implemented by hepatocyte nuclear factors (HNFs). Derangement of HNF regulatory network is clearly associated with hepatocarcinogenesis and progression. We suppose that tissue-specific factors, playing the most important role in the differentiation of particular epithelial cell types, are the preferential targets for inactivation in the progression of corresponding tumors. Moreover, these transcriptional regulators may mediate the interaction of epithelial cells with the microenvironment.