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Centrosome Abnormalities in Cancer Cells and Tissue

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Centrosome Abnormalities in Cancer Cells and Tissue Centrosome abnormalities in cancer cells and tissue Heide Schatten,* Maureen Ripple,** Ron Balczon,*** and Meghan Taylor* *Department of Veterinary Pathobiology, University of Missouri-Columbia, Columbia, MO 65211 ** University of Wisconsin Comprehensive Cancer Center, Department of Medicine, Environmental Toxicology Center, and the William S. Middleton Veterans Administration Hospital, University of Wisconsin, Madison, WI 53792 *** Department of Structural and Cellular Biology, The University of South Alabama, Mobile, AL 36688 This paper addresses cancer as a disease characterized by uncontrolled cell divisions in which the molecular controls for cytoskeletal regulation are bypassed. The focus of our studies are on centrosomes, microtubule-organizing cell organelles which are crucial for the organization of the mitotic apparatus during mitosis and cell division (1). The importance of centrosomes during normal cell division had been recognized by the classical cytologist Theodor Boveri (2) who also recognized that centrosome abnormalities are observed during cancer (3). Following up on these studies, we analyzed centrosome structure and function in the prostate cancer cell lines LNCaP and DU145 (45) as well as in fresh and archived prostate cancer tissue. Cancer cells and tissue was compared with normal human foreskin fibroblast (HFF) cells. The goal of these studies was to investigate the organization and the structural behavior of centrosomes in cancer and normal cells. Transmission electron microscopy of whole cells revealed centrosome and spindle abnormalities resulting in tri- and multipolar spindles in LNCaP and DU145 cells during mitosis which was not observed in normal HFF cells. Figure 1 depicts one section through a DU145 prostate cancer ceil with abnormal mitosis. Tri- and multipolar spindles are the result of centrosome instability which will lead to imbalances in chromosome distribution. The TEM results were confirmed by immunofluorescence studies with the autoimmune antibody SPJ (6) to detect centrosomes, with the monoclonal antibody E7 (7) to detect microtubules, and with DAPI to detect DNA. Centrosome abnormalities are also noted in interphase cells. Figure 2 shows centrosome material in DU145 cells in close association with the nucleus during interphase that is accumulated with much higher density and size as compared to HFF cells. Centrosome abnormalities are also observed in LNCaP cells which had been treated with 1nM of the synthetic androgen R1881 for 48 and 72 hours (4,5). This treatment results in increase of centrosome material while cells are arrested in the G2 phase. Future studies are aimed at determining the structure and protein composition of centrosomal material with high resolution scanning electron microscopy (7). These investigations are expected to allow insights in the complex nature of centrosome material and it’s functions during normal and abnormal cell divisions as observed during cancer. References 1. Schatten, H., et al., Proc. Natl. Acad. Sci. USA 84, 8488-8492 (1987). 2. Boveri, T. Ueber die Natur der Centrosomen. Jena: Fischer, Vol 4 (1900). 3. Boveri, T. The origin of malignant tumors. Jena: Fischer (1914). 4. Ripple, M.O., et al., J. Natl. Cancer Inst. 89 (l), 40-48 (1997). 5. Ripple, M.O., Pickhardt, and Wilding, G., Cancer Res. 57, 2428-2433 (1997). 6. Balczon, R., and West, K. Cell Motil. Cytoskel. 20, 121-135 (1991). 7. Thompson-Coffe et al., Cell Motil. Cytoskel. 33, 197-207 (1996). 8. This work was supported by funds from the University of Missouri-Columbia . Figure 1. TEM of DU145 cell during mitosis depicting chromosomes in irregular alignment which indicates centrosome instability. Figure 2. Immunofluorescence microscopy depicting centrosome staining with the SPJ centrosome antibody (left) in DU14.5 cells during interphase which stains brighter and denser than in normal HFF cells. Fluorescence staining with DAPI to detect DNA in corresponding cells is shown on the right. .
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