The Role Of Cellular Retinoid Binding Proteins And Nuclear Retinoic Acid Receptors In The Pathogenesis Of Endometrial Adenocarcinoma

Author : Anindita Gupta
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (759 download)

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Download or read book Study of the Role of Retinoic Acid Signaling in Colon Cancer written by Anindita Gupta and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Stem cells in normal and cancer tissues have been studied using different markers developed over the past few years such as ALDH1, CD34, CD133 and many others. Other approaches to identifying stem cells are based on their nuclear morphology and chromosomal organization. Dr. Gostjeva from MIT proposed that stem cells have bell-shaped nuclei (Gostjeva et al. 2009). Cells having this nuclear morphology are called metakaryotes. They undergo amitotic cell division instead of mitosis. These metakaryotic cells are thought to have stem cell properties (stemness) and have been seen more in fetal tissues and in cancers. Fetal mouse intestine and normal and cancer tissue of colon were used in my project to study metakaryotes. A fetal human colon cell line (FHC) was also studied. Different histologic techniques were used to study the presence of this nuclear morphology. While a few cells with bell shaped nucleus could be identified using the Gostjeva protocol, no metakaryotes were detected with any other approach studied. Immunostaining showed that the stem cell marker ALDH1 is expressed in fetal mouse tissue and in the FHC cell line, but no cells were found in these tissues having bell shaped nuclear morphology. These results suggest that the identification of cells with a bell shaped nucleus is dependent on the histologic method and that Gostjeva protocol may affect nuclear morphology. Retinoid receptors are members of a nuclear hormone receptor family of proteins and are regulators of retinoid acid (RA) signaling pathways. Two types of retinoid receptors that regulate RA signaling are retinoid acid receptors (RAR) and retinoid X receptor (RXR). Both these receptor types are important for normal retinoid acid signaling and homeostasis of cells. Retinoic acid signaling plays a vital role during embryonic development by regulating stem cell function and is also crucial for normal functioning of different types of adult cells. Dysregulation of retinoic acid signaling has been reported in different types of cancer. Retinoic acid signaling is important for proper proliferation and differentiation of cells because of its role in cell cycle arrest. Retinoic acid derivatives (ATRA and 9-cis RA) are necessary signaling molecules for the activation of this pathway. They act via binding to retinoid receptors. Retinoid receptors are not only important for retinoic acid signaling, but also, for other signaling pathways. They dimerize with other receptor types like pPAR gamma, thyroid hormone receptors and many others. Thus, the involvement of the RA pathway with several other pathways makes understanding normal human RA signaling more complicated. This gets further complicated in cancerous conditions. Previous studies have shown the involvement of retinoic acid signaling in the development of different cancers including colorectal cancer. I hypothesize that specific retinoid receptors and other members of the RA signaling pathway are crucial for colorectal cancer development. To study this hypothesis, I investigated expression levels of retinoid receptors (RAR alpha and RXR alpha) and members of the RA signaling pathway (ALDH1, CYP26A1 and CtBP1) in normal and cancer cells of the colon. ALDH1, a marker for normal and cancer stem cells, was used to determine the role of stem cells in colorectal cancer development. First, expression of each protein and protein levels were investigated in colorectal cancer cells and normal and cancer tissue of colon using immunocytochemistry and western blot analysis, respectively. Second, I studied the effects of retinoic acid derivatives on colorectal cancer cells. Colorectal adenocarcinoma cell lines, SW480 and HT29 cells, were used as models to study the effects of RA derivatives on cell survival and growth. To study RA signaling in fetuses, a fetal human colon cell line (FHC) was investigated. Increased expression of RAR alpha, ALDH1, CYP26A1 and CtBP1 was seen in cancer tissue from colon compared to normal colon, whereas the expression of RXR alpha did not substantially change. Expression of RAR alpha, RXR alpha, and ALDH1 was detected in SW480 and HT29 cells by immunocytochemistry and western blot analysis and by immunocytochemistry in FHC cells. Treatment of colorectal cancer cell lines with ATRA and 9-cis RA derivatives had different effects on each cell line. ATRA inhibited growth in both SW480 and HT29 cells, but 9-cis RA significantly inhibited proliferation only in SW480 cells but not in HT29 cells. 9-cis RA induced a proliferative response in HT29 cells. Thus different colorectal cancer cell lines respond differently to these two naturally occurring derivatives of retinoic acid. Taken together, my experimental results suggest that changes in various components of the retinoid signaling pathway in colonocytes can affect cellular response to retinoid derivatives. The study of stem cells in association with retinoic acid signaling in colorectal cancer development can prove crucial for use of retinoic acid derivatives as therapeutic agents for colorectal cancer treatment if they have the potential to kill cancer stem cells.