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Geriatric Research, Education, and Clinical Center American Lake/Seattle Veterans Administration (S.R.P., L.M., L.S.Q.), Tacoma, Washington 98493; the Department of Medicine, University of Washington (S.R.P., L.S.Q.), Seattle, Washington 98195; and the Department of Pathology, Medical College of Virginia (V.L.B., J.L.W.), Richmond, Virginia 23298
Address all correspondence and requests for reprints to: Dr. S. R. Plymate, Geriatric Research Education and Clinical Center (182B), American Lake Veterans Administration Medical Center, Tacoma, Washington 98493.
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Abstract |
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The IGF-1R was reexpressed in M12 cells using a retroviral vector containing a 7-kilobase coding sequence for the IGF-1R, LISN, to create several clones of the M12-LISN cell line. As a control, M12 cells were also infected with a retroviral vector (LNL6) without the 7-kilobase IGF-1R insert (M12-LNL6 clones). Functional assays were performed with two separate clones each of M12-LNL6 and M12-LISN cells. Each clone of M12-LISN cells regained the proliferative response to IGF that was lost in the transition from P69SV40T cells to M12 cells. In addition, M12-LISN clones had a significantly decreased growth rate compared to the M12-LNL6 cells when injected sc in athymic/nude mice (P < 0.001). Tumorigenicity, as assessed by anchorage-independent growth of colonies in soft agar, was also decreased by 75% in the M12-LISN clones compared to that in the M12-LNL6 control cells.
These data demonstrate that reexpression of the IGF-1R in a malignant human prostate epithelial cell line results in decreased tumor growth and decreased anchorage-independent colony formation independent of an increased proliferative response to IGF. Reexpression of the IGF-1R may be associated with reacquisition of the regulation of cellular proliferative and differentiation functions mediated by the IGF-1R that are lost as prostate epithelial cells undergo conversion to a malignant phenotype.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous work by our group has indicated that changes in several components of the IGF system occur in the development of prostate carcinoma (9, 10, 11, 12). Using immunohistochemistry and in situ hybridization, we have shown that IGF-II messenger ribonucleic acid (mRNA) and protein expression are higher in malignant prostate epithelium compared to normal prostate epithelium (9). However, a much more dramatic and unexpected change was noted in the expression of the IGF-1R, such that both IGF-1R mRNA and protein decreased significantly as prostate epithelial cells underwent transformation to malignancy (9). Also, using a human in vitro model system of prostate epithelial cell transformation, we observed a significant decrease in IGF-1R in the transition from benign to malignant cells (12, 13). The present study was undertaken to investigate the relationship between changes in IGF-1R expression levels and prostate malignancy.
In the present study, we examined the effects of reexpressing the IGF-1R in the highly malignant M12 subclone of the P69SV40T (SV40T = simian virus 40 T antigen) immortalized prostate tumor cell line (12, 13, 14). An advantage of this system is the availability of the parental, poorly tumorigenic, cell type. We found that reexpressing the IGF-1R at levels comparable to those of the parental cell type induced concomitant reductions in anchorage-independent growth and tumor growth in vivo, whereas increasing the proliferative response to IGF in vitro. These findings suggest the IGF system may have a dual function, mediating both proliferation and differentiation in prostate epithelium, such that high levels of IGF-1R expression may act as an inhibitor of tumor growth, possibly due to the induction of a differentiation program.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IR3 monoclonal antibody to the
human IGF-1R was obtained from Oncogene Science (Uniondale, NY).
Gentamicin, fungizone, geneticin (G418), and deoxyribonuclease were
obtained from Life Technologies (Grand Island, NY). FBS was obtained
from Hyclone (Logan, UT). Insulin, transferrin, and selenium were
purchased as the additive ITS from Collaborative Research (Waltham,
MA). The Vectastain ABC illumination kits were purchased from Vector
Laboratories (Burlingame, CA). The Cell Titer 96 AQueous
cell proliferation kit was obtained from Promega (Madison, WI).
Nitrocellulose and electrophoresis reagents were purchased from Bio-Rad
Laboratories (Richmond, CA). Horseradish peroxidase-linked donkey
antirabbit IgG, enhanced chemiluminescence detection reagents, and
[125I]IGF-I were obtained from Amersham (Arlington
Heights, IL). Bovine pituitary extract was purchased from Upstate
Biotechnology (Lake Placid, NY). Ultrafree-MC filter units were
obtained from Millipore (Bedford, MA). The BCA protein assay kit was
obtained from Pierce Chemical Co. (Rockford, IL). Human IGF-1R
complementary DNA (cDNA) was obtained from American Type Culture
Collection (Rockville, MD). Each experiment was performed at least
three times.
Cell culture
The derivation of the P69SV40T cell line and that of its subline
M12 have been previously described by Bae et al. (13, 14).
Briefly, human prostate epithelial cells were immortalized with SV40T
antigen to produce the poorly tumorigenic P69SV40T cell line. P69SV40T
cells were injected sc into athymic nude mice producing tumor nodules
in 2 of 18 animals after 180 days (14). These nodules were reimplanted
in athymic mice, and after three passages resulted in the M12 cells,
which demonstrated a short latency period of 7–10 days to tumor
formation in all 10 animals and were locally invasive and metastatic
(13, 14, 15). Cells were cultured in RPMI 1640 supplemented with 23
mM HEPES, 10 ng/ml epidermal growth factor, 0.1
µM dexamethasone, 5 µg/ml insulin, 5 µg/ml
transferrin, and 5 ng/ml selenium, 5 ng/ml bovine pituitary extract,
fungizone, and gentamicin. All cells used in these experiments were
mycoplasma free as determined by the Gen-Probe Mycoplasma T.C. Rapid
Detection System (Gen-Probe, San Diego, CA).
Immunocytochemistry
Immunocytochemistry on cultured cells was performed essentially
as described previously (10). For IGF-1R immunocytochemistry, dishes
were blocked with PBS containing 0.5% Triton X-100 (Sigma Chemical
Co.) and 2% nonfat dry milk (Bio-Rad Laboratories, Hercules, CA) and
with PBS containing 3% BSA and 1.5% normal sheep serum. The dishes
were then incubated overnight at 4 C with a 1:100 dilution of mouse
monoclonal antibody to the IGF-1R, IR3. The Vectastain Enhanced ABC
Kit was used to detect the primary antibody. Dishes were then
counterstained with hematoxylin and mounted under coverslips.
Western blots
Cells were collected for Western blots by washing with PBS and
0.1% BSA. The supernatant was then discarded, and the cells were
suspended in 100 µl SDS sample buffer (10% glycerol, 2% SDS,
ß-mercaptoethanol, and 0.001% bromophenol blue) and heated for 5 min
at 100 C. Electrophoresis of this cell solution was performed on a 10%
SDS-PAGE gel. A separate aliquot of the cells was used for
determination of protein content by the BCA protein assay reagent. The
amount of cell extract added to each lane was normalized to protein
content. After electrophoresis, proteins were transferred to
nitrocellulose, and membranes were probed with IR3 antibody to the
IGF-1R -subunit. Bound antibody was detected using a horseradish
peroxidase-linked second antibody and the enhanced chemiluminescence
detection system. Buffers and wash times were suggested in the
Vectastain Enhanced ABC kit, except that nitrocellulose was first
washed with 10% hydrogen peroxide for 10 min.
IGF binding studies
For determination of IGF receptor number and affinity, cells
were cultured in 24-well plates until they were 90–100% confluent.
The wells were washed twice at 37 C for 15 min each time with the
binding medium (RPMI with 1% BSA) and preincubated with binding medium
for 1 h at 4 C. Cells were then incubated in duplicate with
varying concentrations (0.05–2 nM) of
[125I]IGF-I for 3 h at 26 C in a total volume of
0.15 ml binding medium. Nonspecific binding was determined by adding a
500-fold molar excess of unlabeled IGF-I (0.025–1.0 µM).
After the incubation period, the cells were incubated at 4 C for 15 min
and then rinsed quickly twice with ice-cold PBS and 0.1% BSA. Cells
were solubilized with 0.2 ml 0.2 M NaOH, and
cell-associated radioactivity was counted in a 
-counter using the
entire 0.2-ml aliquot. The same 0.2-ml aliquot was then used for
protein measurements using the BCA protein assay reagent kit. In each
experiment, replicate wells were used to determine cell number.
Specific binding was calculated as the difference between total and nonspecific binding and was corrected for the number of cells per well. Nonspecific binding represented about 5% of the total [125I]IGF-I binding. The maximum binding capacity and the apparent dissociation constant (Kd) of binding were determined by Scatchard plots subjected to linear regression analysis (16). The number of receptors per cell was calculated using Avagadro’s constant.
Proliferation assays
Cell proliferation was measured by conversion of a tetrazolium
salt into a blue formazan product by viable cells using the Cell Titer
96 AQueous kit and quantitated by absorbance at 570 nm. In
this assay, 2500 cells were added to each well of a 96-well plate.
IGF-II (100 ng/ml) was added at the time of plating. After 72 h in
culture, the tetrazolium salt and the dye solution were added, and the
plates were read 2–3 h later. Each cell type was tested at least three
times. The correlation between cell number and the tetrazolium assay in
our laboratory is r = 0.97.
mRNA analysis
Cells were cultured until they reached approximately 90%
confluence, at which time total cytoplasmic RNA was isolated using an
acid guanidinium thiocyanate-phenol-chloroform extraction method.
Approximately 10 µg of each RNA preparation (quantitated by optical
density at 260 nm) were separated by electrophoresis on a 1%
agarose-6% (2.2 M) formaldehyde gel, transferred overnight
by capillary action onto a nylon membrane (GeneScreen, DuPont,
Wilmington, DE), and cross-linked to the membrane by UV irradiation in
a Stratalinker 1800 (Stratagene, La Jolla, CA). Northern blot analysis
was performed by hybridizing the membrane overnight with the IGF-1R
cDNA probe labeled with [32P]deoxy-CTP to a specific
activity of 108 dpm/µg DNA by the random primers method
(17). Hybridization was carried out at 42 C in a solution of 5 x
Denhardt’s solution (1 x Denhardt’s = 10 g polyvinylpyrrolidone, 10
g BSA, and 10 g Ficoll 400 to 470 ml water) with 50 µg/ml
sonicated salmon sperm DNA and 50% deionized formamide. After a final
wash with 0.1 x SSC at 65 C, the blot was exposed to x-ray film
(Kodak X-Omat-AR) with 2 intensifying screens at -80 C for 48–72
h.
IGF-1R retroviral vectors
LISN and LNL6 replication-deficient retroviruses were
constructed as described by Kaleko et al. (18). The LISN
virus contained the 7-kilobase (kb) human IGF-1R cDNA sequence driven
by the retroviral long terminal repeat and also contained the Neo
resistance gene (neomycin phosphotransferase) driven by an internal
SV40 promotor. The control LNL6 virus contained the Neo resistance gene
without the IGF-1R sequence. Amphotropic retroviruses were prepared in
PA317 packaging cells cultured in DMEM supplemented with 10% FCS.
Virus-containing medium was harvested from these cells and the titers
of infectious particles per ml were determined by assay of
antibiotic-resistant colonies of NIH-3T3 cells.
To produce M12 cells expressing increased levels of the IGF-1R (M12-LISN) or control cells infected with the vector LNL6 (M12-LNL6), M12 cells were cultured in RPMI 1640 complete medium with 5% FCS. Cells were infected with either LISN or LNL6 retroviral particles at a ratio of one viral particle to three M12 cells. Twenty-four hours after infection, the cells were transferred to 100-mm plastic culture dishes containing RPMI complete medium with 0.8 mg/ml G418. In addition to the infected M12 cells, control plates of M12 cells were treated with the same medium. After 7 days, no viable cells were present in the control plates. The infected cells were maintained in 0.8 mg/ml G418 for an additional week, and subsequent cultures were maintained in RPMI complete medium containing 0.5 mg/ml G418. Receptor numbers per cell were determined by Scatchard analysis as described above.
After initial transfection, clones expressing high levels of IGF-1R
were picked using the method of Gibson-D’Ambrosio et al.
(19). Briefly, cells were sparsely plated on plastic culture dishes and
grown until individual colonies were visible. When the colonies were
visible, a sterile nylon membrane was placed over the colonies, and the
medium was aspirated. After 3 h, the membrane was marked for
orientation on the plate and removed. Medium was replaced, and the
culture was maintained. The membrane was immediately probed with the
IR3 antibody. Areas on the membrane that demonstrated high levels of
reactivity to the antibody were matched to the cultures, and the
isolated colonies were removed from the plate using cloning rings and
subcultured. After G418 selection, individual clones of the M12-LNL6
cells were selected at random, and receptor numbers were determined.
For the experiments described in this paper, clones from two separate
infections of M12 cells with either the LISN or LNL6 vectors were
selected. The characteristics of these clones are presented in the
table in Results.
Anchorage-independent growth
For studies of anchorage-independent growth of M12-LISN and
M12-LNL6 lines, each well of a 24-well plate was first layered with
0.6% agarose and 2-fold concentrated RPMI 1640. A top layer containing
106 cells suspended in 2-fold concentrated
RPMI-supplemented 0.3% agar was then added. Plates were maintained at
37 C in 5% CO2 for 21 days. Colonies greater than 50 µm
in diameter were counted.
Assays of tumor growth in vivo
The tumorgenicity of M12-LISN and M12-LNL6 lines was assessed by
the sc injection of 106 cells into male athymic nude mice
that were 6–8 weeks old at the time of injection. Ten mice were
injected with M12-LISN cells, and 10 mice were injected with M12-LNL6
cells. To control for possible variations in injection technique, mice
were injected in separate groups of 5 animals each. Mice were monitored
weekly for the appearance of tumor nodules. Once a nodule appeared,
tumor volume was measured weekly over a 4-week period. In
vivo tumor volume was estimated by the formula: volume =
L x W2/2. All mice were killed 4 weeks after the
onset of detectable tumor growth. All mice were maintained in a
specific pathogen-free barrier facility. The in vivo
experiments were conducted under a protocol approved by the Virginia
Commonwealth institutional animal care and use committee.
Statistical analyses
Statistical analyses were performed using ANOVA or Student’s
t test, as appropriate, with significance accepted at
P 
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Before infection,
M12 cells expressed a small amount of an 11-kb IGF-1R mRNA transcript,
as previously reported (12); after infection, M12-LISN cells expressed
a 7.46-kb transcript derived from the LISN vector. The 11-kb transcript
was an expected form of the IGF-1R mRNA expressed in primary cultures
of prostate epithelial cells as well as benign prostate tissue (12, 20). The 7.46-kb transcript expressed by the LISN vector encoded the
complete IGF-1R sequence. This transcript expressed a functional
IGF-1R, as documented by the binding, immunological, and functional
assays described below as well as by other investigators (18, 21).
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and Fig. 2). The M12-LNL6
cells, like the M12 line (12), expressed about 10-fold fewer receptors
than either P69SV40T or M12-LISN lines (P < 0.0001).
Receptor affinities for IGF-I were not different among the three cell
lines, with Kd values ranging from 2.1–3.3
x 10-10 nM (Table 1). We have previously
demonstrated by affinity cross-linking studies that in these cell lines
we are measuring the IGF-1R and not cell surface-associated IGF-binding
proteins (12). The similarities in affinities also support previous
cross-linking studies, which indicated that in these cell lines,
radioligand binding reflects the IGF-1R alone and not cell
surface-associated IGF-binding proteins.
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IR3 antibody to the
IGF-1R (M12-LISN 2 and M12-LNL6 1 clones are shown in Figs. 3 and 4). The Western blot with the
IR3 antibody demonstrates a single protein species and a
qualitatively greater amount of IGF-1R in M12-LISN cells than in
M12-LNL6 cells (Fig. 3). In the immunocytochemical stain of the
monolayer cultures with IR3, a marked increase in membrane staining
for IGF-1R in the M12-LISN cells vs. the M12-LNL6 control
cell line was also observed (Fig. 4).
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).
Reexpression of the IGF-1R in the M12 cell line enhanced the
proliferative response to IGF-II of the M12-LISN cells to levels
comparable to or greater than those of P69SV40T cells (Fig. 5, A and
B). However, as shown in Fig. 5A, basal proliferation rates without
added IGF-II of the M12-LISN and M12-LNL6 clones were similar.
Therefore, the reexpressed transcript coded for a functional receptor
that transduced IGF-driven proliferative signals.
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). M12-LISN 1 and 2 cell lines produced
75% fewer colonies in soft agar monolayers than did M12-LNL6 1 and 2
cells (P < 0.0001). P69SV40T cells did not form
colonies in the soft agar assay. These results demonstrate that even
though there was an increase in the proliferative response to IGF-II,
reexpression of the IGF-1R at high levels decreased tumorigenicity, as
determined by anchorage-independent growth.
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, there was a
6-fold difference in tumor volume between the two cell lines 2, 3, and
4 weeks after injection (P < 0.01). All of the animals
injected with either M12-LISN or M12-LNL6 cells developed tumors that
could be detected within 10 days of injection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism(s) involved in decreased tumor growth with reexpression of the IGF-1R are not immediately evident. Intuitively, one might expect that reexpression of a receptor for a proliferative factor would increase the rate of growth of the tumor. However, that was not the case in this situation. Several possibilities exist that could explain our findings. One that has been proposed comes from recent data for the MCF-7 human breast cancer cell line. In this cell line, overexpression of the IGF receptor results in an alteration in postreceptor signaling mechanisms for IGF-induced proliferation such that the normal enhanced effect on proliferation to IGF induced by estrogen treatment was lost when IGF-1R was increased (29). If this were the case, then one might expect to see a decrease in the in vitro proliferative response to IGF in the present system. However, we observed that the proliferative response of the M12-LISN cells to exogenously administered IGF was greater than that of the M12-LNL6 cells. This suggests that the postreceptor proliferation signals are intact and that the introduced gene did not act as a dominant negative inhibitor of the endogenous IGF-1R.
Another interpretation is that at high levels of expression, the IGF-1R is inducing a differentiation pathway that suppresses the malignant phenotype. Evidence for such dual IGF-1R-mediated pathways have been found in several model systems, including skeletal muscle, bone, and neural tissue (8, 21, 30, 31, 32). As IGF, acting through the IGF-1R, has both proliferative and differentiating actions, the greater rate of tumor growth at a lower receptor number suggests that postreceptor signaling, as determined by receptor number, may determine which of these actions would predominate. That is, with a low receptor number and a decreased number of postreceptor signals in response to ligand, the proliferation pathway may predominate. When the receptor number is increased and the signal number is increased, a process of cellular differentiation may predominate over the proliferation pathway.
Despite the demonstration in this study that reexpression of the IGF-1R results in decreased tumor growth, this finding does not negate the importance of the IGF system in stimulating the growth of prostate cancers (23, 24, 25, 26). Multiple studies, using antibodies, antisense oligonucleotides, blocking peptides to the IGF-1R, and IGFBPs, have shown that disruption of the IGF system results in decreased tumor growth. Furthermore, an active IGF system has been demonstrated to be important in the prevention of apoptosis that is necessary for progression to tumor formation (27, 33, 34, 35). Our results present a contrasting view of the IGF-1R to those studies in which it appears necessary for tumor formation. However, the IGF-1R is necessary for normal differentiation of tissues as well as for mitogenesis, so the possibility of dual roles in modifying tumor growth and development should not be surprising (8, 21, 31, 35, 36). As the result of either increasing or decreasing the IGF-1R from its ambient level results in a slowing of tumor growth, we propose that in prostate cancer, a specific level of IGF-1R expression is optimum for tumor proliferation. A further loss of receptor results in decreased tumor growth by a decrease in IGF signaling. On the other hand, an increase in IGF-1R results in the generation of signals that, in addition to proliferation, regulate cell growth by mechanisms such as cellular differentiation.
Although this study was not designed to determine postreceptor mechanisms of action, our findings may suggest some determinants of the functions of the IGF-1R. This receptor is of interest in tumor proliferation in part through its similarity to the insulin receptor, where the cytoplasmic domains of the insulin and IGF-1R are similar (32). Recently, Blakesley et al. have shown that removal of tyrosine-1316 in the cytoplasmic domain of IGF-1R resulted in a receptor that, although mitogenic, had decreased tumorgenicity (37). Blakesley’s data provide evidence that the tumorigenic and proliferation-stimulating functions of the IGF-1R may be separable. Our data suggest that these two functions can be differentially regulated by changing the receptor number to alter tumor growth.
In summary, we have previously demonstrated both in vivo and in vitro that IGF-1R expression is decreased in human prostate epithelial adenocarcinomas (9). In this study we have demonstrated that restoration of IGF-1R number to that of a nontumorigenic epithelial cell results in a decreased rate of anchorage-independent cell growth in vitro as well as decreased tumor growth in vivo.
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Acknowledgments |
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Footnotes |
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Received August 29, 1996.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-reductase
and steroid receptor messenger ribonucleic acid (mRNA) levels, but not
in insulin-like growth factor mRNA levels. J Clin Endocrinol
Metab. 77:1203–1208
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