Vol. 3, 1707-1711. October 1997 Clinical Cancer Research 1707

Intracellular Levels of SGP-2 (Clusterin) Correlate with Tumor

Grade in Prostate Cancer1

Joseph Steinberg, Ryoichi Oyasu, Sharon Lang,

Sharon Sintich, Alfred Rademaker, Chung Lee,

James M. Kozlowski, and Julia A. Sensibar�Departments of Urology [J. S., S. L., S. S., C. L., J. M. K., J. A. S.],

Pathology [R. 0.], and Preventive Medicine [A. RI, Northwestern

University Medical School, Chicago, Illinois 6061 1

ABSTRACT

Our previous observations in LNCaP cells in vitro dem-onstrated an association between apoptotic cell death resist-

ance and SGP-2 (Clusterin) overexpression. Accordingly, wehypothesized that high levels of cellular SGP-2 would aid in

identifying biologically aggressive prostate cancer cells with

unique survival advantages. To test this hypothesis, 40 ar-chival radical prostatectomy and/or biopsy specimens ofvarying grades of prostate cancer were subjected to immu-nohistochemical SGP-2 staining. The resulting epithelial

stains were quantified subjectively on a scale of 1-3 by four

independent observers. Benign prostatic epithelial cells fromyoung donors served as controls and showed a consistently

weak staining intensity. In contrast, prostate cancer speci-mens showed varying degrees of staining intensity that cor-

related with a Gleason pattern (P 0.006). This correlationsupports the hypothesis that protection from apoptoticdeath may account, in part, for biologically aggressive tu-mor behavior.

INTRODUCTION

Here, we describe the biological significance of SGP-2

(Clusterin) in prostate cancer progression. SGP-2 has been iden-

rifled as an inhibitor of apoptosis ( I ). It is a heterodimeric

glycoprotein that was first isolated from ram rete testes, and it

was so named for its ability to cluster Sertoli cells (2). This

protein has been found in a multitude of organisms and is highly

conserved. In the human genome, it exists as a single copy,

located on chromosome 8 (3). It is present in virtually all body

fluids and is expressed by cells lining body cavities. SGP-2 has

a multitude of proposed functions, including roles in tissue

Received 3/24/97; revised 6/6/97; accepted 6/17/97.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with I 8 U.S.C. Section 1734 solely to

indicate this fact.

� This research was supported in part by NIH Grants CA 95006 and CA60553 to the Lurie Cancer Center and by a gift to the Abraham “Terry’SRogovin Urological Oncology Laboratory, Lurie Cancer Center, North-western University Medical School, Chicago, IL.2 To whom requests for reprints should be addressed, at Department ofUrology, Northwestern University Cancer Center, 710 North FairbanksCourt, Room 8360, Chicago, IL 6061 1 . Phone: (3 12) 908-5301 : Fax:(312) 503-1831; E-mail: jas8S6@nwu.edu.

remodeling, reproduction, lipid transport, complement regula-

tion, and apoptosis (4). In models of apoptosis, SGP-2 expres-

sion is markedly elevated (5). Despite the original notion that

SGP-2 is merely a marker of programmed cell death, results of

our previous studies have suggested a protective role of SGP-2

in apoptosis (1). The protective effect of this protein is not

limited to prostate tissue but has been shown in other patholog-

ical conditions involving apoptosis, including kidney injury,

myocardial infarction, and the negative selection of thymocytes

(6-8). In these systems, SGP-2 is associated with surviving

cells, not with those undergoing apoptosis. It has been hypoth-

esized that its function is mediated through the stabilization of

cell membranes (9, 10).

This study was undertaken to determine whether there is a

difference in SGP-2 expression between low- and high-grade

prostate carcinomas, as classified by their Gleason pattern.

Prostate cancer has a low mitotic rate, compared to those of

other malignancies (I I , I 2). In addition, the apoptotic rate in

prostate cancer is significantly lower than the apoptotic index of

normal prostate tissue ( I 3). Consequently, the overall growth of

prostate adenocarcinoma is, at least in part, determined by its

rate of apoptosis. If SGP-2 protects cells from apoptosis, we can

expect those cells that express higher levels of this protein to be

relatively resistant to programmed cell death. In prostate cancer,

those tumors with a higher Gleason score tend to act in a more

aggressive manner. Therefore, if a positive correlation is found

between levels of SGP-2 and Gleason pattern, then SGP-2

might, at least in part, be a determining factor of this phenotypic

trait and may prove useful in the diagnosis and treatment of this

disease.

MATERIALS AND METHODS

Prostate Tissue Specimens. Prostate tissue, which was

obtained from the archival tissue bank in the Department of

Pathology, Northwestern Memorial Hospital, was used in ad-

cordance with the approved protocol of the Institutional Review

Board of Northwestern University Medical School. All tissues

were from either prostate needle biopsy or radical prostatectomy

specimens that were stored in paraffin blocks. Specimens were

chosen so as to represent the full range of Gleason scores. None

of these specimens came from patients who had had any pre-

operative hormonal ablative therapy in an attempt to down-stage

their tumor or to control their obstructive symptoms. Forty

archival samples were screened for prostate cancer, revealing 60

distinct regions of frank adenocarcinoma, 17 regions of benign

prostatic hyperplasia, and 8 regions of prostatic intraepithelial

neoplasia.

Immunocytochemical Staining for SGP-2. All patho-logical specimens were reviewed by one of us (R. 0.), and

Gleason scores were assigned. If a given specimen contained

tumors of more than one grade, then each area was considered

separately. Immunocytochemical staining was conducted using

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120

100

80

C0)C) 600,

0.

40

20

0

Fig. 1 SGP-2 immunointensity in varying grades of prostate cancer.Cytoplasmic staining was compared by using the mean results of fourdifferent reviewers. A total of 60 cancer specimens were evaluated. Thestaining intensities of the various grades differed significantly using the

Fisher exact test (P 0.006). �, +; D, ++: U, +++.

30 � 4 5

Gleason’s Grade

1708 Clusterin and Prostate Cancer

Table I SGP-2 immunostaining intensity in prostate tumor

specimens

Gleason’s score

Intensity 2 (a = 9) 3 (‘1 = 28) 4 (F, = 13) 5 (,i = 10)

+ 33% 11% (Yk 0%

++ 56% 64% 31% 30%+++ 11% 25% 69% 70%

a commercial kit (ABC kit: Vector Laboratories, Burlingame,

CA). Normal goat serum was used to block the nonspecific

binding sites on the slides, which were then incubated in a

humidified chamber for 18 h at 4#{176}Cwith a 1:1000 dilution (10

�.tg/ml) of an IgG antibody to SGP-2 (Quidel, San Diego, CA).

The antigen was visualized by subsequent incubation with bi-

otinylated secondary antibody and an avidin-biotin-horseradish

peroxidase complex and a 4-mm incubation in diaminobenzi-

dine tetrahydrochioride before counterstaining with Gill’s he-

matoxylin.

Negative control slides were processed in an identical

manner, with substitution of the primary antiserum with nonim-

mune rabbit IgG at the same concentration as that used for the

primary antiserum. No color reaction was observed in any

negative control slide.

Photomicrographs were taken through an Olympus Vanox

AHBS Research Microscope (Olympus Corp., Woodbury, NJ)

using Kodak Daylight 100 Ektachrome Professional film (East-

man Kodak, Rochester, NY).

Staining Intensity. The staining intensity of each slide

was reviewed by four independent evaluators (J. M. K., J. A. S.,

S. S., and S. P.), two of whom had no knowledge regarding

Gleason’s scores. Results were scored as “+,“ “+ +,“ and

“+ + +,“ representing mild. moderate, and heavy staining, re-

spectively. All comparisons of staining intensity were made at

X40 magnification. The average pattern of the four viewers for

each specimen was used in the final statistical analysis.

Statistics. Once a staining pattern was assigned to each

specimen, specimens could then be grouped according to grade

and staining intensity. The Fisher exact test was used to deter-

mine whether or not staining intensity increased with Gleason’s

grade. A P of less than 0.05 was considered statistically signif-

icant.

RESULTS

Staining Intensity of SGP-2 in Malignant Prostate

Tissues. To determine whether or not SGP-2 expression

increased with Gleason grade, samples containing frank

adenocarcinoma were stained for SGP-2 expression by immu-

nohistochemistry. Staining for SGP-2 was found in the cyto-

plasm of luminal epithelial cells. No nuclear staining was noted

in this study. When observed under higher magnification, the

cytoplasmic staining was noted to have a granular pattern,

suggesting that SGP-2 may be contained within secretory yes-

ides. There was a wide variation in staining intensity among the

specimens; however, there was a significant positive correlation

between SGP-2 staining intensity in carcinoma cells and in-

creases in Gleason’s grade (Table I : Figs. I and 2). Further-

more, when a carcinoma demonstrated more than one histolog-

ical pattern, the staining intensity of each of these areas differed

significantly (Fig. 3).

Staining Intensity of SGP-2 in Normal Prostatic Tissue.

Prostatic tissues derived from two organ donors (ages 13 and

18) were used for comparison with pathological specimens. All

specimens stained very lightly and were uniformly given a +

score (Fig. 4A).

Staining Intensity of SGP-2 in Benign Prostatic Hyper-

plasia. Tissue with benign prostatic hyperplasia was obtained

from benign areas present in prostates removed for carcinoma as

well as from benign glands removed solely for obstructive

symptoms. The staining intensity of this group was variable,

with the resulting divisions being 35% +, 59% + +, and 6%

+++ (Fig. 4B).

Staining Intensity of SGP-2 in Prostatic Intraepithelial

Neoplasia. Foci of prostatic intraepithelial neoplasia were se-

lected from specimens with frank carcinoma. The staining in-

tensity varied, with the resulting divisions being 12.5% +,

37.5% ++‘ and 50% +++ (Fig. 4C).

DISCUSSION

Results of the present study demonstrated that SGP-2 is

expressed in benign and malignant human prostate glands. As

the malignant specimens demonstrated more aggressive histo-

logical patterns, their staining intensity for SGP-2 increased.

Furthermore, the benign specimens showed a faint but consis-

tently positive stain for SGP-2. The persistence of this protein in

benign tissues lends credence to the hypothesis that SGP-2 not

only protects from apoptotic death in malignant tissues but is

also an important physiological protein needed for the mainte-

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Clinical Cancer Research 1709

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Fig. 2 Immunostaining of SGP-2 in various malignant prostate specimens. A, negative control of moderate grade tumor using sheep IgG. No stainingwas noted. B, immunostaining of a typical low-grade tumor; this is representative of a + intensity. C, immunostaining of a moderate-grade tumor;this is representative of a + + intensity. D, immunostaining of a high-grade tumor; this is representative of a + + + intensity. All specimens werecompared at X40 magnification.

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Fig. 3 Differential immunostaining intensities of SGP-2 within the same specimen. A. benign tissue showing a staining intensity of + . B, high tumorgrade showing an intensity of + + +. Magnification, X40.

nance and viability of all cells ( 1 ). Because it has been previ- human glioma, carcinogen-induced rat prostate carcinoma, and

ously shown that SGP-2 protects cells from apoptotic death (I, the Shionogi rat mammary carcinoma model (14-17). In these

6-8), increased expression ofthis protein may impart a survival systems, malignant tissues showed higher levels of SGP-2 than

advantage to a given cell or tissue. Therefore, SGP-2 could be did normal controls. In the Shionogi model, not only is there

an important factor in determining the aggressive nature of a increased expression of this protein compared to that in normal

given prostatic tumor. tissues, but persistent high levels of SGP-2 are associated with

To date, increased expression of SGP-2 has been described the progression to an apoptotic-resistant and androgen-indepen-

in four tumor systems. These include human renal carcinoma, dent phenotype ( I 8). To our knowledge, the present study is the

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1710 Clusterin and Prostate Cancer

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Fig. 4 Immunostaining of SGP-2 in benign and premalignant prostate specimens. A, normal prostate tissue from an organ donor (X 100). This wasconsidered an intensity of +. B, benign prostatic hyperplasia (X40). This was considered an intensity of + +. C, prostatic intraepithelial neoplasia(X40). This was considered an intensity of + + +.

first report of SGP-2 expression in human prostatic adenocar-

cinoma.

Here, we have observed that SGP-2 was localized to the

cytoplasm of prostate cancer cells. None of our specimens

showed any localization of SGP-2 to the nucleus. Using the

Shionogi carcinoma model, both cytoplasmic and nuclear stain-

ing for SGP-2 were noted. However, nuclear staining was only

found in androgen-independent cells ( I 5). A nuclear form of

SGP-2 has recently been identified in two epithelial cell lines

( 19). Whether or not this phenomenon occurs in human prostate

cancer remains to be seen.

Although the mechanism of its action remains unclear, it is

postulated that SGP-2 is required for cell survival. Prolonged

depletion of intracellular SGP-2 will result in apoptosis. Our

previous observations showed levels of SGP-2 rise in response

to TNF-ci (an apoptotic inducer) in the LNCaP cell model.

These same cells were found to undergo apoptosis only after

depletion of this protein occurred (1). Because similar kinetics

of SGP-2 expression were observed in the rat prostate following

castration (4, 20), it is proposed that SGP-2 has a similar role in

normal prostate tissue as well. Results of the present study

indicate that malignant epithelial cells contain more SGP-2 than

do benign cells. This suggests that tumor cells will require a

larger stress to induce apoptosis than their benign counterparts.

This difference in apoptotic threshold may provide these malig-

nant cells with an added survival advantage compared to benign

prostatic epithelial cells.

In addition to SGP-2, the BcI-2 family of proteins is also

known to inhibit apoptosis (21-24). However, these proteins

differ from SGP-2 in their distribution and possibly in their

functional mechanisms. To date, of the apoptotic inhibitory

proteins, only Bcl-2, Bdl-xL, and Mcl-l have been correlated to

Gleason pattern (25). Although this correlation has not consis-

tently reached significance in the literature, increased expression

of these proteins have consistently correlated with hormone

refractory tumors (26, 27). Expression of antiapoptotic proteins

appears to be a common feature of aggressive prostate cancers.

In conclusion, these results suggest a positive correlation

between staining intensity of SGP-2 by immunohistochemical

analysis and Gleason pattern in prostate cancer. If increased

levels of this protein protect from apoptosis in a given tumor,

then those cells that express SGP-2 at high levels may have a

survival advantage. This advantage can, in part, account for their

aggressive nature. As we found variability in staining intensity

among tumors of the same Gleason pattern, SGP-2 expression

may prove to be a prognostic indicator independent of grade.

Therefore, SGP-2 may play an important role in determining the

phenotypic aggressiveness of prostate cancer. It may ultimately

prove to be of prognostic and therapeutic value in the future.

ACKNOWLEDGMENTS

We would like to thank Shaina Pruden for her help with grading thevarious prostate specimens according to stain intensity.

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Clinical Cancer Research 1711

REFERENCES

1. Sensibar, J., Sutkowski, D., Raffo, A., Buttyan, R., Griswold, M.,Sylvester, S., Kozlowski, J., and Lee, C. Prevention of cell deathinduced by tumor necrosis factor a in LNCaP cells by overexpression of

sulfated glycoprotein 2 (Clusterin). Cancer Res., 55: 2431-2437, 1995.

2. Sylvester, S. R., Skinner, M. K., and Griswold, M. D. A sulphatedglycoprotein synthesized by Sertoli cells and by epididymal cells is a

component of the cell membrane. Biol. Reprod., 31: 1087-1101, 1984.

3. Koch-Brandt, C., and Morgans, C. Clusterin. A role of cell survivalin the face of apoptosis? In: Y. Kuchino and W. E. B. Muller (eds.).Apoptosis, pp. 130-148. Berlin: Springer Verlag, 1996.

4. Rosenberg, M. E., and Silkensen, J. Clusterin. Physiologic and patho-

physiologic considerations. Int. J. Biochem. Cell Biol., 27: 633-645,1995.

5. Lee, C., and Sensibar, J. A. Proteins of the rat prostate II: synthesisof new proteins in the ventral lobe during castration induced regression.

J. Urol.. 138: 903-908, 1987.

6. Rosenberg, M. Cellular responses to renal injury. Presented at the10th International Symposium on Cellular Endocrinology: Molecularand Cell Biology of Apoptosis in Development, Disease, and Cancer,held September 29-October 2, 1994 at the W. Alton Jones Cell ScienceCenter, Lake Placid, NY.

7. Swertfeger D. K., Witte, D. P., and Harmony, J. A. K. Cardiac injuryinduces apolipoprotein J expression in ventricular thymocytes. Pre-

sented at The Second Clusterin Workshop, held September 3-5, 1994, inCoeur d’Alene, ID. Abstract no. 7.

8. French, L. E., Sappino, A. P., Tschopp, J., and Schifferli, J. A.

Distinct sites of production and deposition of the putative cell death

marker Clusterin in the human thymus. J. Clin. Invest., 90: 1919-1925,

1992.

9. Aronow, B. J., Lund, D. S., Brown, T. L., Harmony, J. A. K., andWitte, D. P. Apolipoprotein J expression at fluid-tissue interfaces.Potential role in barrier cytoprotection. Proc. Natl. Acad. Sci. USA, 90:

725-729, 1993.

10. Jordan-Starck, T. C., Witte, D. P., Aronow, B. J., and Harmony,J. A. K. Apolipoprotein J: a membrane policeman? Curr. Opin. Lipidol.,3: 75-85, 1992.

II. Berges, R. R., Vukanovic, J., Epstein, J. I., CarMichel, M., Cisek,

L., Johnson, D. E., Veltri, R. W., Walsh, P. C., and lsaacs, J. T.Implication of cell kinetic changes during the progression of humanprostatic cancer. Clin. Cancer Res., 1: 473-480, 1995.

12. Denmeade, S. R., Lin, X. S., and Isaacs, J. T. Role of programmed

(apoptotic) cell death during the progression and therapy for prostatecancer. Prostate, 28: 251-265, 1996.

13. Tu, H., Jacobs, S. C., Borkowski, A., and Kyprianou, N. Incidence

of apoptotis and cell proliferation in prostate cancer: relationship withTGF-�3 and bcl-2 expression. Int. J. Cancer, 69: 357-363, 1996.

14. Parczyk, K., Pilarsky, C., Rachel, U., and Koch-Brandt, C. Gp80(Clusterin;TRPM-2) mRNA level is enhanced in human renal clear cell

carcinomas. J. Cancer Res. Clin. Oncol., 120: 186-188, 1994.

15. Rennie, P. S., Bruchovsky, N., Akakura, K., Goldenberg, S. L.,Otal, N., Akakura, S., Wong, P., and Tenniswood, M. Effect of tumour

progression on the androgenic regulation and the androgen receptor,

TRPM-2 and YPT1 genes in the Shionogi carcinoma. J. Steroid Bio-chem. Mol. Biol., 50: 31-40, 1994.

16. Kadomatsu, K., Anzano, M., Slayter, M. V., Winokur, T. 5., Smith.J. M., and Sporn, M. B. Expression of sulfated glycoprotein 2 is

associated with carcinogenesis induced by N-nitroso-N-methylurea in

rat prostate and seminal vesicle. Cancer Res., 53: 1480-1483, 1993.

17. Danik, M., Chabot, J-G., Mercier, C., Benabid, A-L., Chauvin, C..

Quirion, R., and Suh, M. Human glioma and epileptic foci express highlevels of a mRNA related to rat testicular sulfated glycoprotein 2, a

purported marker of cell death. Proc. Natl. Acad. Sci. USA, 88: 8577-8581, 1991.

18. Bruchovsky, N., Snoek, R., Rennie, P., Akakura, S., Goldenberg,

L., and Gleave, M. Control of tumor progression by maintenance ofapoptosis. Prostate, 6 (Suppl.): 13-21 , 1996.

19. Reddy, K. B., Jin, G., Karode, M. C., Harmony. J. A., and Howe,P. H. Transforming growth factor �3 (TGF-�3)-induced nuclear localiza-tion of apolipoprotein J/Clusterin in epithelial cells. Biochemistry. 35:

6157-6163, 1996.

20. Sensibar, J. A., Griswold, M. D., Sylvester, S. R., Bunyan, R.,Bardin, C. W., Cheng, C. Y., Dudek, S., and Lee, C. Prostatic ductal

system in rats: regional variation in localization of an androgen re-

pressed gene product, sulfated glycoprotein-2. Endocrinology, 128:

2091-2102, 1991.

21. Reed, J. C. Regulation ofapoptosis by Bcl-2 family proteins andits role in cancer chemoresistance. Curr. Opin. Oncol., 7: 54 1-546.

1995.

22. McConkey, D., Greene, G., and Pettaway, C. Apoptosis resistanceincreases metastatic potential in cells of the human LNCaP prostate

carcinoma line. Cancer Res., 56: 5594-5599, 1996.

23. Boise, L. H., Gonzalez-Garcia, M., Postema, C. E., Ding, L..

Lindsten, T., Turka, L., Mao, X., Nunez, G., and Thompson, C. D.

Bcl-x, a Bcl-2 related gene that functions as a dominant regulator ofapoptotic cell death. Cell, 74: 597-608, 1993.

24. Reynolds, J. E., Yang, T., Qian, L., Jenkinson, J. D., Zhou. P.,

Eastman, A., and Craig, R. W. Md-I, a member of the Bcl-2 family

delay apoptosis induced by c-Myc overexpression in Chinese hamster

ovary cells. Cancer Res., 54: 6348-6352, 1994.

25. Krajewska, M., Stanislaw, K., Epstein, J. I., Shabaik, A., Sauvegeot,J., Song, K., Kitada, S., and Reed, J. C. Immunochemical analysis Bcl-2,Bax, Bcl-x, and Mcl-l expression in prostate cancers. Am. J. Pathol.,148: 1567-1576, 1996.

26. Columbel, M., Symmans, F., Gil, S., O’Toole, K. M., Chopin. D.,

Benson, M., Olsson, C. A., Korsmeyer, S., and Buttyan, R. Detection of

apoptosis-suppressing oncoprotein bcl-2 in hormone refractory prostate

cancers. Am. J. Pathol., 143: 390-399, 1993.

27. McDonnell, T. J., Troncoso, P., Brisbay, S. M., Logothetis, C..Chung, L. W. K., Hsieh, J. T., Tu, S. M., and Campbell, M. L.Expression of the protooncogene bcl-2 in the prostate and its association

with emergence of androgen-independent prostate cancer. Cancer Res..52: 6940-6944, 1992.

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