Role Of Stem Cell Division Modes During Prostate Development And Tumorigenesis

Background:Asymmetrical and symmetrical divisions of stem cell play an important role during tissue development, regeneration and tumorigenesis. Although the precise regulation of symmetrical and asymmetrical divisions of stem cells have been extensively studied in Drosophila, C.elegans and mammalian neural epithelia, their role remains largely unknown in mammalian non-neural epithelial tissue. Here, using cell specific markers and lineage tracing approach, we investigated the cell division modes of prostates basal and luminal cells during development and tumorigenisis.Objects:(1) To investigate the cell polarity, spindle orientation patterns and cell fates specification of prostate basal and luminal during normal development and regeneration process.(2) To track the cell fates of basal and luminal cell using cell lineage tracing and basal-lineage deleted mice.(3) To explore whether Pten loss affects cell polarity, spindle orientation patterns and cell fates specification of prostate basal and luminal during prostate cancer development.Materials and Methods:(1) We examined prostate epithelial cell polarity and spindle orientation patterns using basal and luminal cell-specific markers.(2) In our research,several transgenic mice were used, including basal and luminal cells lineage tracing mice, basal lineage deleted mice, and prostate-specific Pten mutant mice.(3) We utilized fluorescence microscope and confocal to visualize the cell fate specification of derived progeny cells.Results:In the chapter 1, we found that basal and luminal cells exhibited different polarity and spindle orientation patterns. In the chapter 2, by cell fates analysis, we visualized that a horizontal division of basal exhibited symmetrical divisions to generate two basal cells, while vertical division of basal cells underwent asymmetrical division to give rise to one basal daughter cell and one luminal daughter cell. In contrast, luminal cells generally divided symmetrically to generate two luminal cells.Cell lineage tracing studies confirmed the bi-potency of basal stem cells and the uni-potency of luminal cells. In the chapter 3, we demonstrated that luminal cells could generate luminal prostate tumors by their symmetrical divisions. In contrast,transformed basal cells still had the potential to generate luminal progeny cells and led to luminal-like prostates tumors. In the chapter 4, we demonstrated that both Sox2+ and Trop2+ luminal cells expanded in prostate tumors. By cell lineage analysis and cell division modes analysis, luminal cells were proved to be derived from basal cells.Conclusion: Overall, by analyzing the cell division modes of prostates epithelial cells,we found that basal cells could generate luminal cells by asymmetrical divisions during development and tumorigenesis, while luminal cells could maintain and expand their population by symmetrical divisions. This finding gives a clear interpretation about prostate stem cell hierarchy and the cell-origins for prostates cancer.