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Tumor Biology |
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.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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20% (2, 3, 4, 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 tumor 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, 14, 15, 16, 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 (reviewed in Refs. 19 and 20 ). As organizers of microtubules, centrosomes 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, 22, 23, 24) . Centrosomes also coordinate numerous intracellular activities in part by providing docking sites for regulatory molecules, including those that control cell cycle progression, centrosome and spindle function, and cell cycle checkpoints (20 , 24, 25, 26, 27, 28, 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 dysfunction 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 centrosome protein pericentrin reproduces many features of aggressive prostate cancer. We discuss our results in terms of a centrosome-mediated mechanism for tumor progression. Centrosome abnormalities in prostate cancer 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.
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MATERIALS AND METHODS |
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Criteria for Centrosome Defects.
We considered centrosomes abnormal if they had a diameter at least twice that of centrosomes in normal prostate gland epithelium, if they were present in numbers >2, and if they were structurally abnormal, as described previously (18)
. In some cases, we analyzed levels of the centrosome protein pericentrin at centrosomes and in the cytoplasm by quantifying the opacity/translucence of immunoperoxidase staining. Briefly, bright-field immunoperoxidase images of tumor and normal prostate glands taken at x1000 were digitally color-inverted so the immunoperoxidase product was a bright signal whose luminosity was proportional to the intensity of the original brown signal. Signals were measured as the integral of a 5-µm area about five times the size of a centrosome, as delineated with the marquee function of Photoshop. Signal emanating from the neighboring cytoplasm was subtracted from the respective centrosome measurement. For cytoplasmic pericentrin measurements, background signals emanating from nontissue sources were subtracted. Inclusion of internal controls (normal glands present within the same section) allowed us to obtain semiquantitatively measurements of pericentrin levels within and between tumors. This approach has been used to establish differences in protein levels of other proteins (33)
. Members of our Biostatistics core (Dr. Chung Cheng, University of Massachusetts Medical School) performed statistical analysis.
In Situ Hybridization with Chromosome-specific Centromere Probes.
For in situ hybridization studies, tissue sections parallel to those stained for centrosomes were deparaffinized and heated in a microwave pressure cooker for 20 min in a solution containing 0.01 M sodium citrate (pH 6.0). After cooling to room temperature, sections were treated with a solution of pepsin (40 µg/ml) in 0.1 N HCl for 10 min. Pepsin digestion was stopped by washing the sections several times in 2x SSC at room temperature, and slides were dehydrated in a series of alcohols and air-dried. Biotinylated probes to the centromeric regions of chromosomes 1 or 8 were added in hybridization buffer, and slides were mounted, sealing coverslips with rubber cement. Target DNA and probes were codenatured in a Hybrite oven (Vysis, Downers Grove, IL; Ref. 18
), and slides were washed several times in SSC buffers for maximum stringency (Vysis), processed to detect signals (NEN Life Science Products, Boston, MA), and lightly counterstained with hematoxylin to reveal nuclei. Data are shown for chromosome 8 (Figs. 5
and 7
) and is similar to that observed with probes to chromosome 1 (not shown).
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Pericentrin Transfections into Normal or Tumor-derived Prostate Cell Lines.
Full length HA-tagged pericentrin in pcDNA I (2 µg; Ref. 32
; Invitrogen) was used for transient transfection (Lipofectamine; Life Technologies, Inc., Gaithersburg, MD) of the 1542-NPTX cell line derived from normal prostate epithelium by transformation with E6 and E7 from human papillomavirus type 16 (35)
. Cells transfected with vector alone served as controls. Permanent pericentrin-expressing PC-3 cells were constructed by cloning full-length HA-pericentrin into the pRetroON vector (Clontech), which codes for a reverse tetracycline transactivator protein and contains tetracycline transactivator responsive elements that drive transcription of the gene of interest. The transactivator is reported to bind and activate the promoter in the presence of tetracycline/doxycycline. After sequence confirmation, the cDNA was introduced into PC-3 cells (American Type Culture Collection) by transient transfection (as above), and 24 permanent lines were obtained after antibiotic selection (Clontech); cell lines expressing vector alone served as controls. We found that HA-pericentrin in these lines was expressed in the absence of doxycycline and did not significantly increase in the presence of doxycycline. The pericentrin-expressing cells exhibited dramatically different features than control cells in the absence of the drug; these features did not noticeably increase in the presence of drug, and they were indistinguishable from features observed in transiently transfected 1542 NPTX cells (Fig. 6)
and COS cells (32)
. Protein expression in the absence of induction from the pRetroON vector and the lack of inducibility of the vector has been noted by Clontech,4
and they have discontinued its sale. Imperfections in the inducibility of the vector did not impact on our study because we obtained several permanent pericentrin-expressing cell lines. In this study, we present data from cells treated with doxycycline for 48 h.
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-tubulin to label centrosomes and HA to locate transfected cells (1542 NPTX) as described (32)
. DNA was stained with 4',6-diamidino-2-phenylindole, and levels were quantified as described (32)
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Growth in Agarose of Prostate Cell Lines Permanently Expressing Pericentrin.
To study the in vitro behavior of cells with deregulated expression of pericentrin, we used the agarose colony assay of Bishop with minor modifications (36)
. One hundred thousand HA-pericentrin-expressing cells or empty vector cells were plated in duplicate in six-well plates in 0.35% low-melting point agarose over a cushion of 0.7% agarose. Cells were fed full growth medium (10% FCS, 90% RPMI, plus antibiotics and glutamine) and assessed for growth at 3 and 7 days using an inverted microscope equipped with a film camera. Images were then taken at x40, and colonies were counted and sized after an additional x10 projection onto a screen. A total of 10 images/cell line were analyzed (between 500 and 1000 colonies).
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RESULTS |
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Three parameters were initially used to monitor centrosome abnormalities: larger diameter, elevated number, and abnormal structure (Figs. 1
and 2
). These parameters were used previously by our group to provide the first evidence for centrosome abnormalities in malignant tumors of multiple tissue origin (18)
. Analysis of metastatic carcinomas using these criteria demonstrated that all had abnormal centrosomes (31 of 31; Table 1
). The proportion of tumor with centrosome defects varied from 15% to virtually 100% of tumor cells. These results confirm our previous results showing that centrosomes are abnormal in prostate tumors (18)
and extend these observations to demonstrate that centrosome abnormalities in metastatic tumors appear to be universally present and severe. The majority of carcinomas confined to the prostate (Gleason grades 2–5) also had abnormal centrosomes (101 of 109, Table 1
; Fig. 1
). However, abnormalities in this heterogeneous group of tumors were more variable than those observed in metastatic carcinomas. Some exhibited defects in only one or two of the three parameters, and the proportions of tumor tissue with centrosome abnormalities were generally lower than in metastatic tumors. In no instance did we observe centrosome abnormalities in nontumor tissues adjacent to tumors (Table 1
; Fig. 1
).
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). Of the five parameters measured, four were significantly higher in tumors of high Gleason grades (combined 4 and 5) compared with those of low Gleason grades (combined 2 and 3; Figs. 3
and 4
). Centrosome size and number were 2-fold higher in tumors of high Gleason grade (Fig. 4, A and B)
, and pericentrin levels at the centrosome and in the cytoplasm were significantly higher in high-grade tumors (Fig. 4, C and D)
. In contrast, neither the severity nor prevalence of structural abnormalities in centrosomes increased with higher Gleason grade (data not shown). Among the structural defects were elongated centrosomes (length:width ratio >5; Figs. 1E
and 3I
) that were never observed in normal human prostate cells. This suggested that elongated centrosomes were tumor specific and had potential to serve as a diagnostic marker (see "Discussion"). For all five categories of centrosome defects, the distribution within tumors was somewhat heterogeneous, a pattern reminiscent of that reported for tumor DNA content (38, 39, 40, 41)
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). As expected, the extent of CIN in tumor tissues was significantly greater than in nontumor tissues (Fig. 5)
. Interestingly, the extent of CIN was significantly greater in Gleason grade 4/5 than in Gleason grade 2/3 (Fig. 5C)
. Finally, the extent of CIN correlated with the extent of centrosome abnormalities in parallel sections from the same set of tumors (Fig. 5D)
, suggesting a relationship between centrosome defects and genomic instability in prostate tumor progression.
Induction of Centrosome Defects in Prostate Cells by Ectopic Expression of the Centrosome Protein Pericentrin Induces a Prostate Tumor-like Phenotype.
If elevated pericentrin levels and centrosome defects observed in prostate tumor tissues contribute to cellular and genetic changes that occur during tumor progression, they may have the potential to induce similar changes when experimentally induced in cultured cells. To directly test this idea, we induced centrosome defects in prostate cells in vitro. We expressed a HA-tagged pericentrin protein in cell lines derived from normal prostate epithelium (1542-NPTX; Ref. 35
) and from metastatic prostate cancer (PC-3) both by transient transfection and by construction of permanent cell lines (Figs. 6
and 7
).
Elevation of pericentrin levels induced or exacerbated genetic instability and cellular changes in 1542-NPTX and PC-3 cells, respectively. 1542-NPTX cells transiently transfected with the HA-pericentrin construct exhibited numerous defects in centrosome size, shape, and number (Fig. 6E)
as revealed by immunofluorescence staining for the centrosome protein -tubulin (42)
. Defective centrosomes were usually associated with structurally disorganized mitotic spindles, and chromosomes associated with these abnormal spindles were often misaligned and missegregated, indicating that the cells were undergoing aberrant mitoses (data not shown). Consistent with this idea were dramatic changes in nuclear morphology observed in interphase cells (lobate and misshapen nuclei, micronuclei, and multiple nuclei). Moreover, DNA levels were elevated in a large proportion of HA-pericentrin cells but not in control cells, demonstrating that pericentrin expression induced aneuploidy/polyploidy (Fig. 6, B–D)
. Control cells included cells transfected with vector alone (Fig. 6)
, a truncated pericentrin construct (43)
and ß-galactosidase (data not shown). Similar results were observed in green fluorescent protein-pericentrin transfected cells (data not shown), indicating that this phenotype was attributable to pericentrin overexpression and unrelated to the expression tag. These studies demonstrate that tumor-like changes in cellular architecture and genetic composition can take place within one to three cell cycles after HA-pericentrin expression.
To examine the long-term effects of HA-pericentrin expression, we constructed permanent prostate tumor-derived cell lines (PC-3; see "Materials and Methods"). The pericentrin-expressing PC-3 cell lines (total, 24) exhibited several abnormal features compared with control PC-3 cells containing empty vector (Fig. 7)
. Six cell lines were examined in detail, and all gave a similar phenotype; below we present data from one line (PeriPC-3–4.1). The presence of the HA-pericentrin construct was confirmed by PCR analysis (data not shown), and the HA-tagged pericentrin protein was detected by Western blot (Fig. 7A)
. Defects in centrosomes, spindles, and nuclei were significantly higher than in control cells and were strikingly similar to defects observed in transiently transfected 1542-NPTX cells (Fig. 6)
and in prostate tumors (Figs. 1
and 2
). DNA content analyzed by flow cytometry (Fig. 7, E and F)
and chromosomal instability assayed by in situ hybridization with centromere probes for chromosome 8 (Fig. 7, C and D)
were significantly higher in pericentrin-expressing PC-3 cells. Moreover, the cellular architecture of pericentrin-PC-3 cells was dramatically altered (Fig. 7, G and H)
, and the cells grew more rapidly in soft agar compared with controls (Fig. 7, I–K)
. Taken together, these data demonstrate that expression of a single centrosome protein in normal and prostate tumor cells can induce or exacerbate abnormalities in centrosome number and structure, cellular architecture, nuclear morphology, cell growth, and genomic stability, features that are characteristically altered in aggressive prostate tumors.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The in vivo and in vitro data presented in this report implicate centrosomes in the progression of prostate cancer. In our current model (Fig. 8)
, centrosome dysfunction causes modification of the microtubule cytoskeleton and contributes directly to cellular and glandular disorganization and genomic instability, creating cells that are predisposed to additional changes that lead to aggressive tumor development. We do not know whether centrosome abnormalities develop in a progressive manner (Fig. 8
, solid arrow) or in a discontinuous fashion (Fig. 8
, segmented arrows). Elucidation of the mechanisms by which centrosome changes occur may provide insights into the evolutionary pathway of the cytoarchitectural features that occur during prostate cancer progression (44
, 45)
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Our work has important implications for prostate cancer progression, prognosis, and treatment. Our observations suggest that progressive dysfunction of centrosomes occurs in prostate carcinoma, and that this can have far-reaching effects on cell morphology and genetic composition. Elucidating the mechanism(s) that leads to centrosome dysfunction in prostate carcinoma and the fundamental differences between centrosomes of low- and high-grade tumors could lead to the development of markers for tumor virulence. Such markers could play a critical role in identifying the subset of patients destined to develop aggressive, lethal prostate carcinoma. For example, elevated levels of centrosome proteins could provide a potential marker for early prostate lesions. If released into the circulation like prostate-specific antigen, these proteins could provide a noninvasive method to detect early lesions that lead to aggressive disease. Centrosome abnormalities also constitute an attractive, novel therapeutic target because they are tumor specific. It may be possible to develop chemical inhibitors against molecular components of centrosomes, such as pericentrin, that could correct or reverse centrosome defects, genetic instability, and tumor progression.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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{at}umassmed.edu, or Department of Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605. Phone: (508) 856-1613; Fax: (508) 856-4289; E-mail: stephen.doxey{at}umassmed.edu
3 The abbreviations used are: CIN, chromosomal numerical instability; HA, hemagglutinin antigen.
Received 8/25/00. Accepted 12/29/00.
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G. A. Pihan, J. Wallace, Y. Zhou, and S. J. Doxsey Centrosome Abnormalities and Chromosome Instability Occur Together in Pre-invasive Carcinomas Cancer Res., March 15, 2003; 63(6): 1398 - 1404. [Abstract] [Full Text] [PDF]
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D. Li, J. Zhu, P. F. Firozi, J. L. Abbruzzese, D. B. Evans, K. Cleary, H. Friess, and S. Sen Overexpression of Oncogenic STK15/BTAK/Aurora A Kinase in Human Pancreatic Cancer Clin. Cancer Res., March 1, 2003; 9(3): 991 - 997. [Abstract] [Full Text] [PDF]
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J. J. Keats, T. Reiman, C. A. Maxwell, B. J. Taylor, L. M. Larratt, M. J. Mant, A. R. Belch, and L. M. Pilarski In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression Blood, February 15, 2003; 101(4): 1520 - 1529. [Abstract] [Full Text] [PDF]
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K. Neben, C. Giesecke, S. Schweizer, A. D. Ho, and A. Kramer Centrosome aberrations in acute myeloid leukemia are correlated with cytogenetic risk profile Blood, January 1, 2003; 101(1): 289 - 291. [Abstract] [Full Text] [PDF]
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 B. Spankuch-Schmitt, J. Bereiter-Hahn, M. Kaufmann, and K. Strebhardt Effect of RNA Silencing of Polo-Like Kinase-1 (PLK1) on Apoptosis and Spindle Formation in Human Cancer Cells J Natl Cancer Inst, December 18, 2002; 94(24): 1863 - 1877. [Abstract] [Full Text] [PDF]
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S. Sen, H. Zhou, R.-D. Zhang, D. S. Yoon, F. Vakar-Lopez, S. Ito, F. Jiang, D. Johnston, H. B. Grossman, A. C. Ruifrok, et al. Amplification/Overexpression of a Mitotic Kinase Gene in Human Bladder Cancer J Natl Cancer Inst, September 4, 2002; 94(17): 1320 - 1329. [Abstract] [Full Text] [PDF]
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V. Bergoglio, M.-J. Pillaire, M. Lacroix-Triki, B. Raynaud-Messina, Y. Canitrot, A. Bieth, M. Gares, M. Wright, G. Delsol, L. A. Loeb, et al. Deregulated DNA Polymerase {beta} Induces Chromosome Instability and Tumorigenesis Cancer Res., June 1, 2002; 62(12): 3511 - 3514. [Abstract] [Full Text] [PDF]
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 M. R. Flory, M. Morphew, J. D. Joseph, A. R. Means, and T. N. Davis Pcp1p, an Spc110p-related Calmodulin Target at the Centrosome of the Fission Yeast Schizosaccharomyces pombe Cell Growth Differ., February 1, 2002; 13(2): 47 - 58. [Abstract] [Full Text] [PDF]
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W. L. Lingle, S. L. Barrett, V. C. Negron, A. B. D'Assoro, K. Boeneman, W. Liu, C. M. Whitehead, C. Reynolds, and J. L. Salisbury Centrosome amplification drives chromosomal instability in breast tumor development PNAS, February 19, 2002; 99(4): 1978 - 1983. [Abstract] [Full Text] [PDF]
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