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Cancer Therapy: Preclinical |
Authors' Affiliations: Departments of 1 Medicine, Gerontology and Geriatric Medicine, and 2 Urology and Immunology, University of Washington, Seattle, Washington; 3 Geriatric Research and Education Clinical Center, Veterans Affairs Puget Sound Health Care Systems, Seattle, Washington; and 4 ImClone Systems, New York
Requests for reprints: Jennifer D. Wu, Department of Medicine, University of Washington, Box 359625, Seattle, WA 98104. Phone: 206-341-5349; Fax: 206-341-5302; E-mail: wuj{at}u.washington.edu.
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Abstract |
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Experimental Design: Androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate tumors were implanted s.c. into intact and castrated severe combined immunodeficient mice, respectively. When tumor volume reached about 150 to 200 mm3, A12 was injected at 40 mg/kg body weight thrice a week for up to 5 weeks.
Results: We find that A12 significantly inhibits growth of androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate xenografts, however, by different mechanisms. In LuCaP 35 xenografts, A12 treatment induces tumor cell apoptosis or G1 cycle arrest. In LuCaP 35V xenografts, A12 treatment induces tumor cell G2-M cycle arrest. Moreover, we find that blocking the function of IGF-IR down-regulates androgen-regulated gene expression in androgen-independent LuCaP 35V tumor cells.
Conclusions: Our findings suggest that A12 is a therapeutic candidate for both androgen-dependent and androgen-independent prostate cancer. Our findings also suggest an IGF-IR–dependent activity of the androgen receptor in androgen-independent prostate cancer cells.
Key Words: Prostate cancer • targeting IGF-IR • xenograft
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Introduction |
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The type I insulin-like growth factor receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are potent mitogens and are critical in maintenance of the transformed phenotype for a variety of cancer cells (4–7). Malignancy associated modifications in the IGF-IR system have been reported in a broad range of human cancers (8–13), including prostate cancer (14–16). Reagents that impair the function of IGF-IR have been shown to inhibit tumor cell growth effectively in vitro and in vivo (17–20).
Using an antagonistic antibody to target IGF-IR has become a potential attractive therapy for cancers. Several anti-IGF-IR antibodies have been developed (21–25). However, not all the antibodies show inhibitory affects on tumor growth in vivo or are immunologically ideal for future clinical implications. The recently developed fully human monoclonal antibody, A12 specific to IGF-IR, has exhibited potent antitumor effects in breast, colon, and pancreatic cancers in vitro and in vivo (25). A12 was shown to induce apoptosis and inhibit tumor growth by two mechanisms (25). One is mediated by blocking ligands binding to IGF-IR. The other is mediated by rapid induction of IGF-IR internalization and degradation.
Increasing evidence has shown that IGF-IR and its ligands are important in the development and maintenance of prostate cancer. Elevated levels of plasma IGF-I and reduced levels of the main serum binding protein, IGF-BP3, have been shown to be associated with an increased risk of prostate cancer (26–29). Although the level of IGF-IR expression during progression of prostate cancer has been shown to be variable, its expression is not lost at any stage of the disease (14, 15). Blocking the interaction of IGF ligands with IGF-IR using a small IGF-like peptide has exhibited inhibition of growth of the PC-3, DU-145, and LnCaP prostate cell lines (30). Several studies have shown that IGF-IR antisense oligonucleotides inhibit human prostate cancer cell line growth and migration in vitro (31) and murine prostate tumor growth in vivo (32). These studies suggest that targeting IGF-IR is an important therapeutic alternative for prostate cancer.
In this study, we test the in vivo effect of the human IGF-IR antibody A12 on xenograft prostate tumor growth. The availability of the androgen-dependent xenograft model, LuCaP 35 (33) and its variant androgen-independent xenograft model, LuCaP 35V (33) enables us to examine the effects of the human IGF-IR on both androgen-dependent and androgen-independent prostate cancers. The LuCaP 35 and LuCaP 35V tumors exhibit many in vivo properties analogous to those of prostate cancer in man and represent an excellent model system to evaluate new treatment modalities (33). For the first time, we show that the human IGF-IR antibody, A12, causes growth inhibition of both androgen-dependent and androgen-independent prostate tumors in vivo. Most significantly, we show differential mechanisms of A12 effects in androgen-dependent and androgen-independent prostate tumors. In androgen-dependent tumors, A12 induces apoptosis or G1 cell cycle arrest. In androgen-independent tumors, A12 induces G2-M cell cycle arrest. The results suggest that the human IGF-IR antibody A12 has therapeutic potential for both androgen-dependent and androgen-independent prostate cancer.
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Materials and Methods |
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Cell culture. The human prostate tumor cell line M12 and its parental cell line P69 were cultured in RPMI 1640 supplemented with 5% FCS, 10 ng/mL epithelial growth factor, 0.02 mmol/L dexamethasone, 5 µg/mL insulin, 5 µg/mL transferrin, 5 ng/mL selenium, fungizone, and gentamicin at 37°C with 5% CO2. The derivation of these cell lines has been previously described (34).
In vivo study. To study the in vivo effect of A12 on androgen-dependent and androgen-independent prostate tumor growth, tumor bits (20-30 mm3) of LuCaP 35 and LuCaP 35V were implanted subcutaneously into 6- to 8-week-old intact or castrated severe combined immunodeficient mice respectively as previously described (33). The tumors express IGF-I and IGF-II.5 Twenty-six intact and 32 castrated mice were used in this study. When the implanted tumor was observed to reach a volume of 150 to 200 mm3, half of the animals in each xenograft group were administrated A12 antibody interperitoneally at a dose of 40 mg/kg body weight thrice a week for up to 5 weeks. The remaining animals in each xenograft group were given with the vehicle saline buffer as the control reagent. Animals were weighed twice a week. Blood samples were collected from orbital sinus weekly. Serum was separated and prostate-specific antigen (PSA) level was determined using the IMx Total PSA Assay (Abott Laboratories, Abott Park, IL). Tumors were measured twice weekly and tumor volume was estimated by the formula, volume = L x W2/2. Following our University of Washington–approved animal protocol, some animals were euthanized at an earlier time when tumor reached a volume of 1,000 mm3 or when animal weight loss exceeded 20% of initial body weight. Bromodeoxyuridine (BrdUrd) was injected into the tumors 1 hour before the animals were euthanized for evaluation of in vivo tumor cell proliferation rate. To study the toxicity of A12, tumor-free 6- to 8-week-old severe combined immunodeficient mice were injected with A12 (n = 12) or control saline buffer (n = 8) as described above.
After euthanization, tumors were collected and quartered. A portion of the tumors were fixed in 10% neutral buffer formalin and embedded in paraffin. Five-micrometer sections were prepared for immunohistochemistry staining. The remaining portion of the tumors were separated into single cells mechanically by mincing and filtering through 70-µm nylon sieves.
Flow cytometry. To measure tumor IGF-IR expression, 5 x 105 cells were incubated with anti-IGF-IR
antibody SC-461 (Santa Cruz Biotechnology, Santa Cruz, CA) at 4°C for 30 minutes. After two washes, cells were incubated with phycoerythrin-conjugated goat anti-mouse antibody and analyzed using a BD FACscan. Data was analyzed using CellQuestPRO software (BD BioScience, San Jose, CA).
Apoptosis and cell cycle assay. Apoptosis and cell cycle were measured by terminal deoxynucleotidyl transferase-mediated nick-end labeling assay and propidium iodine staining using the Apop-Direct kit (BD BioScience) as previously described (35). Briefly, 1 x 106 cells from the single-cell suspension were fixed with 10% neutral buffer formalin followed by 70% ethanol alcohol at –20°C for 30 minutes. After several washes, cells were permeabilized with 0.1% Triton X-100 and incubated with FITC-conjugated dUTP and terminal deoxynucleotidyl transferase enzyme at 37°C for 1 hour followed by an incubation with propidium iodine/RNase buffer (100 µg/mL of propidium iodine, 50 µg/mL RNase) at room temperature for 60 minutes. Samples were analyzed by flow cytometry using a BD FACscan. Data were analyzed with CellQuestPRO software.
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. To compare cell growth rate, LNCaP, C4-2, and M12 cells were plated at a density of 2,500 cells per well in a 96-well plate using T-medium supplemented with 1% charcoal-stripped serum. DHT (10–9 mol/L) was added to the medium of LNCaP cells at the time of seeding. Following overnight incubation, A12 antibody or control human IgG was added to the culture at a concentration of 20 µg/mL and incubated for 48 hours. Number of viable cells was quantified by a colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method using the Cell Titer 96 AQueous kit (Promega, Madison, WI) following manufacturer's instructions.
Immunohistochemistry. Tumor samples were fixed in 10% neutral buffer formalin, embedded in paraffin, and sectioned at 5 µm onto slides. After deparaffinization and rehydration, antigens were retrieved with 0.01 mol/L citric acid (pH 6.0) at 95°C for 2 x 5 minutes. Slides were allowed to cool for 30 minutes, followed by sequential rinsing with PBS. Endogenous peroxidase activity was quenched by an incubation with 0.3% H2O2 in methanol for 15 minutes. After blocking with 1.5% normal goat serum in PBS containing 0.05% Tween 20 (PBST) for 1 hour, slides were incubated with mouse anti-BrdUrd antibody (1 µg/mL) for 1 hour followed by sequential incubation with biotinylated goat antimouse IgG for 30 minutes, peroxidase-labeled avidin for 30 minutes (Santa Cruz Biotechnology), and diaminobenzidine/hydrogen peroxide chromogen substrate (Vector Laboratories, Burlingame, CA) for 5 to 10 minutes. All incubation steps were done at room temperature. Slides were counterstained with hematoxylin (Sigma, St Louis, MO), and mounted with permount (Fisher Scientific, Fair Lawn, NJ). For negative control, mouse IgG (Vector Laboratories) was used instead of the primary anti-BrdUrd antibody. Slides were examined under a Zeiss Microscope and digital images were obtained. Numbers of BrdUrd-labeled nucleus and total nucleus were collected from 10 random views of each section. Proliferation index was calculated by the number of BrdUrd-positive nuclei divided by the total number of nuclei. Ten fields were counted per slide. H&E staining was done by using H&E (Richard Allen, Kalamazoo, MI).
Western blotting. For assaying in vitro effect of A12 on M12 and P69 cell lines, cells were serum starved in T and S medium (Invitrogen, San Diego, CA) for 24 hours followed by addition of 50 ng/mL of recombinant human IGF-I (rhIGF-I; R&D Systems, Minneapolis, MN) alone or combined with 10 µg/mL of A12 to the medium for 15 minutes before harvesting. Cells were washed with PBS and lysed with cold lysis buffer [50 mmol/L HEPES (pH 7.5), 150 mmol/L NaCl, 1.5 mmol/L MgCl2, 1 mmol/L EGTA, 10% Triton X-100] containing phosphatase Inhibitor Cocktail II (Sigma) and protease inhibitors (Complete Mini Tablets, Roche, Indianapolis, IN). For assaying in vivo effect of A12, freshly prepared xenograft tumor cells were washed with PBS and lysed as described above. Protein (25 µg) was resolved on 4% to 15% SDS-PAGE, transferred onto a nitrocellulose membrane, and probed with anti-IGF-IRß (BioSource International, Inc., Camarillo, CA), anti-phospho-IGF-IRß (pYpYpY1158/1162/1163, BioSource International), anti-phospho-Akt1/2 (BioSource International), or anti-phospho-ERK (Santa Cruz Biotechnology) primary antibody overnight at 4°C. The blot was washed and incubated with a horseradish peroxidase-conjugated secondary antibody (Pharmacia Biotech, Piscataway, NJ) for 1 hour. Immunoreactive proteins were detected by enhanced chemiluminescence (Pharmacia Biotech). The membranes were stripped for 30 minutes in stripping buffer (Pierce, Rockford, IL) and reprobed with anti-GAPDH antibody (Chemicon, Temecula, CA) as described above. Independent experiments validated that this stripping procedure did not lead to loss of signal.
Statistical tests. Statistical significance between means of control and A12-treated animals was assayed using Student's t test; 95% confidence interval (P < 0.05) was considered significant.
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Results |
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4-fold fewer IGF-IR than P69 (34). The growth of both P69 and M12 cell lines are shown to be regulated by IGF (34). As shown on Fig. 1A, A12 inhibits phosphorylation of IGF-IR and its downstream signaling molecules Akt and extracellular signal–related kinase (ERK) in both P69 and M12 cell lines. The inhibitory effect may be in part due to A12-induced degradation of IGF-IR (Fig. 1B) as have been shown previously (25).
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Inhibition of A12 on androgen-dependent and androgen-independent prostate tumor growth. We first assessed the in vivo effect of A12 on androgen-dependent prostate tumor growth using the LuCaP 35 xenograft model. As shown in Fig. 2A and B, by end of the study, 54% (7 of 13) of animals in the saline-treated control group had tumors reaching the volume of 1,000 mm3 (Fig. 2A), whereas none of the animals in A12-treated group had tumors reaching a volume of 1,000 mm3 (Fig. 2B). It has to be noted that four animals in the control group had to be sacrificed due to large tumor volumes (exceeding 1,000 mm3) 4 weeks after A12 treatment initiation. At this time point, the mean tumor volume in A12-treated animals was reduced 60% compared with that in the control saline–treated animals (Fig. 2C, t test, P < 0.05).
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A12 induces apoptosis and/or cell cycle arrest in xenograft prostate tumors. To elucidate the mechanisms by which A12 inhibits androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate tumor growth in vivo, we first examined the events of apoptosis and/or cell cycle progression in these tumors. As represented in Fig. 3A, A12 treatment exhibits two typical effects on LuCaP 35 tumors: cell cycle G1 arrest and/or apoptosis. In 7 of 13 LuCaP 35 xenograft animals, A12 treatment predominantly induced an increase in cell cycle G1 index from an average of 77.5 ± 3.5% to 91.3 ± 4.8% (t test, P < 0.05) with minor apoptotic events (apoptotic index, <5%). Some tumor cells were shown to possess pyknotic nuclei in H&E-stained sections, indicative of programmed cell death (Fig. 3B). In 6 of 13 LuCaP 35 xenograft animals, A12 treatment predominantly induced apoptosis with an index of 62.26 ± 14%. Tumor cells from these animals possess a noticeable level of pyknotic nuclei in comparison with those from control saline–treated animals (Fig. 3B). A greater inhibition of tumor growth (74% reduction in average tumor volume) was seen in the A12-treated animals where induction of apoptosis was a predominant effect (Fig. 2C). A12 had a different effect on the LuCaP 35V xenograft animals. In 11 of 16 animals, A12 treatment resulted in cell cycle G2-M arrest (Fig. 3A), an increase in G2-M index from 13.81 ± 1.0% to 90.4 ± 1.5% (t test, P < 0.001). An average of 57% reduction in tumor growth was seen in these 11 animals 2 weeks after A12 treatment initiation (Fig. 2E). In 5 of 16 LuCaP 35V xenograft animals, A12 treatment did not show an effect on cell cycle progression (data not shown) or inhibition of tumor growth (Fig. 2E and F). No apoptotic event was observed in A12-treated LuCaP 35V tumor cells. No noticeable level of pyknotic nuclei were seen in H&E-stained sections of these tumors (Fig. 3B). These results suggest possible differential roles of IGF-IR in the maintenance of androgen-dependent and androgen-independent prostate tumor growth.
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To further investigate whether the discriminating effect of A12 on LuCaP 35 and LuCaP 35V tumors is due to different degrees of inhibition of principle IGF-IR signaling pathways, we analyzed phosphorylation status of Akt and ERK in tumor cell lysates with and without A12 treatment. As shown in Fig. 3C, A12 treatment resulted in a remarkable inhibition of Akt phosphorylation in both LuCaP 35 and LuCaP 35V tumors in which G2-M arrest is induced. No noticeable change in ERK phosphorylation in LuCaP 35 or LuCaP 35V tumors with A12 treatment was observed in Western blots (data not shown). These data suggest that other alternative pathways may regulate the responses of LuCaP 35 and LuCaP 35V tumors to A12 treatment.
A12 inhibits cell proliferation in xenograft prostate tumors. To assess cell proliferation between experimental groups, paraffin sections of A12-treated and control saline–treated tumors were immunohistochemically stained with anti-BrdUrd antibody. In the LuCaP 35 model, a noticeable reduction in BrdUrd uptake was seen in all A12-treated tumors as representatively shown in Fig. 4A and cell proliferation was significantly inhibited with A12 treatment (Fig. 4C, t test, P < 0.05). However, no significant difference was observed between A12-treated tumors that are apoptotic and undergoing cell cycle G1 arrest (Fig. 4C). In the LuCaP 35V model, with A12 treatment, a noticeable reduction in BrdUrd uptake and a significant inhibition in cell proliferation was only seen in those undergoing G2-M cell cycle arrest (Fig. 4B and D, t test, P < 0.05). Because cell cycle arrest, in particular G1 arrest, has been proposed to be a prerequisite step for induction of apoptosis (37, 38), these results suggest that A12 inhibits cell proliferation in LuCaP 35 and LuCaP 35V tumors by induction of G1 or G2-M cell cycle arrest.
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Discussion |
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Various strategies, including antisense technology (31, 32), inhibitory antibodies (21), and dominant-negative IGF-IR (35), have been used to inhibit prostate cancer cell growth in vivo or in vitro by disrupting IGF-IR function. These studies suggested that inhibition of IGF-IR function is a potent strategy for inhibition of prostate cancer growth. However, relevant clinical implications of these strategies have not been defined. The current study defines the effect of a human anti-IGF-IR antibody, A12, on prostate tumor growth in androgen-dependent and androgen-independent xenograft models, which reflect the primary and advanced hormone-refractory human prostate cancers, respectively (33). Although a considerable cross-reactivity of A12 with mouse IGF-IR has been observed6, no significant toxicity of A12 was observed in this study. Together, our results suggest that the human IGF-IR antibody A12 has potential direct clinical therapeutic implication for human prostate cancer.
IGF-IR signals through two principle pathways: the phosphoinositide 3-kinase/pAkt anti-apoptotic pathway and the mitogen-activated kinase/ERK pathway (40). Activati on of phosphoinositide 3-kinase protects cells from apoptosis via activation of Akt and downstream phosphorylation of many proapoptotic proteins (4–6). Our in vitro data have clearly showed that A12 treatment down-modulates IGF-IR levels and inhibits Akt and ERK phosphorylation in prostate tumor cell lines. In LuCaP 35 and LuCaP 35V xenograft tumors, we were not able to show evident changes in ERK phosphorylation with A12 treatment, suggesting that the in vivo effects of A12 are predominantly mediated through the phosphoinositide 3-kinase/Akt pathway. The ERK pathway is maintained possibly by other growth factors in vivo such as epithelial growth factor.
Our data suggest that IGF-IR may function differently in androgen-dependent and androgen-independent prostate cancers. Our in vivo studies have shown that A12 down-modulates surface IGF-IR expression and inhibits Akt phosphorylation in androgen-dependent and androgen-independent prostate tumors; however, apoptosis was only induced in androgen-dependent prostate tumors. The results are consistent with our in vitro observation with androgen-dependent LNCaP and androgen-independent C4-2 cell lines. The discrepancy of A12 effect did not correlate with the level of surface IGF-IR expression albeit down-regulation of IGF-IR expression has been shown important for obtaining the full biological response of targeting IGF-IR in vitro (41). Our results suggest that IGF-IR signaling is a pivotal survival pathway for androgen-dependent prostate cancer cells, consistent with the up-regulation of IGF-IR in primary prostate cancers (14) and up-regulation of IGF-IR expression by androgen (34). Available literature suggests that IGF-IR may be down-regulated in androgen-independent prostate cancer (15); however, current understanding on the function of IGF-IR in androgen-independent prostate cancer is limited. Our data suggests that IGF-IR plays an important role in the growth of androgen-independent prostate cancer and that a pAkt-independent antiapoptotic pathway may play a role in the survival of androgen-independent prostate cancer cells. Li et al. have recently shown that inactivation of the proapoptotic protein FKHR by AR via a complex formation may play a role in protection of androgen-independent prostate cancer cells from apoptosis (42). Thus, one might explain the resistance of the A12-treated androgen-independent LuCaP 35V tumors and C4-2 cell lines to apoptosis as a consequence of decreased phosphorylation of Akt and the downstream target FKHR, which would result in an increase the antiapoptotic AR-FKHR complex formation.
There is evidence that, in androgen-dependent LNCaP prostate cancer cells, activation of IGF-IR down-regulates AR function through pAkt phosphorylation of AR (43). Consistent with these findings, here we show that blocking IGF-IR function in androgen-dependent LuCaP 35 tumor cells resulted in an increase in PSA expression. In androgen-independent LuCaP 35V xenografts, disruption of IGF-IR function with A12 resulted in a decrease in PSA expression, suggesting that the activity of AR in androgen-independent prostate cancer cells is also regulated by IGF-IR signaling but via different pathways. It has to be noted that, although androgen was depleted by castration in androgen-independent LuCaP 35V xenograft animals, androgen receptor transcriptional activity remained, which was evidenced in a previous study by nuclear localization of AR and secretion of the androgen-regulated protein, PSA (33). Hypotheses exist on transactivation of AR in the absence of ligand (44–46); however, the mechanism for this activity of AR remains unknown. How the activity of AR in androgen-independent prostate cancer cells is regulated by IGF-IR signaling remains to be explored as well.
This study shows that the human IGF-IR antibody A12 inhibits growth of androgen-dependent and androgen-independent xenograft prostate tumor growth, although via different mechanisms. Activation of IGF-IR signaling has been shown to play a critical role in the development and maintenance of prostate cancer. Therefore, this study has established a preclinical basis for A12 as a potential effective therapeutic reagent for treatment of both androgen-dependent and androgen-independent human prostate cancers.
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Acknowledgments |
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Footnotes |
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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.
Received 8/ 9/04; revised 1/10/05; accepted 1/13/05.
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IR-3 inhibits non-small cell lung cancer growth in vitro and in vivo. J Cell Biochem Suppl 1996;24:269–75.[Medline]
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