* Departments of Pharmacology and Toxicology and
Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755;
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190
Received June 27, 2003; accepted August 21, 2003
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ABSTRACT |
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Key Words: arsenic; angiogenesis; Matrigel; chicken chorioallantoic membrane; melanoma.
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INTRODUCTION |
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Arsenic therapies and environmental exposures have been associated with significant cardiovascular effects. While the underlying causes are controversial, careful measures must be taken to avoid cardiac arrhythmias in patients receiving As(III) infusions to treat leukemias (Barbey, 2001; Ohnishi et al., 2000
; Singer, 2001
; Unnikrishnan et al., 2001
). This is due to the propensity of As(III) to cause slow, progressive prolongation of the QT interval, which can result in potentially fatal Torsades de Pointes (Ohnishi et al., 2000
; Unnikrishnan et al., 2001
). In addition, prolonged injection of As(III) was recently shown to produce cardiac toxicities in mice (Li, Y. et al., 2002
). Environmental exposures are associated with increased incidence of ischemic heart disease, arrhythmias, hypertension, and peripheral vascular disease (Engel et al., 1994
; Lewis et al., 1999
; Tseng et al., 2003
; Wang et al., 2002
). The mechanisms for these vascular effects are unknown. However, depending on the dose, As(III) stimulates clonal expansion of vascular smooth muscle, which may contribute to blood vessel occlusion (Engel et al., 1994
; Wang et al., 2002
). Cell culture-based studies have demonstrated differential, concentration-dependent effects of As(III) on vascular cells ranging from increased proliferation to increased apoptosis (Barchowsky et al., 1996
; Roboz et al., 2000
).
Angiogenesis, the development of new blood vessels from existing ones, is fundamental to growth and invasion in both solid and hematologic tumors (Herbst et al., 2002; Jung et al., 2002
; Orpana et al., 2002
; Papetti et al., 2002
; Yang et al., 2002
). One hypothesis for the antitumor effects of As(III) is that it inhibits angiogenesis by reducing expression of vascular endothelial cell growth factor (VEGF) or by being directly toxic to endothelial cells in high doses (Lew et al., 1999
; Roboz et al., 2000
). As discussed in several recent reviews, this hypothesis and the impetus for using arsenic as an antiangiogenic agent to treat solid tumors are based primarily on observations made in three studies (Anderson et al., 2002
; Davison et al., 2002
; Waxman et al., 2001
). The first study demonstrated that injecting mice with high doses of As(III) (10 mg/kg) acutely collapses the tumor vasculature and sensitizes the tumor to radiation therapy (Lew et al., 1999
). The second study demonstrated that clinically relevant concentrations of As(III) inhibited log-phase growth of endothelial cells in culture and VEGF expression in leukemic cells (Roboz et al., 2000
). The relevance of the endothelial cell model used is questionable since endothelial cells in vivo are generally in close contact with matrix and not in log-phase growth. These studies have recently been repeated with slightly lower doses of As(III) and increased angiogenesis or endothelial cell growth and tube formation in three-dimension was found (Kao et al., 2003
). These findings confirm an earlier report which demonstrated that As(III) causes dose-dependent endothelial cell proliferation in confluent, but not in log-phase cultures (Barchowsky et al., 1996
). Finally, arsenic has been demonstrated to induce expression of angiogenic vascular endothelial cell growth factor (VEGF) in endothelial cells (Kao et al., 2003
) and cervical cancer cells (Duyndam et al., 2001
, 2003
), but not in leukemic cells (Roboz et al., 2000
). These conflicting results suggest that the effects of As(III) on the angiogenic process are dose-, cell-, and context-specific.
There have been no reports on the effects of As(III) on the angiogenic process in vivo. Therefore, the following studies were conducted to investigate the hypothesis that As(III) causes dose-dependent stimulation of blood vessel growth and thereby contributes to tumor growth. In the studies presented below, avian and mammalian in vivo models of angiogenesis were used to establish the dose-dependent capacity of As(III) to promote or inhibit the growth of new blood vessels. The range of As(III) doses used in these studies approaches the levels that are used clinically to treat leukemias and that are being evaluated for treating solid tumors. The data demonstrate complex kinetics with increased angiogenesis at both low and higher doses of As(III). A solid-tumor model in mice was used to demonstrate that instead of reducing tumor size, lower doses of injected As(III) increased both growth and metastasis. The data suggest that As(III) may not be a reasonable therapy for treating solid tumors, since low concentrations may enhance tumor growth, and high therapeutic levels may not limit this growth.
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MATERIALS AND METHODS |
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Mouse Matrigel assay for angiogenesis.
Matrigel plug assays in mice were performed in accordance with institutional guidelines for animal safety and welfare, as previously described (Colorado et al., 2000; Swift et al., 1999
). Normal male mice (C57BL/6NCr) 68 weeks of age and weighing ~20 g were obtained from the National Cancer Institute (Frederick, MD) and allowed to acclimate for 34 days prior to the start of treatments. Fresh sodium arsenite stock solutions (5 mmol/l) were prepared every other day and kept at 4°C. Dosing solutions of 0.162, 1.62, and 16.2 µg/ml were diluted in sterile H2O, and 0.1 ml was administered ip daily for 3 weeks to groups of four animals per dose. The average weight of the mice was 20 g, which yields a dose range of 0.880 µg/kg/day. The rationale for this dosing range was to provide daily injections of 0.125 to 12.5 nmol of As(III)/animal/day. Assuming a 2.5 ml blood volume, this would cause circulating levels of 0.05 to 5.0 µmol/l, which are relevant to anti-leukemic therapies and are comparable to the range of As(III) concentrations used in the CAM assays. Control animals received 0.1 ml of sterile water ip daily. Following the first week of As(III) injections, the mice were anesthetized with 0.2 ml avertin (35.3 mmol/l 2,2,2 tribromomethanol; Aldrich, Milwaukee, WI) dissolved in 1:40 2-methyl-2-butanol (Fisher Chemical Co, Fairlawn, NJ):H20). Matrigel (0.30.4 ml; Fischer Scientific, Pittsburgh, PA) was then injected between the skin and abdominal muscle of each mouse. The Matrigel was injected alone or supplemented with 50 ng/ml or 250 ng/ml of recombinant FGF-2. This range of concentrations of As(III) yielded no overt signs of toxicity, either in behavior or body weight over the course of the three-week study. At necropsy, the animals exhibited no signs of infection at the site of either the Matrigel or arsenic injections.
Histopathology.
Matrigel plugs were removed two weeks after implantation and were fixed in 10% neutral buffered formalin prior to paraffin processing. Sections were stained with H&E and assessed microscopically for blood vessel formation. Blood vessels were counted in ten non-overlapping fields of each section at 400 x magnification. The number of the vessels in all 10 fields from a single animal is summed and the data are reported as the mean sum ± SD for each treatment group.
Preparation of B16-F10 (GFP) cells.
B16-F10 mouse melanoma cells were purchased from American Type Tissue Collection (Manassas, VA) and maintained in Dulbeccos minimal essential media (DMEM) containing 10% FBS and penicillin/streptomycin. To enhance the ability to detect metastatic tumor cells, stable transfectants that express green fluorescent protein (GFP) were prepared. The pLNCX-GFP vector was prepared by removing the CMV immediate-early gene promoter, EGFP protein, and the polyadenylation signal from the pEGFP-C1 vector (Clontech) and inserting this into the multiple cloning site of pLNCX retroviral vector (Clontech). This vector was transfected into PT67 packaging cells (Clontech), viral titer determined, and high-titer virus-containing supernatant used to infect B16-F10 cells overnight. Cells were then grown in G418 selection media for one week, resulting in GFP-expressing cells isolated using fluorescence automated cell sorting (FACS), and clones were selected by limiting dilutions. A single clone designated B16-F10 (GFP), to be used in the mouse tumor experiments, was selected for its high GFP fluorescence and for a doubling time similar to that of the parental cells.
Mouse tumor studies.
All animal studies were conducted in accordance with AALAC-approved guidelines using a protocol approved by the IACUC at the University of Oklahoma. Six-week-old male NCr nu/nu mice (NCI APA breeding stock, Frederick MD) were housed in ventilated cages with autoclaved chow, water, and bedding. Following one week of acclimation, 5 x 105 B16-F10 (GFP) cells in 100 µl PBS/1 µmol/l EDTA were injected subcutaneously into the external surface at the base of the right ear of mice. At days 7, 11, 14, 18, 21, and 25, post-implantation, animals received injections of 0, 0.5, 1, or 5 mg/kg arsenic trioxide (Sigma Chemical), ip, in 100 µl sterile water for injection. These higher levels of As(III) produce steady-state blood levels in the mice that are comparable to those seen in leukemic patients receiving As(III) therapy (Lallemand-Breitenbach et al., 1999). Animals were assessed for the presence of tumors every other day, and tumor measurement began 10 days after implantation and continued biweekly until tumors reached approximately 810% of animals body weights. The length (L) and width (W) of tumors were measured using Vernier calipers (Mitutoyo, Kawasaki Kanagawa, Japan) and tumor volume calculated using the formula L x W2. After sacrifice, the tumor and lungs were excised, fixed overnight in neutral buffered formalin, embedded in paraffin, and sectioned.
Immunohistochemical staining.
Mouse tumor sections were de-paraffinized using traditional protocols and then incubated in 6% peroxide for 20 min to further minimize melanin coloration. The sections were then permeabilized using 0.1 mM CaCl2, 0.1 mM MgCl2, and 0.1 mM MnCl2 containing 1% Triton X-100 in PBS for 15 min at room temperature. Antigen retrieval was accomplished in 0.1 M sodium citrate brought to boiling in a microwave oven at high power and then heating was continued at 30% power for 10 min. Tissues were blocked with rabbit serum (VectaStain ABC rabbit kit; Vector Labs, Burlingame, CA), and antibody against Tie-2 (Santa Cruz; sc9026; 1:500 dilution) was added for 4 h at room temperature. Secondary antibody, conjugated to horseradish peroxidase, and Vector® VIP peroxidase substrate were added according to protocol (Vector ABC). Sections were then counterstained with Gomori trichrome stain (Harleco, Gibbstown, NJ).
Statistics.
All analysis was done using Prism 3.0. (GraphPad Software, San Diego, CA). One-way ANOVA was conducted, with multiple comparisons tested by the Bonferroni post hoc test at a significance level of p 0.05. Tumor volumes were compared using two-way ANOVA, with treatments and days after implantation as independent variables.
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RESULTS |
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DISCUSSION: |
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The angiogenic process in normal tissue and in disease has been extensively reviewed (Carmeliet et al., 2000; Papetti and Herman, 2002
; Shacter et al., 2002
). In general, endothelial cells and the vasculature are very stable in normal adult tissues until wounded. When stimulated, angiogenesis is highly ordered and tightly regulated by the release of positive and negative factors that include several soluble peptides, growth factors, inflammatory mediators, cellcell and cell-matrix interactions, and hemodynamic effects (Papetti et al., 2002
; Shacter et al., 2002
). Thus, modeling angiogenesis in cell culture compromises the ability to investigate many potential mechanisms for the pro-angiogenic effects of specific compounds such as As(III). For example, previous studies from this laboratory demonstrated that As(III) directly stimulated postconfluent endothelial cells to proliferate (Barchowsky et al., 1996
, 1999
). It is likely that these proliferative signals are generated by stimulation of a growth pathway involving low level generation of reactive oxygen species following As(III)-induced activation of vascular NADPH oxidase and tyrosine kinases (Barchowsky et al., 1999
; Smith et al., 2001
). However, in vivo proliferative and angiogenic stimuli are more likely to arise from cells surrounding the endothelial cells and not the endothelial cells themselves (Papetti et al., 2002
). Thus, monoculture of endothelial cells may not model the full complement of effects for agents that promote angiogenesis by stimulating release of factors from pericytes, and vascular smooth muscle, epithelial, and tumor cells.
One of the difficulties with As(III) as a therapeutic agent is that the dose dependence of its cellular and molecular effects are nonlinear and are cell- or context-specific. It is apparent from recent reports that the potential for As(III) to stimulate tumor cells to release angiogenic factors depends on the tumor type and the As(III) concentration (Duyndam et al., 2001; Kao et al., 2003
; Roboz et al., 2000
; Roboz and Roboz, 2000
) demonstrated that five µmol/l As(III) inhibited VEGF release from a human leukemic cell line and inhibited the proliferation of subconfluent human endothelial cells. In contrast, As(III) increased VEGF expression in both human umbilical veins and in cervical cancer cells (Duyndam et al., 2001
). The studies presented in Figures 4
and 5
suggest that low doses of As(III) promote growth and metastasis of the B16-F10 tumors in vivo. The highest dose of 5 mg/kg As(III) biweekly trends towards less tumor growth (Fig. 4
), but is the most significant for lung metastasis (Fig. 6
). The difference in tumor growth appears to result from differential effects on blood vessel density and tumor morphology. Low-dose As(III) greatly increases the density of blood vessels in the tumors, and tumor size is increased (Fig. 5B
). Blood vessel size was decreased to near control levels by the highest dose of As(III), but the number of vessels was still high (Fig. 5C
). At high dose, the tumors were of a looser morphology and there were more metastases. Thus, there may have been more tumor masses invading into tissue at the highest dose of As(III), but this dose may have retarded the growth of the invading blood vessels and melanoma cells.
The data in Figure 3 suggest that dose is an extremely important consideration and indicate that As(III) produces nonlinear effects. The general implication is that there is no threshold for As(III) effects, since it is quite easy to arrive at doses that are both pro- and antiangiogenic. The clinical implication of these nonlinear effects is that there may be only a narrow window of blood levels that will provide both antiangiogenic and antitumor effects. In humans, the pharmacokinetics of a single dose of 10 mg arsenic trioxide IV shows a peak blood level of approximately 7 µmol/l within four h of ip administration (Shen et al., 1997
). Blood levels fall, however, to 1 µmol/l at around 10 h after arsenic administration, and reach approximately 0.3 µmol/l at 24 h after administration. The peak levels from this ip dose could cause endothelial cell toxicity (Barchowsky et al., 1996
; Roboz et al., 2000
) and do appear to decrease blood vessel density in the CAM assay (Fig. 1
). In contrast, the highest dose used in the mouse Matrigel study of approximately 0.08 mg/kg per day produced significant angiogenesis (Fig. 3
) and higher biweekly doses of 0.5 and 1.0 mg/kg seemed to enhance tumor growth (Fig. 4
). Taken together, these data suggest that caution should be taken when dosing patients with solid tumors that are dependent on blood vessel growth.
The complexity of the As(III) actions was indicated by the observation that As(III) had no effect in the Matrigel assays unless a threshold level of FGF-2 was added to the plugs (Fig. 3). It is common that systemically administered agents fail to produce angiogenesis in this assay when FGF-2 is absent or until inflammation is present (Claffey et al., 2001
; Shacter et al., 2002
). In contrast, As(III) added alone increased blood vessel density in the CAM assay (Fig. 1
) and tumors tended to be larger in response to lower doses of As(III) (Fig. 4
). In these latter cases, synergy may be provided by the high background level of angiogenic and remodeling factors normally present in developing systems or in tumors. The major significance derived from these studies is that As(III) facilitates the angiogenic process, but may not act as a direct promoter. For many years, arsenic has been associated with various types of cancer, including skin cancers (Hughes, 2002
). Historically, however, it has been very difficult to observe a direct carcinogenic effect of arsenic (Hughes, 2002
; Rossman et al., 2002
). Instead, arsenic is now thought to be a cocarcinogen when given with known carcinogens such, as UV radiation (Rossman et al., 2002
). The data in the current study indicate that low doses of As(III) are capable of inducing angiogenesis, a process critical to the growth of most tumors. This provides another means by which low-dose arsenite can enhance tumor growth and may help to explain the cocarcinogenicity of this compound.
The mechanisms for As(III)-induced angiogenesis are unclear. As(III)-induced proliferative responses in a variety of cultured cell types, including vascular cells, are associated with increased Src-tyrosine-kinase activity (Barchowsky et al., 1999; Simeonova et al., 2002
), enhanced growth factor responses (Kao et al., 2003
; Simeonova et al., 2002
; Trouba et al., 1999
), increased MAP kinase activity (Bode et al., 2002
; Trouba et al., 2000
) of and activation of transcription factors, such as AP-1 and NF-
B (Barchowsky et al., 1996
, 1999
; Bode et al., 2002
; Drobna et al., 2003
; Simeonova et al., 2002
). Most recently, Kao et al.(2003)
demonstrated that concentrations of arsenite below 5 µM induced angiogenesis and increased the expression of the angiogenic mitogen, VEGF. It is known that VEGF and FGF-2 synergize to induce pathological angiogenesis in vivo (Lindner et al., 2001
). While synergy between an As(III)-induced mitogenic response, such as increased VEGF expression, and FGF-2 is a plausible mechanism, many more studies will be required to define this pathway as rate limiting in vivo. In addition, few studies have examined sustained signaling events that might manifest during the one-week As(III) priming period used in the studies shown in Figures 2
and 3
, which allowed for synergistic increases in angiogenesis. It is not unreasonable to speculate that these long-term signaling or phenotypic changes contribute to the etiology of diseases caused by chronic environmental arsenic exposures.
In conclusion, these studies present the dose-dependent effects of As(III) in two in vivo models of angiogenesis. Depending on the systemic level, arsenic can promote or reduce angiogenesis. Further, As(III) may synergize with other factors to promote cardiovascular remodeling and tumor growth. These effects occur at levels of arsenic that are relevant to both cancer therapies and environmental exposures. Thus, the implication of the results of these studies is that caution should be used when treating solid tumors with arsenic. Dosing at subtherapeutic levels may actually enhance tumor growth and tumoristatic doses may enhance tissue remodeling. For environmental exposures, the ability of As(III) to induce angiogenesis may represent an axis for the progression of vascular disease. For clinical use as an anticancer agent, As(III)-induced angiogenesis may represent an unacceptable toxic side effect.
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ACKNOWLEDGMENTS |
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NOTES |
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