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NEOPLASIA
From the University of Southern California School of
Medicine and Pathology, Norris Cancer Hospital and Research Institute,
Los Angeles, CA, and from Allergan Pharmaceuticals, Irvine, CA.
Kaposi sarcoma (KS) is responsive to a number of different steroid
hormones, such as glucocorticoids and retinoids. An active metabolite
of vitamin D, 1 Kaposi sarcoma (KS) occurs predominantly in
men with human immunodeficiency virus (HIV) infection at a rate of
about 100 000 times that of the general population and occurs in
approximately 15% of patients with acquired immune deficiency syndrome
(AIDS).1 KS is a highly vascular tumor, and the tumor
cells display features of activated endothelial cells, including high
expression of several phenotypic markers, such as CD34, PAL-E, and UEA
binding,2 as well as various tyrosine kinases, such
as Flt-1, Flk-1/KDR,3 Flt-4,4 Tie-1,
and Tie-2 (R. Masood, unpublished data), otherwise only expressed in
endothelial cells. Biological studies have shown that the tumor cells
produce and respond to several factors, including interleukin
(IL)-1,5 IL-6,6 IL-8,7
Oncostatin-M,8 vascular endothelial growth factor
(VEGF),3 and basic fibroblast growth factor
(bFGF).5 HIV proteins also up-regulate some of these
factors, in addition to the mitogenic effects of HIV tat protein.9
Glucocorticoids have been shown to be associated with the
development of KS in several clinical settings, including skin
disorders, lymphoproliferative disorders, HIV infection, and renal
transplant recipients.10-12 Furthermore, withdrawal of
glucocorticoids can lead to regression of KS in nearly a quarter of the
cases. The effect appears to be directly through the blockage in
transforming growth factor- The nuclear receptor for the active form of vitamin
D3, 1 Chemicals
Recombinant plasmids
Cell culture Long-term spindle isolate KS-59 was established from a KS lesion of an AIDS-KS patient and propagated in gelatin-coated flasks in culture medium that consisted of RPMI 1640 supplemented with 10% charcoal-stripped, heat-inactivated fetal calf serum (FCS), 1% sodium pyruvate, 1% Nutridoma HU (Boehringer Mannheim, Indianapolis, IN), 1% essential and nonessential amino acids, 2 mmol/L glutamine, 1% penicillin and streptomycin (Gibco/BRL, Gaithersburg, MD)3,13 in the absence of conditioned medium of transformed T-cell lines. Immortalized KS cell line KS Y-1 was established from the pleural effusion of an AIDS-KS patient without the use of exogenous growth factors as previously reported.2 It is monoclonal and has been propagated for more than 100 passages. KS Y-1 was propagated on gelatin-coated plates in RPMI 1640 culture medium supplemented with 2% FCS; 1% each sodium pyruvate, essential amino acids, and nonessential amino acids; 1 mmol/L glutamine and antibiotics as above. Human umbilical vein endothelial cells (HUVECs), human aortic smooth muscle cells, and human skin fibroblasts (Clonetics, San Diego, CA) were cultured in the media as recommended by the manufacturer.Tumor tissues KS tumor tissue and normal adjoining skin from the same patient were collected after informed consent and were snap frozen until analysis. Samples of the biopsies were fixed in formalin, and both frozen sections and the formalin-fixed tissues were sectioned for immunocytochemistry for VDR.Immunocytochemistry Cultured human KS isolate (KS-59) and cell line (KS Y-1), HUVECs, and fibroblast cells were trypsinized and collected onto glass slides with the use of a cytospin centrifuge (Shandon, Astmoor, England), and fixed. Slides were treated with monoclonal antibody to rat VDR with 1:50 dilution in phophate-buffered saline (PBS) and 10% FCS as the primary antibody. The receptor was visualized by immunoperoxidase stain by the method of Berger et al.35 Tissue sections of KS biopsy material were also stained with the use of the same antibodies.Northern analysis KS Y-1 and HUVEC cells were grown to near confluence and treated with various concentrations of vitamin D3, ranging from 10 9 to 106 mol/L for 24 hours. Total RNA
was extracted from washed cell pellets by the guanidium thiocyanate
method (RNAzol, Tel-Test Inc, Friendswood TX) and separated on a 1%
agarose formaldehyde gel, followed by transfer onto a nylon membrane
and cross-linking with UV-light (Stratagene, La Jolla, CA). The
transferred RNA was prehybridized at 68°C for at least 30 minutes in
Quick Hyb solution (Stratagene, San Diego, CA) that contained 100 µg
of salmon sperm DNA. The filters were then hybridized with
32P-nick translated full-length complementary DNA (cDNA)
probes for IL-6, IL-8, VEGF, bFGF (generous gift from J. Abraham, Scios Nova, Mountain View, CA), VDR, and  -actin at 68°C for 2 hours. Signal was visualized by overnight exposure to autoradiography film.
The membranes were hybridized with 1 probe at a time, stripped of the
radiolabeled probe, and reprobed. The level of -actin messenger RNA
(mRNA) was used to normalize for the quantity of total mRNA. The
quantitative difference in the mRNA for the target genes was calculated
relative to the -actin levels with the use of a Molecular Dynamics
Phosphor Imager model 445SI.
Cell proliferation studies Early passage AIDS-KS spindle cell isolates (KS-59) and neoplastic KS cell line (KS Y-1) were seeded at a density of 1.0 × 104 cells/well in a 24-well plate in culture medium. T1 fibroblasts (ATCC, Manassas, VA) were seeded at the same density in DMEM supplemented with 10% FCS and antibiotics. The cells were allowed to attach overnight and were treated with varying concentrations of 1 ,25 dihydroxyvitamin D3 on days 1 and
3. Cells were counted on day 6 with the use of a Coulter Particulate
Counter (Hialeah, FL). Cell proliferation assays were performed on
HUVECs and on human skin fibroblasts in a similar manner.
Enzyme-linked immunosorbent assay Early passage AIDS-KS spindle cell isolates (KS-59) and neoplastic KS cell line (KS Y-1) were seeded at a density of 5 × 104 cells/well on 24-well plates coated with gelatin. Supernatants were collected from KS cells treated with various concentrations of 1,25 dihydroxyvitamin D3
(106 mol/L to 109 mol/L) for 24 hours. The
supernatants were centrifuged to remove cell debris and were stored at
 70°C until analysis. IL-6 and IL-8 levels were measured with the
use of commercially available enzyme-linked immunosorbent assay (ELISA)
kits (R&D Systems, Minneapolis, MN), using the manufacturer's
recommended procedure. The cytokine levels were corrected for the cell
numbers present at the time of supernatant collection.
Transfection and chloramphenicol acetyltransferase assay KS Y-1 cells were transfected by the cationic liposome-mediated transfection procedure. Cells were plated 18 hours before transfection at about 50% confluence (about 60 000 cells/well) in 12-well plates. The cells were transfected with either pIC225 or pIC596 reporter constructs (1.0 µg), along with VDR expression vector (0.2 µg), using 4 µg of Lipofectamine (Life Technologies) for each well in a total volume of 500 µL. All of the transfections were performed in triplicate. 1,25 Dihydroxyvitamin D3 was added 18 hours
after transfection, and 6 hours later the cells were treated with
12-O-tetradecanoyl-13-acetate (TPA; 50 ng/mL). The cells
were harvested on the following day and lysed in a hypotonic buffer
(100 µL/well) that contained DNase I, Triton X-100, Tris-HCl, and
EDTA. Chloramphenicol acetyltransferase (CAT) activity was assayed in a
total volume of 50 µL that contained 25 µL of the lysed cell
extract with 5 µL of 4 mmol/L acetyl coenzyme A and 0.1 µCi of
[14C]-chloramphenicol for 2 hours at 37°C.
Chloramphenicol, mono-, and di-acetylated chloramphenicol were
extracted with ethyl acetate and resolved by thin-layer chromatography
on silica gel plates in a chloroform-to-methanol ratio of 19:1 (v:v).
[14C]-labeled products were visualized by
autoradiography, and the conversion of [14C]
chloramphenicol to [14C] acetyl chloramphenicol was
quantitated with the use of a model 445SI phosphorimager.
In vivo studies KS Y-1 cells (5 × 106) were inoculated subcutaneously into the right front armpit of 12 male Balb/c NU/nu mice at 5 weeks of age (day 0). Starting on the following day, half of the mice received 1,25 dihydroxyvitamin D3 orally at a dose
of 5 mg/kg body weight, and the other half received diluent alone. The
treatment was carried out every day for 12 consecutive days.
Mice were killed after the final measurements on day 12. Tumor sizes
were measured externally with calipers to determine the length (L) and
width (W) of the tumor nodule. Tumor volume was calculated according to
the formula V = L × W2 × 0.52. Animals were
treated in accordance with the guidelines of the Animal Use and Care
Committee at the University of Southern California.
Vitamin D3 receptor is expressed in KS cells at high levels We examined the expression of VDR in KS cell lines by Northern blot and immunocytochemistry. High levels of a single species of VDR mRNA (4.6 kilobase [kb]) were expressed in KS Y-1 (Figure 1A). All KS cell lines examined showed similar expression (data not shown). Very low-level expression was observed in endothelial cells (Figure 1B), whereas human skin fibroblasts had no expression (data not shown). Interestingly, VDR mRNA levels did not change significantly after treatment of the KS Y-1 cells with 1,25 dihydroxyvitamin D3 (Figure 1A). Constitutive
and nonregulatable expression of VDR in KS Y-1 cells may reflect
cellular changes associated with transformation. VDR localization
studies by immunocytochemical analysis showed specific cytoplasmic and
nuclear staining of both KS Y-1 cells (Figure 1D) and HUVECs (Figure
1F) in comparison to the lack of specific staining in both these cell
types obtained with isotype specific antibodies (Figure 1C,E; KS Y-1
and HUVECs, respectively). Consistent with the Northern blot data, the
amount of VDR-antibody-specific staining in endothelial cells was far lower than that in KS cells. No staining was observed in human fibroblasts (data not shown). Tumor tissues obtained from the KS lesion
biopsy were also studied for VDR protein localization. Protein
expression was noted in the spindle cells and the cells lining the
small vascular structures in the tumors (Figure 1H). No staining of the
KS tumor was observed with control rat immunoglobulin (Figure 1G). This
finding is in contrast to the lack of expression in vessels of
normal tissues.
1 ,25 dihydroxyvitamin D3, and cell proliferation was measured. 1,25
Dihydroxyvitamin D3 inhibited proliferation of both KS cell
lines in a dose-dependent manner. The concentration of 1,25
dihydroxyvitamin D3 required for 50% inhibition of cell
proliferation (IC50) was 5 × 108 mol/L
(Figure 2). In contrast, 1,25
dihydroxyvitamin D3 did not significantly inhibit the
proliferation of endothelial cells and human T1 fibroblasts.
1 ,25 dihydroxyvitamin D3 for 24 hours. ELISA assays of
the supernatants showed that 1,25 dihydroxyvitamin D3
inhibited IL-6 and IL-8 protein levels in KS Y-1 (Figure
3, upper left, lower left) and KS-59
(Figure 3, upper right, lower right) cells in a dose-dependent manner.
The IC50 for IL-6 and IL-8 inhibition was between 0.1 and 1 µmol/L for both cell lines examined. It should be mentioned that RA,
which also inhibits KS cell growth by down-regulating IL-6, showed a
similar IC50 for inhibition of IL-6 protein in KS cell
lines.18
IL-6 abrogates the inhibitory effect of 1 ,25 dihydroxyvitamin
D3-mediated inhibition of KS cell growth was secondary to
the effect on IL-6 expression, we tested whether addition of exogenous
recombinant human IL-6 (rhIL-6) was able to compensate for cell growth
inhibition in the presence of 1,25 dihydroxyvitamin D3.
As illustrated in Figure 4, 1,25
dihydroxyvitamin D3 produced a dose-dependent inhibition of
KS Y-1 proliferation. Addition of exogenous rhIL-6 (10 ng/mL) effectively counteracted the growth inhibitory effect of 1,25 dihydroxyvitamin D3, despite having no effect on cell
proliferation on its own (Figure 4). This finding indicates that
1,25 dihydroxyvitamin D3 inhibits KS cell growth through
inhibition of IL-6 expression.
1 ,25
dihydroxyvitamin D3 showed a decrease in IL-6 but not in
IL-8 mRNA levels at 24 hours (Figure
5A,B). VEGF and bFGF mRNA levels were
unchanged in KS cells after 1,25 dihydroxyvitamin D3
treatment for 24 hours (data not shown). To determine if 1,25
dihydroxyvitamin D3 regulates the IL-6 promoter, we
performed transient transfection assays. Two different constructs,
containing either 596 or 225 base pairs (bp) of IL-6 5'-flanking DNA
upstream of the transcription start site fused to the CAT reporter gene
were studied in cotransfection experiments with the VDR expression
vector in KS Y-1 cells. Because of low basal activity of the IL-6
promoter in KS Y-1 cells (Figure 6, lane
1), TPA was added to induce the reporter expression. The activity from
both constructs declined in a dose-dependent manner, but the effect was
more marked in the 225 construct (shown), with more than 70%
inhibition of activity at a dose of 106 mol/L 1,25
dihydroxyvitamin D3 (Figure 6). These data show that ligand-activated VDR regulates the IL-6 promoter, and the active site
lies within the first 225 nucleotides of the promoter upstream of the
transcription start site. We have shown previously that pIC110, which
contains nucleotides 110/+13 had no activity in KS Y-1
cells.18 The response elements thus must reside between positions 225 and 110.
1 ,25 dihydroxyvitamin D3, or vehicle alone, daily for 12 days. Mice treated with
1,25 dihydroxyvitamin D3 showed significant retardation
of tumor growth compared with mice treated with the vehicle alone
(Figure 7).
1
KS is a disease with strong angiogenic and inflammatory aspects. Inflammatory cytokines that are of special interest in KS are IL-6 and IL-8, both of which are autocrine growth factors for KS cells6 (R. Masood, unpublished data). Because IL-8 is an angiogenic factor and chemokine for inflammatory cells, it is likely that large amounts of IL-8 production by KS cells is at least in part responsible for exuberant angiogenesis and abundance of mononuclear cells in the tumor lesions. The differentiation and antiproliferative activities of 1 This study showed that KS responds to a vitamin D analog (1 We show that KS cells, and to a much lesser extent endothelial cells, express the VDR and so are capable of responding directly to active vitamin D metabolites. We observed a marked up-regulation of VDR in KS tumor biopsy tissue compared with normal skin from the same patient. In the tumor, both the tumor (spindle) cells and endothelial cells lining the vascular spaces showed strong nuclear staining for VDR. A significant difference between vascular endothelial cells in the tumor compared with normal vessels is that these cells are proliferating rapidly to sustain neo-angiogenesis stimulated by the tumor. Endothelial cells lining vessels in normal skin are essentially quiescent. Added to this situation in KS is the nature of the tumor cells themselves. KS tumor cells share so many of the phenotypic markers and morphological characteristics of activated endothelial cells that they might be considered to be neoplastic (and thus rapidly dividing) endothelial cells. In this light, it is interesting to note that a 4.5-fold up-regulation of VDR number has previously been noted in rapidly growing compared with growth-arrested endothelial cells.36 The mechanism whereby the tumor cells up-regulate VDR expression in the tumor vasculature is unknown. However, it is likely related to the changes in endothelial cell growth rate integral to neo-angiogenesis. It is possible that VDR is up-regulated by angiogenic factors, such as VEGF, bFGF, and IL-6 produced by the KS tumor cells. KS cells produce the cytokines IL-6 and IL-8,7,8 which are
autocrine growth factors6 (R. Masood, unpublished data). Vitamin D analogs have been shown to down-regulate the production and/or expression of these 2 cytokines in a number of cell types. IL-6
is down-regulated in fibroblasts,33,51 in PBMCs from
psoriatic patients,31 and in monocytic and thymocytic
cells.39,40 IL-8 is down-regulated in
fibroblasts,33,51,52 keratinocytes,24-26 osteoclasts,30 and A3 human melanoma cells.32
In KS cells, we found that the VDR agonist inhibited IL-6 secretion
that could be accounted for by a reduction in activity of the IL-6
promoter, whereas it reduced IL-8 protein secretion, but not mRNA
levels, implying posttranscriptional effects. In addition, we showed
that the 1 Transient expression analysis revealed that the response element that
transduces the down-regulation of the IL-6 promoter by 1 Because retinoids inhibit KS growth in vitro and in vivo, the next obvious question was whether a VDR agonist would work in vivo in KS patients. Calcipotriene (Dovonex), a VDR agonist, is available commercially as a topical preparation. Calcipotriene was thus tested in patients with KS once a day. Eight patients were treated, with significant tumor regression noted in 4 patients within a period of 4 to 9 weeks. A larger prospective trial of calcipotriene is under development. As observed for KS cells, recombinant IL-6 acts as a growth factor for primary myeloma cells.59 Thus, VDR agonists also hold promise in the treatment of multiple myeloma as well as other proliferative and inflammatory diseases in which IL-6 and IL-8 production contributes to the pathogenesis of the disease. In psoriatic skin lesions, an increase in IL-6 and IL-8 has been reported,28,31 and these cytokines could theoretically result in proliferation of keratinocytes. Therefore, inhibition of IL-6 and IL-8 production might be the mechanism of action of VDR agonist in psoriasis. Similarly, rheumatoid arthritis, an inflammatory condition with increased IL-6 and IL-8 levels in synovial fluid,60,61 might be therapeutically responsive to VDR agonists.
Submitted May 4, 2000; accepted July 6, 2000.
Supported in part by the Bridges & Larson Foundation.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Parkash S. Gill, Norris Cancer Hospital and Research Institute, Rm 3438, 1441 Eastlake Ave, Los Angeles, CA 90089; e-mail: parkashg{at}hsc.usc.edu.
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© 2000 by The American Society of Hematology.
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  I. Chung, M. K. Wong, G. Flynn, W.-d. Yu, C. S. Johnson, and D. L. Trump Differential Antiproliferative Effects of Calcitriol on Tumor-Derived and Matrigel-Derived Endothelial Cells. Cancer Res., September 1, 2006; 66(17): 8565 - 8573. [Abstract] [Full Text] [PDF]
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A. G. Polson, D. Wang, J. DeRisi, and D. Ganem Modulation of Host Gene Expression by the Constitutively Active G Protein-coupled Receptor of Kaposi's Sarcoma-associated Herpesvirus Cancer Res., August 1, 2002; 62(15): 4525 - 4530. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
) or absence (
) of
rhIL-6 (10 ng/mL). Cell counts were determined with a Coulter Counter.
The right-hand side of the graph (
) shows the effect of rhL-6 alone
on cell proliferation. Each value is the mean ± SEM of the assays
performed in triplicate.
.
in culture systems of
mononuclear cells or T lymphocytes.