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Experimental Therapeutics |
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Decorin is a small proteoglycan that is a normal component of the cell matrix involved in tissue scaffolding through its ability to bind to collagen (2) . Decorin has been shown to inhibit the growth of cancer cells, and it may induce the cyclin-dependent protein kinase inhibitor p21Waf1/Cip1 (hereafter referred to as p21), which is a potent inhibitor of cell growth. Decorin was also shown to inhibit the growth of various nonovarian tumor cells by up-regulating expression of p21 (3, 4, 5) . Decorin was shown to act through activation of the EGF3 receptor (4) , and endocytosis receptors are used for decorin degradation (5) .
Decorin may also inhibit TGF-
signaling by binding to TGF- such that it interferes with binding to the TGF- receptor complex (6)
. This effect may inhibit the immunosuppressive activity of tumor-produced TGF-, as suggested recently by the successful treatment of experimental glioma in mice with decorin (7)
. Inactivation of TGF- by decorin can restore in vitro T-cell responses in isolates obtained from persons infected with Mycobacterium tuberculosis (8)
. Decorin may also interfere with tumor cell metastasis by competitively inhibiting cell attachment to thrombospondin-1 (9)
, which has been shown to enhance the invasiveness of breast cancer cells (10)
. Interestingly, TGF- also forms complexes with thrombospondin-1 (11)
and may facilitate metastasis by enhancing the adhesion of melanoma cells to endothelial cells (12)
.
Overexpression of TGF- by tumor cells can increase their resistance to chemotherapy (13)
. Decorin has shown synergism in vivo with several chemotherapy agents (including cisplatin) in reducing the growth of murine mammary carcinomas, presumably through its ability to block the activity of TGF- (14)
. Although the matrix of a tumor is virtually decorin free (15)
, the stroma surrounding the tumor may have a high decorin content, suggesting a site-generated attempt to block the growth of the tumor (4)
.
In the present study, we have examined the inhibitory effects of decorin on the growth of ovarian tumor cells in vitro, explored possible mechanisms of decorin-induced inhibition of ovarian tumor cell growth, and examined the effects of decorin plus carboplatin on tumor cell growth in vitro. We also showed that the decorin-induced growth suppression seen in cells grown on plastic is probably attributable, mainly if not exclusively, to the up-regulation of p21.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1, TGF-2, c-myc, and horseradish peroxidase-conjugated goat antirabbit serum (sc-2004) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). The neutralizing anti-TGF- antiserum (AB-100-NA) was obtained from R & D Systems (Minneapolis, MN). Monoclonal antibody (MAB374) to the housekeeping gene GAPDH was obtained from Chemicon International, Inc. (Temecula, CA). Porcine TGF-1 (101-B1–002) and TGF-2 (102-B2–001) were obtained from R & D Systems.
Cell Culture.
The established human ovarian cancer cell lines SKOV3 and 2774 were maintained in RPMI 1640 (Life Technologies, Inc., Gaithersburg, MD) supplemented with 10% FCS and incubated at 37°C in 5% CO2. The 2774 cell line was obtained from J. Sinkovics and characterized in our laboratory (16)
, and the SKOV3 line was from the American Type Culture Collection (Rockville, MD).
Tumor Cell Inhibition Assays.
Cell proliferation assays were performed, with some modifications, using MTT uptake (Sigma Chemical Co., St. Louis, MO) to monitor growth as described previously (17)
. Cells were seeded into flat-bottomed 96-well plates in 100 µl of growth medium/well and allowed to attach and grow overnight. The medium was then replaced with 100 µl of growth medium containing human decorin (>95% pure), produced from genetically modified Chinese hamster ovary cells as described (18)
and kindly provided by Integra Lifesciences, Inc. (San Diego, CA) and/or carboplatin (Bristol Laboratories, Princeton, NJ) at the indicated concentrations and cultured for 2 additional days. MTT (26 µl of a 5-mg/ml solution in RPMI) was added and incubated at 37°C for 2.5 h. The purple formazan product (produced by reduction of MTT by succinyl dehydrogenase in the mitochondria of living cells) was solubilized overnight at 37°C with 20% SDS and 50% dimethyl formamide. In a modification used in most of the experiments reported here, the MTT-containing tissue culture fluid was removed from the wells, and the product was solubilized in 100 µl of DMSO for 5–10 min at room temperature. The plate was read at 570 nm in a plate reader (BioTech, Winooski, VT). Four replicate wells were used to obtain all data points, and all of the reported experiments were performed at least twice.
In some of the experiments, cells were added to wells pretreated with Matrigel (Becton Dickinson Labware, Franklin Lakes, NJ), an artificial basement membrane matrix. In these experiments, Matrigel was first diluted with RPMI (0.5 ml RPMI plus 1.0 ml Matrigel), and 25 µl of the diluted Matrigel were added per well. The matrix was allowed to gel for 30 min at 37°C before adding the cell suspension.
Western Blot Assays.
Decorin-treated and -untreated cells were released from the plastic with trypsin-EDTA (Life Technologies, Inc., Gaithersburg, MD) and suspended in growth medium. The cells were spun down, washed once by centrifugation with PBS, incubated in NP40 cell lysis buffer (150 mM NaCl, 1.0% NP-40, and 50 mM Tris base, pH 8.0; Ref. 19
) for 2 h at 4°C, and clarified for 10 min in a microcentrifuge. An aliquot was reserved for protein determination (Bio-Rad Laboratories, Hercules, CA), and the remainder was precipitated at -20°C in 80% acetone. The precipitate was pelleted in a microcentrifuge, suspended in gel loading buffer [50 mM Tris (pH 8.6), 2% SDS, 2% -mercaptoethanol, 0.1% bromphenol blue, and 10% glycerol], and boiled for 90 s. The samples were clarified for 1 min in a microcentrifuge, layered over a 10% polyacrylamide gel, and separated by electrophoresis for 30–40 min at 30 mA in a mini-gel apparatus (Bio-Rad Laboratories) using a discontinuous buffering system as described previously (20)
. The gel was soaked for 15–20 min in transfer buffer (running buffer containing 20% methanol) and transferred onto nitrocellulose (Amersham Life Sciences, Arlington Heights, IL) with a Bio-Rad semidry transfer apparatus. The Western blots were processed as described by the antibody suppliers (Santa Cruz Biotechnology), treated with luminol (Kirkegaard & Perry Laboratory, Gaithersburg, MD), and exposed on X-ray film (Amersham Life Sciences). Band intensities were measured by densitometry as described previously (21)
.
Test for Synergism.
To test for synergism, cells were plated in 96-well plates and treated with dilutions of decorin, carboplatin, and mixtures of both compounds. After 48 h incubation, the MTT assay was performed as described above. Whether synergism existed between the two agents was determined as described previously (22
, 23) . By this method, synergism was determined using the equation: Ac/Ae + Bc/Be = D, whereas Ac was the tested concentration of carboplatin used in combination with decorin, Bc was the tested concentration of decorin used in combination with carboplatin, Ae was the concentration of carboplatin alone, and Be was the concentration of decorin alone that would result in the observed growth inhibition seen for that drug combination. A D value of 1 indicated additive activity, a D value <1 indicated synergism, and a D value >1 suggested an antagonistic interaction between the two tested compounds.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, the growth of both cell lines was inhibited by decorin. On the basis of the data from these and other experiments, the estimated IC50 determined for decorin in both cell lines ranged from 150 to 400 µg/ml (3.8–10.1 µM). Interestingly, when the cells were grown on Matrigel, little effect was detected upon treatment with decorin (Fig. 1B)
. Additionally, no growth inhibition was seen, even with 200 µg/ml of decorin (data not shown).
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in the growth of ovarian cancer cells is unclear. In previous studies, when low-passage-number ovarian cancer cell lines isolated from ascites were exposed to TGF-, the majority of them exhibited growth inhibition (24)
, although they were isolated from an environment rich in TGF- (25)
. In the present study, neither of the two established cell lines used exhibited any degree of growth inhibition when exposed to TGF-. The 2774 cell line showed a small degree of stimulation by both forms of TGF- used, whereas the SKOV3 cell line was significantly stimulated by TGF-1 but was not stimulated by TGF-2 (Fig. 2)
.
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(6)
, we wondered whether any decorin-induced growth inhibition measured in vitro was attributable to inhibition of TGF- produced by the tumor cells. We had determined previously that culture fluid collected from the SKOV3 cell line contained, after acid treatment, 
150 pg/ml of TGF-2 (produced either by the cells or perhaps a component of FCS) when assayed with the ELISA (data not shown). This was in its latent form, because no TGF-2 was detected prior to activation by acid treatment (data not shown). Others have shown that SKOV3 cells do not produce biologically significant amounts of active TGF- protein (26)
. We also knew that these tumor cell lines make RNA transcripts for both TGF-1 and TGF-2 (27)
. Also, we have shown previously that both SKOV3 and 2774 cell lines express receptors (TR1 and TR2) for TGF- (28)
. Thus, there was a remote possibility that either or both cell lines had modified their own growth via autologous TGF- production.
To test this possibility, both cell lines were cultured in the presence of neutralizing anti-TGF- serum in two separate experiments. In one experiment, the cells were cultured in 500 ng/ml of pan-specific anti-TGF- antibody. In the second experiment, 5 µg/ml of antibody was used. There was no significant effect on the growth of either cell line after 48 h of exposure to the antibody (Table 1)
. This led us to conclude that probably none of the in vitro suppression of ovarian tumor cell growth shown in Fig. 1
was because of neutralization of autologous TGF- by decorin, particularly because decorin cannot bind to latent TGF- (6)
.
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was not involved, it seemed likely that decorin-induced suppression of ovarian cancer cell growth could have been attributable to up-regulation of p21, as had been reported for other types of tumor cells (3, 4, 5)
. To investigate this possibility, an experiment was performed essentially as was described with squamous cell carcinoma cells (4)
. Ovarian cancer cells were serum starved for 24 h and exposed for 6 h to 50 µg/ml of decorin in complete growth medium. Extracts were made as described in "Materials and Methods," loaded on a 10% polyacrylamide gel, blotted onto nitrocellulose, and analyzed for expression of the p21 protein by densitometry. To test loading, the blots were also analyzed for expression of GAPDH. Three separate experiments were performed. The SKOV3 cells showed an increase of p21 expression ranging from 0 to 165%, whereas 2774 cells showed an increase of 38–53%. One example of these experiments is shown in Fig. 3A
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Experiments were also performed to determine whether decorin could synergize with carboplatin to block the growth of ovarian tumor cells. The SKOV3 and 2774 cell lines were treated with carboplatin to determine an IC50 for that compound. Cells were treated for 48 h with various combinations of carboplatin, and growth was measured using the MTT assay. As can be seen in Fig. 4
, the SKOV3 cell line was considerably more resistant with IC50 of 100 µg/ml (268.7 µM) than the 2774 cell line, with an IC50 of 35.5 µg/ml (95.4 µM). Thus, the more resistant SKOV3 cells were used in the following experiments to test for synergism.
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. Whether synergism existed between the two agents was determined as described in "Materials and Methods." As shown in Table 2
, synergism was seen when the concentrations of both agents were 
12.5 µg/ml but well below the IC50 of either compound (35 µg/ml for carboplatin and 400 µg/ml for decorin).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, decorin has been studied extensively, primarily as a potential treatment for such conditions as glomerulonephritis (30)
. It has also exhibited an impressive number of ways to inhibit the growth of a variety of tumor types, as was shown previously in both in vivo and in vitro experiments (4
, 5
, 8)
. Decorin can block tumor growth by neutralizing the activity of TGF- (8
, 15)
and by up-regulating the expression of p21 (31)
via binding to the EGF receptor (4)
. It may also prevent tumor metastasis (and/or angiogenesis) by competitively binding to thrombospondin-1 (11)
. Additionally, overexpression of TGF- by tumor cells induces chemoresistance to several agents (including cisplatin) that can be overcome by ectopic treatment with decorin (14
, 15)
. Because of the poor prognosis of stage III-IV ovarian cancer patients in current treatment protocols (1) and particularly because we are interested in finding treatment modalities with low toxicity that can be used in combination with current treatments, we were intrigued by the antitumor activity of decorin seen thus far. Also, the various ways that decorin inhibits tumor cell growth provides an excellent research tool for investigating the growth of ovarian tumor cells in vitro.
We showed that decorin could inhibit the growth of two ovarian cancer cell lines in vitro (Fig. 1A)
. The IC50 of decorin ranged from 150 to 400 µg/ml. Previous studies have resulted in the successful treatment of cisplatin-resistant tumors in mice given 4.5 mg/kg decorin i.v. in combination with i.p. cisplatin (14)
.
We also demonstrated that when tumor cells were grown on an artificial cell matrix (i.e., Matrigel), ectopic application of decorin was ineffective in slowing the growth of the cells (Fig. 1B)
. This was unexpected. Either the activity of the decorin was blocked by some component(s) in the Matrigel, or the cells growing on Matrigel were somehow rendered resistant to decorin. However, others have shown that systemic application of decorin at the levels used in our experiments can be biologically effective (14)
.
We also showed that the decorin-mediated growth inhibition of the tested ovarian tumor cell lines appeared not to be attributable to neutralization of TGF- (Table 1)
. This may be particularly relevant when considering the question of synergism with other drugs.
As was reported for other types of tumor cells (3, 4, 5)
, we showed that decorin up-regulated expression of p21 in ovarian tumor cells (Fig. 3)
. Interestingly, this is another example of p53-independent up-regulation of p21 by decorin, because SKOV3 cells do not express any detectable p53 protein (32)
, as confirmed by us (data not shown). In fact, up-regulation of p21 could be the sole mechanism used by decorin to inhibit growth of ovarian tumor cells in vitro. An earlier report showed that decorin up-regulated p21 through the EGF receptor (4)
. However, we failed to detect any up-regulation of c-myc in decorin-treated ovarian tumor cells (Fig. 3B)
. However, this may not be too surprising, because ovarian tumor cells have been reported to overexpress c-myc (33)
. It has been shown that both EGF and TGF-
can up-regulate expression of c-myc through EGF receptors (29)
. It has also been shown that ovarian cancer cells, although constitutively expressing EGF receptors (34)
, did not exhibit constitutive activation of EGF receptors, although the cell lines tested produced significant amounts of TGF- (35)
. For these reasons, some investigators suggest that the growth of ovarian tumor cells may not be regulated through the EGF pathway (35)
.
We showed that synergism existed between decorin and carboplatin, a drug commonly used in treating ovarian cancer (Fig. 5
; Table 2
). What is particularly significant is that these data were obtained entirely in in vitro experiments. This suggests that up-regulation of p21 by decorin may be an important factor that is involved in the synergism between these two compounds. However, it has been shown that overexpression of TGF- may play a significant role in the drug resistance of tumor cells (36)
. Thus, it is reasonable to expect an even greater degree of synergism between carboplatin and decorin in vivo against tumors that overproduce TGF-.
Finally, overproduction of TGF- has also been shown to block immunological responses to tumors (37)
. Thus, decorin in combination with conventional chemotherapy might facilitate any immune response that can be directed by the patient’s immune system against the tumor. Decorin has been shown to reverse the TGF--induced nonresponsiveness of T-cells in peripheral blood cells obtained from patients infected with M. tuberculosis (8)
.
In summary, we have shown that decorin can inhibit the growth of ovarian cancer cells in vitro, primarily through up-regulating expression of the growth-inhibitory protein p21. Although decorin has been reported to act through EGF receptors, we failed to see up-regulation of c-myc expression in decorin-treated ovarian tumor cells. This may be attributable to the fact that c-myc is already overexpressed in these cell lines. Finally, we demonstrated that decorin had synergistic activity with carboplatin on ovarian tumor cells, including one line (SKOV3) that historically shows an increased resistance to chemotherapy. We believe that additional studies are needed to determine whether decorin might have a role in the treatment of patients with ovarian cancer.
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FOOTNOTES |
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1 This work was supported in part by a grant from the Elsa U. Pardee Foundation. 
2 To whom requests for reprints should be addressed, at Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 67, Houston, TX 77030.
3 The abbreviations used are: EGF, epidermal growth factor; TGF, transforming growth factor; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
Received 7/30/99. Accepted 10/15/99.
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