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[Cancer Research 61, 3882-3885, May 15, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Secreted Caveolin-1 Stimulates Cell Survival/Clonal Growth and Contributes to Metastasis in Androgen-insensitive Prostate Cancer1

Salahaldin A. Tahir, Guang Yang, Shin Ebara, Terry L. Timme, Takefumi Satoh, Likun Li, Alexei Goltsov, Michael Ittmann, Joel D. Morrisett and Timothy C. Thompson2

Scott Department of Urology [S. A. T., G. Y., S. E., T. L. T., T. S., L. L., A. G., T. C. T.], Department of Pathology [M. I.], Department of Medicine [K. D. M.], Department of Cell and Molecular Biology [T. C. T.], and Department of Radiology [T. C. T.], Baylor College of Medicine, Houston, Texas 77030, and Veterans Affairs Medical Center [T. L. T., M. I., T. C. T.], Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Caveolin-1 is an integral protein of caveolae, known to play important roles in signal transduction and lipid transport. We demonstrate that caveolin-1 expression is significantly increased in primary and metastatic human prostate cancer after androgen ablation therapy. We also show that caveolin-1 is secreted by androgen-insensitive prostate cancer cells, and that this secretion is regulated by steroid hormones. Significantly, caveolin-1 was detected in the MDL3 fraction of serum specimens from patients with advanced prostate cancer and to a lesser extent in normal subjects. Conditioned media from high passage caveolin-1 secreting, androgen-insensitive, LNCaP cells stimulated increased viability and clonal growth of low passage, caveolin-1-negative, androgen-sensitive, LNCaP cells in vitro, and this effect was blocked by treating the media with caveolin-1 antibody. i.p. injections of caveolin-1 antibody suppressed the orthotopic growth and spontaneous metastasis of highly metastatic, androgen-insensitive caveolin-1-secreting mouse prostate cancer. Overall, our results establish caveolin-1 as an autocrine/paracrine factor that is associated with androgen-insensitive prostate cancer. We demonstrate the potential for caveolin-1 as a therapeutic target for this important malignancy.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Caveolins (designated cav-1, cav-2, and cav-3) are major structural proteins of caveolae, specialized plasma membrane invaginations that are abundant in smooth muscle cells, adipocytes, and endothelium. Numerous studies have shown that cav-1 regulates multiple signal transduction pathways and mediates intracellular trafficking of cholesterol (1, 2, 3) . We have shown previously that cav-1 mRNA and protein expression are elevated in metastatic mouse and human prostate cancer cells compared with their matched primary tumor counterparts, and that cav-1 expression has independent prognostic value in prostate cancer patients after radical prostatectomy (4 , 5) . In addition, we demonstrated that enforced cav-1 expression can suppress apoptosis stimulated by withdrawal of growth factors and testosterone or by c-myc overexpression in metastatic prostate cancer cells (6 , 7) . Interestingly, Liu et al. (8) have recently reported that cav-1 is secreted from normal pancreatic acinar cells in response to specific secretagogues such as secretin, cholecystokinin, and Dex,3 raising the possibility of an autocrine/paracrine or endocrine function for cav-1.

To analyze the expression of cav-1 in androgen-insensitive prostate cancer we determined the pattern of expression for cav-1 in relevant human prostate cancer tissues. We also investigated the possibility that cav-1 is secreted by prostate cancer cells and that secreted cav-1 could influence metastatic progression.

Our results establish cav-1 as an autocrine/paracrine factor that is highly expressed in androgen-insensitive prostate cancer. We further demonstrate the potential for cav-1 as a therapeutic target for this disease.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Patients and Specimens.
61 Stage D prostate cancer patients were included in this study. For each patient, one primary prostate cancer and one or more metastatic cancer specimens from different organs were obtained either at the time of radical prostatectomy or at autopsy. From the 11 hormone-refractory patients, a total 33 metastases were derived from lymph node (n = 12), lung (n = 8), bone (n = 1), liver (n = 5), adrenal gland (n = 1), bladder (n = 2), brain (n = 1), and soft tissue (n = 3). Fifty-five metastases were obtained from the 50 nontreated patients, which included lymph node (n = 48), lung (n = 2), bone (n = 2), liver (n = 1), bladder (n = 1), and soft tissue (n = 1). Tissues were fixed in 10% formalin and embedded in paraffin according to a routine procedure. Six-µm sections were made from the tissue blocks, and some were stained with H & E for morphological evaluation. They were immunostained using a polyclonal cav-1 antibody and the avidin-biotin complex procedure previously described (4) . The immunostained sections were evaluated at a power of x200 under a Zeiss microscope. For each specimen, the whole cancer area was scanned. Positive cav-1 staining was defined as the presence of any microscopic field in which cancer cells gave rise to cav-1-positive granular immunoreaction products in their cytoplasm. Serum samples were obtained from five patients with radiorecurrent prostate cancer and four healthy individuals. Serum lipoproteins were separated into lipoprotein sub-fractions by KBr density gradient ultracentrifugation following a modified method of Redgrave et al. (9) .

Cell Culture.
Mouse prostate cancer cell lines derived from primary tumors (148-1PA and 151-1PA) or metastatic deposits (178-2BMA, 148-1LMD, 151-2LMB, 151-2LMC, and 151-1LM1), were cultured as described previously (6 , 10) . The growth media for the different cells was in 10% fetal bovine serum as follows: RPMI 1640 for LNCaP; MEM-NEAA for DU145; F12K for PC3; F12K supplemented with heparin and endothelial cell growth supplement for human umbilical vascular endothelial cell; and DMEM for human intestinal smooth muscle and all mouse cells. The human cav-1 cDNA in pcDNA3.1 was transfected into LNCaP cells with Tfx reagent (Promega, Madison, Wisconsin; Ref. 7 ). For conditioned medium preparation, subconfluent cultures were washed three times with PBS and incubated with SFM for 24 h; the media was collected and contamination of membranous cav-1 from cell debris was minimized by centrifugation at 1,000 x g and then at 100,000 x g. Conditioned media for in vitro viability assays (see below) was concentrated x20 and treated with cav-1 antibody or IgG (10 µg/ml) and incubated for 4 h at 4°C.

Western Blot Analysis.
Conditioned media was collected and centrifuged as described above and 1 ml concentrated by TCA precipitation. The precipitate was redissolved in 70 µl of SDS sample buffer and 30 µl were loaded per well. Proteins obtained from lysed cells and from TCA-precipitated conditioned media were separated by 12% SDS-PAGE, and transferred to nitrocellulose membranes. Membranes were prestained with Ponceau S before blocking to verify even loading. The membranes were blotted with rabbit polyclonal cav-1 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) for 24 h at 4°C, with shaking. After incubation with horseradish peroxidase-conjugated secondary antibodies (ICN/CAPPEL, Aurora, OH), the binding was detected by enhanced chemiluminescence, Super Signal (Pierce Chemical Co., Rockford, IL).

Cell Viability Assays.
The viability by MTT was measured according to the previously described method (6) . The cell viability was also measured after the initial period of incubation by an ATP-based assay using the Packard ATPLite-M kit (Packard, Meridian, CT) according to the manufacturer’s procedure, and the cell viability was expressed as the amount of light production/cell number in each well. For the clonogenic assay, 200 cells were treated in SFM or conditioned media as described in the cell viability assay. The medium was then carefully removed, and cells were trypsinized and reseeded to 10-cm plates with complete medium and grown for 10–15 days. Colonies were stained with MTT in the culture medium, and the numbers of colonies were counted using Advanced Colony Counting software (NucleoTech Corp., Hayward, CA). Each experiment was repeated three to five times.

In Vivo Metastasis Analysis.
Orthotopic tumors of 178–2BMA in male mice were generated by injecting 5000 cells directly into the dorso-lateral prostate. The mice were subsequently treated with control rabbit IgG or rabbit polyclonal cav-1 antibody via i.p. injections (10 µg/animal every other day). After 3 weeks, the tumors were removed and the wet-weight determined. Metastatic activity to lung was evaluated by counting Bouin’s fixative-stained lungs under a dissecting microscope. Femur bones and pelvic lymph nodes were removed and processed for paraffin sections after a routine procedure. Five-µm sections were cut and stained with H&E for morphological evaluation. To better identify metastatic cancer cells in bone marrow, the adjacent sections were immunostained using the standard avidin-biotin complex procedures (MOM kit; Vector Laboratories, Burlington, CA) in conjunction with a monoclonal antibody to cytokeratin 8 (Dako Corp., Carpinteria, CA). The metastatic cancer cells were counted and data expressed as cancer cell number/microscopic field of bone marrow area. Pelvic lymph nodes metastatic cancer cells were labeled with cytokeratin-18 antibody. The incidence of positive lymph nodes was recorded for each animal and the percentages of metastatic cancer deposits in individual lymph nodes were also measured.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
We evaluated the effect of androgen ablation therapy on cav-1 expression by immunohistochemistry in a large panel of primary tumor tissues and specimens of lymph node, bone, and soft tissue metastases from stage D prostate cancer patients obtained before and after hormonal treatment (Table 1)Citation . Our previous studies using a distinct set of tissue specimens demonstrated that the frequency of cav-1 positivity was 8% in normal glandular epithelia; 29% in primary cancers with nodal metastases; and 56% in the nodal metastases per se (4) . In this study, the frequency of cav-1-positive primary prostate cancers was increased from 38% in the hormonally naive patient group to 73% in the hormone refractory patient group (P < 0.05; {chi}2 test). Cav-1 positivity was demonstrated in 62% of the metastatic specimens from patients who had not been treated with hormone therapy, and this frequency was also significantly increased to 82% of metastases from patients treated with hormones (P < 0.05; Mann-Whitney test).


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  		Table 1 Caveolin-1 expression in Stage D prostate cancers in response to hormonal treatment

 
Additional analysis demonstrated that the percentage of cav-1-positive cells was significantly increased from 18.6% in primary tumors to 29.9% in hormone-treated primary tumors (P < 0.05; Mann-Whitney test). The percentage of cav-1-positive cells in metastatic specimens of treated patients was higher (38%) than in specimens from untreated patients (35.5%), but this increase was not significant (P > 0.05; Mann-Whitney test). Increased cav-1 positivity in hormone-refractory prostate cancer is consistent with several reports that have correlated overexpression of cav-1 with multidrug resistance independent of P-glycoprotein in human cancer cell lines from various tumor types (11, 12, 13) . It was of interest that the highest percentage of cav-1-positive cells documented (hormone refractory metastases) approached but did not exceed 40%. These results prompted us to investigate the possibility that cav-1 is secreted by prostate cancer cells and functions as a paracrine/autocrine factor.

Cav-1 was detected in conditioned media from androgen-insensitive mouse (151-1LM1, 178-2BMA, 151-2LMC, 151-2LMB, and 148-1LMD), and human (DU145, PC3, and TSU-Pr1) prostate cancer cells in variable amounts. In androgen-sensitive, LP-LNCaP cells, cav-1 was not expressed; yet in HP-LNCaP cells that had reduced androgen-sensitivity, cav-1 was expressed and secreted into the medium. In contrast, nonprostatic cells such as endothelial, fibroblast, and smooth muscle had a substantial amount of intracellular cav-1 yet minimal or nondetectable levels of cav-1 in their conditioned media (Fig. 1A)Citation .



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  		Fig. 1. Cav-1 secretion assessed by Western blot analysis. A, Cav-1 in human and mouse prostate cancer cell lysates and conditioned media. The protein concentration in each well was controlled by loading equal quantities of cell lysate and equal volumes of TCA-precipitated conditioned media. Loading was monitored by staining the membrane after transfer with Ponceau S. No visible protein bands were detected in the conditioned media lanes. B, Cav-1 secretion by HP-LNCaP and 178-2BMA cells in response to DHT and Dex. Conditioned media were collected after incubation of subconfluent cells with SFM in the presence or absence of hormones for 24 h. C, effect of DHT on the ectopically expressed cav-1 secretion in LP-LNCaP cells compared with that of endogenous prostate-specific antigen. Cells were transfected with cDNA encoding for full-length human cav-1; 48 h after transfection, cells were incubated in SFM with or without DHT for 24 h; 0.5 ml of TCA-precipitated media was analyzed. D, cav-1 in dialyzed and lyophilized serum HDL3 fraction (50 µg of protein) of prostate cancer patients and healthy individuals.

 
We used the mouse prostate cancer cell line 178-2BMA,4 derived from a bone metastasis generated from the metastatic mouse prostate reconstitution model, (10) and HP-LNCaP to test the possible regulation of cav-1 secretion by DHT and Dex in vitro. Both cell lines were shown to be insensitive to androgen in vitro, i.e., no significant changes in cell number or viability were detected under serum-free conditions in the presence and absence of 10 nM testosterone (data not shown). The results showed that cav-1 (Mr 21,000) was secreted by 178-2BMA cells in response to these steroid hormones, reaching the highest levels at 10 nM DHT and 100 nM Dex (Fig. 1B)Citation . The increase in secreted cav-1 in response to these secretagogues was paralleled by a decrease in intracellular cav-1 (not shown). A similar pattern for cav-1 secretion was observed in HP-LNCaP cells (Fig. 1B)Citation .

We investigated the secretory route for cav-1 by expressing human cav-1 in cav-1-negative LP-LNCaP cells. After transfection, a substantial amount of ectopically expressed cav-1 was detected in the media compared with that in the cell lysate, and cav-1 secretion was increased in response to DHT. Cav-1 was not detected in the media or cell lysate of the vector control-transfected cells, yet all transfected cells excreted prostate-specific antigen into the media in a DHT-regulated fashion (Fig. 1C)Citation . These results show that cav-1 is secreted by androgen-insensitive mouse and human prostate cancer cells in response to specific steroid hormones. Although we do not provide evidence for the mechanism by which cav-1 enters the secretory pathway, the results show that ectopically expressed cav-1 is secreted by LNCaP cells, and that secreted cav-1 migrates on SDS-PAGE similarly to that derived from endothelial cells and fibroblasts, suggesting that the secreted form is not modified posttranscriptionally. To determine whether cav-1 could also be secreted by human prostate cancer cells in vivo, we fractionated human serum and analyzed various fractions for cav-1. Our results revealed that cav-1 is specifically detected in the serum HDL3 lipoprotein subfraction, and that cav-1 levels may be higher in the serum of prostate cancer patients compared with the serum of normal individuals (Fig. 1D)Citation .

The function of secreted cav-1 was investigated by testing the effects of concentrated conditioned media collected from HP-LNCaP cells on LP-LNCaP cell viability and clonal growth under serum-free conditions. The results indicate that secreted cav-1 was capable of promoting viability, using a standard MTT method (Ref. 6 ; Fig. 2ACitation ) or luminescent technique (Packard ATPLite; Fig. 2BCitation ) and of stimulating viability/clonal growth using a clonogenic assay (Fig. 2C)Citation . To test whether such activities would be specific for the cav-1 molecule, polyclonal cav-1 antibody was added to conditioned media or rabbit IgG as a control. Treatment of the conditioned media with anti-cav-1 antibody reduced the viability significantly (P < 0.001 for MTT and clonogenic assays and P < 0.0001 for ATPLite assay) compared with the IgG-treated medium. We also tested the effect of secreted cav-1 on Tg-induced apoptosis in LP-LNCaP cells. Tg promotes apoptosis (14) , characterized by caspase activation and the appearance of apoptotic bodies in these cells (data not shown). The results indicated that secreted cav-1 was able to protect the cells from the apoptotic effects of this drug (Fig. 2D)Citation . These studies revealed that media containing secreted cav-1 generates antiapoptotic activities in prostate cancer cells similar to those elicited after enforced expression of cav-1 within the cell (6 , 7) .



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  		Fig. 2. Effect of cav-1 in conditioned media on LP-LNCaP cells. A, cell viability measured by MTT assay. Cells were incubated in SFM as a control or in conditioned media for 72 h and stained with MTT, and viable and dead cells were counted. The viability is expressed as a fold of increase relative to SFM. B, ATPLite assay for cell viability on cells treated as in A. C, clonogenic assay for the effect of secreted cav-1 on LNCaP cells. Cells were treated for 72 h in conditioned media then transferred to growth media. D, effect of secreted cav-1 on the viability of LNCaP cells treated with Tg. cav-1 protected the cells from the Tg (0.2 µM) -induced apoptosis. *, P < 0.05; **, P < 0.001.; ***, P < 0.0001 (ANOVA).

 
We then tested whether blocking secreted cav-1 activity in vivo with specific antibodies would result in therapeutic activity, potentially through abrogation of the antiapoptotic effects of secreted cav-1. Androgen-insensitive 178-2BMA cells that spontaneously metastasize with high frequency (nearly 100%) to lung, lymph nodes, and bone were grown as orthotopic tumors in adult male mice. After 21 days of treatment with cav-1 antibody or IgG, the animals were sacrificed. The mean tumor wet-weight (Fig. 3A)Citation and the mean number of lung metastases (Fig. 3B)Citation of the anti-cav-1-treated group was significantly lower than the IgG-treated group (P < 0.01 and P < 0.05, respectively). The cav-1 antibody-treated group also had a significantly lower percentage of cancer cell volume in lymph nodes (P < 0.01; Fig. 3CCitation ). The metastatic cell density in the bone marrow (Fig. 3D)Citation was also reduced significantly (P < 0.05) in the cav-1 antibody-treated mice compared with those of the IgG-treated group. These results show that neutralization of secreted cav-1 in vivo by specific antibody suppresses primary prostate tumor growth and spontaneous metastasis to the lung, lymph nodes, and bone.



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  		Fig. 3. Antitumor and antimetastatic effect of cav-1 antibody treatment in mice with 178-2BMA orthotopic tumors. A, prostate tumor wet-weight in untreated, IgG-treated, and cav-1 antibody-treated mice. B, number of lung metastatic cells. C, percentage of volume of cancer deposits in lymph nodes. D, bone marrow metastatic cell density. *, P < 0.05; **, P < 0.01 (Mann-Whitney test).

 
Overall, the results of this study contribute significantly to the understanding of androgen-insensitive prostate cancer. Previous studies have documented that bcl-2 overexpression may characterize a subset of androgen-insensitive disease (15) . The aberrant expression of HER-2/neu has been implicated in androgen independence in animal models (16) and by immunohistochemical analyses of human specimens (17) . However, as reviewed by Scher (18) , the role of HER-2/neu in prostate cancer progression is not as self-evident as it is in breast cancer. In this study, we demonstrate that cav-1 up-regulation is associated with the development of androgen-insensitive prostate cancer, and that androgen-insensitive prostate cancer cells secrete biologically active cav-1 in a steroid-regulated fashion. We have shown that testosterone up-regulates cav-1 expression in prostate cancer cells, in part, through transcriptional activation.5 Therefore, in the presence of testosterone, cav-1 expression and/or secretion may be significantly stimulated in prostate cancer cells. Androgen ablation may select for alternative pathways of cav-1 regulation that could include glucocorticoid-stimulated cav-1 secretion, as shown here. It was shown previously that polypeptide growth factors can regulate cav-1 expression in NIH 3T3 cells (19) . Therefore cav-1 expression and secretion may be stimulated initially by androgens, yet subsequent androgen ablation may select for alternative pathways that sustain cav-1 activities and thus transition the malignant cell into an androgen-insensitive phenotype. As shown in this study, secreted cav-1 can stimulate viability and clonal growth in adjacent prostate cancer cells that do not express cav-1.

The concept of a secreted autocrine/paracrine factor that directly contributes to androgen resistance in prostate cancer is novel and represents an efficient mechanism for maximizing resistance to various proapoptotic stimuli that metastatic cells often encounter during the highly inefficient process of metastasis (20) . Our in vivo studies indicating that cav-1-specific antibody delivered i.p. can suppress malignant progression of androgen-insensitive, cav-1-secreting mouse prostate cancer cells are remarkable. These results not only indicate that secreted cav-1 promotes metastasis in vivo, but also raise the possibility of using cav-1 as a therapeutic target for androgen-insensitive disease. It is conceivable that when combined with anti-androgen therapy or potentially with chemotherapy, cav-1-specific antibody therapy may have greater therapeutic activity. Additional studies will be required to address this issue.


   FOOTNOTES
 
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 This work was supported by Grants CA 50588, CA 68814, and SPORE P50-58204 from the National Cancer Institute and DAMD17-98-1-8575 from the Department of Defense. Back

2 To whom requests for reprints should be addressed, at Scott Department of Urology, 6560 Fannin Street, Suite 2100, Houston, TX 77030. Phone: (713) 799-8718; Fax: (713) 799-8712; E-mail: timothyt{at}www.urol.bcm.tmc.edu Back

3 The abbreviations used are: cav-1, caveolin-1; Dex, dexamethasone; HDL, high-density lipoprotein; TCA, trichloroacetic acid; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; LP-LNCaP, low-passage LNCaP cells; HP-LNCaP, high-passage LNCaP cells; DHT, dihydrotestosterone; SFM, serum-free medium; Tg, thapsigargin. Back

4 Shaker et al., in press. Back

5 Li et al., in press. Back

Received 1/31/01. Accepted 3/29/01.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
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