Genes Involved in Kidney Development, Differentiation and Tumor Progression

Abstract

Cancer is still the number two cause of death in highly developed countries. Epithelial cells represent the most important cell type in tumor formation and progression, because greater than 90% of human malignancies are carcinomas and thus of epithelial origin. Most, if not all, tumor cells show abnormalities in differentiation (i.e., anaplasia). A major cause of death from cancer in humans is the invasive and metastatic growth of malignant epithelial cells. For this to occur, epithelial cells must lose many of their differentiated properties and take on those of a mesenchymal cell type. Thus, tumor progression is a pathological epithelial-mesenchymal transition (EMT), a process that is a normal part of embryogenesis. Many embryonic genes are reexpressed in cancer cells, but unlike normal cells during embryonic development, tumor cells fail to differentiate and continue to proliferate. Being able to treat cancer through the induction of cellular differentiation is attractive, because the therapy would be more target cell specific and most likely be much less toxic then standard chemotherapeutic agents, which affect normal and tumor cells. However, greater knowledge about the molecular basis for the control of differentiation is necessary to lead to more accurate predictions, as well as the rational design of therapies for controlling tumor growth by manipulating the state of differentiation. To these ends, we employed representational difference analysis (RDA) to identify genes whose expression is altered during EMT and tumor progression. 35 differentially expressed mRNAs were identified and classified into several functional categories, including 9 novel cDNAs. Among the 26 known cDNAs, extracellular matrix and related proteins made up the largest group of differentially expressed genes, followed by growth factors and receptors and transcription factors. Some of the known genes have previously been associated with EMT and/or tumor progression and thus served to validate the system to obtain the desired target genes, while other cDNAs are newly linked with dedifferentiation/malignancy. Array analyses indicated that the cDNAs were specifically upregulated in invasive or metastatic tumors, especially of breast, uterus and lung, suggesting their involvement in the progression of these tumors.