[CANCER RESEARCH 61, 2212–2219, March 1, 2001] Centrosome Defects Can Account for Cellular and Genetic Changes That Characterize Prostate Cancer Progression 1 German A. Pihan, 2 Aruna Purohit, Janice Wallace, Raji Malhotra, Lance Liotta, and Stephen J. Doxsey 2 Department of Pathology [G. A. P., J. W., R. M.] and Program in Molecular Medicine [A. P., S. J. D.], University of Massachusetts Medical School, Worcester, Massachusetts 01655, and Department of Pathology, National Cancer Institute, Bethesda, Maryland 20892 [L. L.] ABSTRACT Factors that determine the biological and clinical behavior of prostate cancer are largely unknown. Prostate tumor progression is characterized by changes in cellular architecture, glandular organization, and genomic com- position. These features are reflected in the Gleason grade of the tumor and in the development of aneuploidy. Cellular architecture and genomic stability are controlled in part by centrosomes, organelles that organize microtubule arrays including mitotic spindles. Here we demonstrate that centrosomes are structurally and numerically abnormal in the majority of prostate carcino- mas. Centrosome abnormalities increase with increasing Gleason grade and with increasing levels of genomic instability. Selective induction of centro- some abnormalities by elevating levels of the centrosome protein pericentrin in prostate epithelial cell lines reproduces many of the phenotypic character- istics of high-grade prostate carcinoma. Cells that transiently or permanently express pericentrin exhibit severe centrosome and spindle defects, cellular disorganization, genomic instability, and enhanced growth in soft agar. On the basis of these observations, we propose a model in which centrosome dysfunction contributes to the progressive loss of cellular and glandular architecture and increasing genomic instability that accompany prostate cancer progression, dissemination, and lethality. INTRODUCTION Prostate carcinoma is the most common gender-specific cancer in the United States, accounting for nearly one-third of all cancers affecting men (1). The lifetime risk of developing invasive prostate carcinoma in the United States is 20% (2–5), whereas that of octogenarians based on histopathological examination of the prostate at autopsy approaches 80% (6). Despite the high incidence of prostate carcinoma, the lifetime risk of dying from the disease is much lower, currently estimated to be 3.6% (1 of 28; Surveillance Epidemiology & End Results, NCI, 2000, personal communication). These epidemiological trends, which may intensify in the coming decades because of the aging of the Baby Boom generation and our increasing ability to recognize tumors at earlier stages, mean that 180,000 new cases of prostate cancer will be diagnosed in the coming year in the United States. Radical prostatectomy is the most common therapy for the small group of patients with high-grade tumors. However, there currently are no sound medical facts to direct treatment of the majority of patients that present with lower grade tumors (7, 8). Because a subgroup of patients with low-grade carcinoma ultimately develop aggressive, often lethal cancers, current therapeutic recommendations are to treat all patients with an intent to cure (7, 8). Thus, the most pressing need in the management of prostate carcinoma is to develop a noninvasive test to distinguish clinically indolent (low-grade) carcinoma from potentially fatal disease (see “Discussion”; Ref. 9). This test would spare the majority of patients with indolent prostate cancer from unnecessary prostatectomy. Reducing such surgeries would result in significant cost savings in health care, decreased therapy-related morbidity, and more focused therapy on the more homogeneous group of patients with aggressive disease, where the efficacy of newer therapies could be assessed more quickly (9). One of the best predictors of prostate cancer progression is the Gleason score, a numerical measure compiled from the two most prevalent histological Gleason grades. The Gleason grade reflects cytoarchitectural features that become increasingly aberrant with tu- mor progression (10, 11). Recent results indicate that the parameter with the greatest predictive power is the proportion of tumor with the highest Gleason grades (4 and 5; Ref. 12). An intimate relationship between Gleason grade, aneuploidy, and unfavorable clinical outcome has long been known (13–17). This suggests that the molecular components and subcellular structures that control cell and tissue architecture and genetic fidelity are likely to contribute to tumor progression. These parameters have the potential to dictate the clinical behavior of tumors and thus serve as predictors of aggressive cancer. In a search for cellular elements that contribute to the constellation of cellular and genetic features found in high Gleason grade prostate carcinoma, we focused on centrosomes (18). Centrosomes are tiny cellular organelles that nucleate microtubule growth and organize the mitotic spindle for segregating chromosomes into daughter cells (re- viewed in Refs. 19 and 20). As organizers of microtubules, centro- somes also play an important role in many microtubule-mediated processes, such as establishing cell shape and cell polarity, processes essential for epithelial gland organization (21–24). Centrosomes also coordinate numerous intracellular activities in part by providing dock- ing sites for regulatory molecules, including those that control cell cycle progression, centrosome and spindle function, and cell cycle checkpoints (20, 24 –29). Because high Gleason grade prostate cancer is characterized by defects in the same set of cellular processes controlled by centrosomes, we hypothesized that centrosome dysfunc- tion may be the biological basis for these phenotypic abnormalities. In this report, we show that centrosome defects are found in essentially all high-grade prostate cancers. Moreover, centrosome defects are present in low-grade tumors, and they increase with increasing Gleason grade and with increasing genomic instability. Artificial induction of centrosome abnormalities in cultured prostate cells by overexpression of the centro- some protein pericentrin reproduces many features of aggressive prostate cancer. We discuss our results in terms of a centrosome-mediated mech- anism for tumor progression. Centrosome abnormalities in prostate can- cer could be exploited to develop markers for tumor virulence and selective therapies that target tumor-specific centrosome abnormalities, thus circumventing the greatest limitation of current chemotherapy–its lack of tumor selectivity. MATERIALS AND METHODS Immunohistochemical Detection of Centrosomes in Archival Tissue Sections of Prostate Carcinoma. Archived cases of invasive prostate carci- noma treated by radical prostatectomy were selected from the files of the Received 8/25/00; accepted 12/29/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by Grants PC970425 and PC000018 (to G. A. P. and S. J. D.) from the Department of Defense, Grant RO1 GM51994 (to S. J. D.) from the NIH, and funds from the Massachusetts Department of Public Health and Our Danny Cancer Fund (to G. A. P. and S. J. D.). S. J. D. is a recipient of an Established Investigator Award 96-276 from the American Heart Association. 2 To whom requests for reprints should be addressed, at Department of Pathology, Room S2–141, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Phone: (508) 856-4124; Fax: (508) 856-5780; E-mail: German. pihan@umassmed.edu, or Department of Molecular Medicine, University of Massachu- setts Medical School, 373 Plantation Street, Worcester, MA 01605. Phone: (508) 856- 1613; Fax: (508) 856-4289; E-mail: stephen.doxey@umassmed.edu. 2212 Research. on November 26, 2021. © 2001 American Association for Cancer cancerres.aacrjournals.org Downloaded from