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Regular Articles |
From the Reproductive Endocrinology Center,*
Department
of Obstetrics, Gynecology and Reproductive Sciences, University of
California, San Francisco, San Francisco, and Department of
Cardiovascular Research,
Genentech, Inc.,
South San Francisco, California
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One angiogenic factor that is thought to play a key role in the vascularization of normal and neoplastic tissue is vascular endothelial growth factor (VEGF), also known as vascular permeability factor. VEGF is a potent and specific mitogen for endothelial cells,12-17 stimulates the full cascade of events required for angiogenesis in vitro and in vivo,17,18 and markedly augments the permeability of existing microvasculatature.19-21 VEGF is expressed in many animal and human malignancies and by most transformed cells lines.21-41 The effect of VEGF on vascular permeability is believed to be crucial for malignant ascites formation.19,42,43 The actions of VEGF are mediated by at least two cell surface receptors, flt-1 and KDR.44,45 The central role of VEGF in tumor growth has been demonstrated in studies using animal models in which tumor growth and vascularization in vivo were inhibited if VEGF activity was neutralized by function-blocking antibodies46 or expression of antisense VEGF mRNA,47 or if signaling was disrupted by dominant-negative mutation of the KDR receptor.48
Ovarian cancer is characterized by widespread intraperitoneal carcinomatosis and the formation of large volumes of ascitic fluid.49 VEGF may play a major role in the progression of ovarian cancer by influencing tumor growth through its promotion of tumor angiogenesis and ascites production through its stimulation of vascular permeability. Although VEGF has been detected in ovarian cancer,26,37,50,51 so, too, have most other known angiogenic factors;37,52-59 therefore, the role of VEGF as a regulator of angiogenesis in ovarian cancer growth is unclear. However, several studies have indicated that VEGF-regulated angiogenesis is an important component of ovarian cancer growth. Microvessel density and the level of VEGF expression in ovarian cancer directly correlate with poor prognosis, suggesting that angiogenesis, possibly mediated at least in part by VEGF, influences disease progression.26,50,51 In a murine model of ovarian cancer, the drug FR118487, which inhibits angiogenesis by inhibiting basic fibroblast growth factor and VEGF activities,60 suppressed the in vivo growth and metastasis of a murine ovarian cancer cell line.61 In the present study, we directly assessed the role of VEGF in the growth and progression of ovarian cancer. To that end, we used the human ovarian carcinoma cell line SKOV-3 to develop an in vivo model of ovarian cancer in immunodeficient mice that recapitulated the intraperitoneal carcinomatosis and ascites production seen in women with this disease. We then used a function-blocking monoclonal antibody, which blocks access of VEGF to both the flt-1 and KDR receptors, to specifically inhibit tumor-derived VEGF activity and assessed the consequences on tumor growth, ascites formation, and disease progression.
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Materials and Methods |
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A mouse monoclonal antibody (A4.6.1) directed against human VEGF was used to neutralize VEGF activity in vivo. Characterization of this antibody, including its high specificity toward human VEGF and its ability to inhibit VEGF activity in vitro and in vivo, as well as to block binding of VEGF to its receptors in vivo, has been described previously.46,62 The antibody does not inhibit the activity of mouse VEGF (unpublished data). The human ovarian cystadenocarcinoma cell line, SKOV-3, was obtained from the American Type Culture Collection (Manassas, VA). One-month-old female immunodeficient mice (BALB/c nu/nu) were obtained from Simonsen Laboratories (Gilroy, CA), housed in isolated conditions, and fed autoclaved standard pellets and water. All protocols involving immunodeficient mice were approved by the Committee on Animal Care, University of California, San Francisco.
Cell Culture
The SKOV-3 cells were cultured in Dulbecco's modified Eagle's medium H-21 containing 10% fetal calf serum, glucose (4.5 g/L), penicillin G (100 U/ml), streptomycin (2.5 µg/ml), glutamine (2 mmol/L), and fungizone (2.5 µg/ml). All cell culture reagents were obtained from the Cell Culture Facility, University of California, San Francisco. Before in vivo inoculation, SKOV-3 cells were grown to confluence, harvested by trypsinization, and resuspended in Ca2+/Mg2+-free phosphate buffered saline (PBS). In preliminary studies, we determined that SKOV-3 cells express VEGF in vivo and in vitro using reverse transcription-polymerase chain reaction and immunocytochemistry, respectively, and that A4.6.1 does not affect their proliferation in vitro (data not shown).
In Vivo Inoculation of SKOV3 Cells
The SKOV-3 cells were prepared for inoculation as described above and injected as a bolus either into the peritoneum (IP group; n = 31; 10 x 106 cells per mouse in 200 µl of PBS) or into the dorsal subcutaneous tissue (SC group; n = 8; 5 to 10 x 106 cells in 50 µl of PBS) of athymic mice. Some SC mice received two boluses of SKOV-3 cells, one in each flank. Seven to 10 days after SKOV-3 inoculation, some of the mice (IP group, n = 16; SC group, n = 5) were treated with A4.6.1 (100 µg in 0.1 ml of PBS, intraperitoneally, twice per week), and the rest were treated with the same volume of vehicle. A4.6.1 treatment was delayed to ensure that tumor engraftment was not inhibited. The size of subcutaneous tumors was measured twice weekly using calipers fitted with a Vernier scale. For each tumor, two perpendicular measurements were obtained from which an estimate of tumor radius was derived. Tumor volume was then calculated based on the assumption that tumors were spherical. At the end of the experimental period, mice were killed by anesthetic overdose. At autopsy, SKOV-3 tumors were excised, fixed in 4% paraformaldehyde/100 mmol/L PBS, pH 7.4, at 4°C for 24 hours, and embedded in paraffin. Paraffin sections (10 µm) were used for histochemical analysis.
Statistics
Data were analyzed using the unpaired Student's t-test for statistical comparison between groups. Differences between groups were considered statistically significant at P < 0.05. Experiments were performed in triplicate.
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Results |
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All IP mice receiving PBS treatment (ie, control mice) developed a
swollen abdomen, indicative of ascites formation and intraperitoneal
carcinomatosis, within 3 to 6 weeks of SKOV-3 administration. Soon
after (within 5 to 7 days) the appearance of abdominal swelling,
PBS-treated IP mice became cachectic and as a consequence were
euthanized in accordance with the animal care protocol. The
intraperitoneal carcinomatosis in the IP mice closely resembled
peritoneal metastases from poorly differentiated stage III papillary
serous ovarian cancer.63
The neoplasms were characterized
by trabecular and solid patterns of growth with variable degrees of
cytological atypia. Numerous mitotic figures were identified, and
papillary growth was common on the luminal side. In most tumors,
desmoplastic stroma typical of ovarian cancer metastases was seen.
Tumors were found on the surfaces of the peritoneum, diaphragm,
intestines (Figure 1)
, uterus and
associated fat, and stomach. Tumors were rarely found on the liver or
spleen, and there was no evidence of visible metastasis to organs
outside of the peritoneum. In general, the tumors did not invade the
host tissue to which they were adherent; however, some focal invasion
into muscle was seen. Extensive tumor growth was detected in the
uterine fat, and foci of tumor were observed in the uterine lymphatics.
The sites and extent of the peritoneal carcinomatosis and the
production of ascitic fluid induced by intraperitoneal administration
of SKOV-3 cells in immunodeficient mice were similar to those seen in
women with ovarian epithelial cancer.
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To examine directly the role of tumor-derived VEGF in SKOV-3 tumor growth, we established an in vivo model in which SKOV-3 tumors were grown subcutaneously in immunodeficient mice. Well defined subcutaneous tumors developed within 7 days of SKOV-3 inoculation and were of sufficient size to permit accurate measurement. Tumor growth was rapid, and within 3 weeks the subcutaneous foci were 5 to 10 mm in diameter and began to exhibit vascular islands that eventually formed blood-filled cysts. By 6 weeks, the largest tumors were approximately 20 mm in diameter and contained numerous cysts that eventually ruptured. At this stage of tumor progression, the mice were killed.
To assess the role of VEGF in tumor growth, some SC mice
(n = 5 mice; 11 tumors) were treated with
A4.6.1. Control mice (n = 3 mice; 6 tumors) were
treated with PBS. In preliminary studies, we found that treatment with
a nonspecific antibody of the same IgG type had no effect on tumor
growth and was essentially equivalent to vehicle alone (data not
shown). A4.6.1 significantly inhibited the growth of subcutaneous
SKOV-3 tumors within 2 weeks of treatment (Figure 2)
; tumor size did not progress beyond
the size attained at the initiation of A4.6.1 treatment and the tumors
did not form cysts. After cessation of A4.6.1 treatment (Figure 2B)
,
tumor growth resumed, and within 2 weeks the tumors developed
blood-filled cysts and the mice had to be killed. In preliminary
studies in which fewer cells were used for subcutaneous inoculation,
after discontinuance of A4.6.1 treatment, tumor growth resumed and
within 3 weeks the rate of growth paralleled that of controls. Tumor
growth also was inhibited when A4.6.1 was administered late in tumor
progression (30 days) (Figure 2B)
. Interestingly, in these tumors
A4.6.1 appeared to deplete the contents of the cysts; their volume was
markedly reduced, and some cysts involuted without rupture. In
addition, tumors lost their red coloration and became more skin toned
in appearance.
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Role of VEGF in Intraperitoneal Tumor Growth
Studies of subcutaneous SKOV-3 tumor growth established the pivotal role of VEGF in tumor progression. However, as ovarian cancer is not a subcutaneous malignancy, we studied the effects of A4.6.1 treatment on the growth and progression of intraperitoneal SKOV-3 tumors. IP mice were treated with A4.6.1 (n = 16) or PBS (n = 15) in an identical fashion to those bearing subcutaneous tumors. However, intraperitoneal tumor growth could not be monitored directly and, because of its spread within the abdomen, could not be quantified accurately. Therefore, intraperitoneal tumor burden was assessed qualitatively at postmortem examination. In all animals, treatment was initiated 8 days after SKOV-3 inoculation and continued for various times.
In experiment 1 (Figure 3A)
, all animals
were killed 21 days after SKOV-3 inoculation. At postmortem
examination, two of the three PBS-treated animals exhibited abdominal
swelling with a moderate level of ascites and had moderate and easily
detectable intraperitoneal tumor burden. The remaining PBS-treated
animal had no detectable abdominal swelling or ascites and only a mild
tumor burden. None of the A4.6.1-treated IP animals showed signs of
ascites formation or cachexia at the time of postmortem examination,
and intraperitoneal SKOV-3 tumor burden was barely detectable.
Interestingly, A4.6.1 inhibited the growth of small subcutaneous tumors
at the site of SKOV-3 injection that developed in some IP animals.
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, the effects of prolonged A4.6.1 treatment
(n = 6) were examined. All of the PBS-treated
animals (n = 6) displayed signs of ascites
formation and cachexia at various times after SKOV-3 inoculation; the
first PBS-treated animal was killed at 4.5 weeks and the last at 6.5
weeks because of severe cachexia associated with the developing
ascites. One A4.6.1-treated animal exhibited ascites and cachexia and
therefore was killed at 5.5 weeks. This mouse had a high tumor burden.
Four of the A4.6.1-treated animals were killed at 6.5 weeks. The
remaining A4.6.1-treated IP mouse was killed the following day. Five of
the six A4.6.1-treated IP animals appeared normal at the time of
postmortem examination, and no ascites formation could be detected. In
A4.6.1-treated mice, intraperitoneal tumor burden was variable: in
three of the six animals it was high and comparable with tumor burden
in those mice receiving PBS alone, whereas in the other IP animals
tumor burden ranged from moderate to scarce. The reason for the
apparent lack of response in the one A4.6.1-treated mouse is uncertain.
In experiment 3 (Figure 3C)
, A4.6.1 treatment was stopped after the
last PBS-treated animal was killed (approximately 7 weeks after SKOV-3
inoculation). At that time, three of the six A4.6.1-treated animals
were killed. As with experiment 2, all of the PBS-treated animals
exhibited abdominal swelling and became cachectic approximately 6 weeks
after receiving SKOV-3 cells. All of these animals had severe ascites
and a high intraperitoneal tumor burden. In contrast, the three
A4.6.1-treated animals killed at 6.5 weeks had no detectable ascites
and a variable, but clearly detectable, tumor burden. Importantly,
within 2 to 3 weeks of cessation of A4.6.1 treatment, the remaining
mice developed severe ascites, became cachectic, and had to be killed.
The tumor burden in these animals varied from moderate to high.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We used the human cell line SKOV-3, derived from a human ovarian serous cystadenocarcinoma, which accounts for 40 to 50% of all ovarian epithelial cancers, to induce peritoneal carcinomatosis and ascites production in immunodeficient mice. This model closely mimicked human ovarian cancer in that: 1) carcinomatosis was confined to the peritoneum; 2) the progression of the disease involved ascites formation and cachexia (IP mice were asymptomatic until they began to develop ascites, which always was associated with a heavy intraperitoneal tumor burden); 3) the morphology of intraperitoneal SKOV-3 tumors closely resembled peritoneal metastases from poorly differentiated stage III ovarian cancer in women; and 4) in preliminary studies, we confirmed that SKOV-3 tumors, like human ovarian carcinomas, express VEGF.
To examine the role of VEGF in ovarian cancer, we specifically ablated tumor-derived VEGF activity in IP mice using the function-blocking antibody, A4.6.1. This neutralizing antibody, which blocks access of VEGF to both VEGF receptors, inhibits the activity of human, but not mouse, VEGF and therefore specifically blocks the activity of tumor-derived VEGF. The effects of A4.6.1 on SKOV-3 tumor development were first examined using the subcutaneous model in which tumor growth could be monitored directly. We found that A4.6.1 was tumoristatic for SKOV-3 tumors grown subcutaneously; tumors failed to grow beyond the size attained at the beginning of the A4.6.1 treatment. However, when A4.6.1 treatment was stopped, the growth of subcutaneous tumors resumed. This observation is consistent with the concept that VEGF regulates, and is essential for, tumor neovascularization. Tumors could not grow further, because they could not stimulate the necessary vascularization to support a greater tumor mass. However, the existing vasculature likely was not affected by A4.6.1 treatment and therefore remained sufficient to maintain tumor size. Interestingly, when A4.6.1 was administered to SC mice bearing advanced tumors (10 to 15 mm in diameter with blood-filled cysts), tumor growth was inhibited and cysts regressed and involuted without rupturing. The regression of blood-filled cysts in response to VEGF inhibition suggests that tumor cyst formation is influenced by VEGF. This observation is consistent with the increase of vascular permeability caused by VEGF and suggests that VEGF may induce cyst formation by augmenting microvessel permeability. These data clearly demonstrated that tumor-derived VEGF is a necessary component of subcutaneous SKOV-3 tumor growth. However, ovarian cancer is not a subcutaneous disease but instead usually is limited to the peritoneal cavity. Therefore, we performed similar experiments using the intraperitoneal model.
In IP mice, inhibition of tumor-derived VEGF activity by A4.6.1 prolonged life and completely inhibited ascites formation. However, unlike its consistent tumoristatic action in SC mice, A4.6.1 only partially inhibited SKOV-3 tumor growth in IP mice. In some A4.6.1-treated IP mice, the extent of intraperitoneal tumor burden was similar to that of PBS-treated animals, whereas in others it was minimal. The reason that tumor-derived VEGF was obligatory for subcutaneous, but not intraperitoneal, SKOV-3 tumor growth is unclear. The peritoneal cavity offers a markedly different environment for tumor growth and spread than does the subcutaneous space. Within the peritoneum, SKOV-3 cells are not confined, as they are when administered as a subcutaneous bolus. Consequently, subcutaneous tumors grew only as a spherical mass under the skin, whereas in the peritoneum, tumors grew as thin sheets over a relatively large surface area with the occasional formation of solid tumor foci extending into the peritoneal cavity. With this mode of tumor growth and spread, it is likely that dependency on angiogenesis would be minimal, as the thin layers of tumor and some of the tumor buds would be small enough to survive by passive diffusion of nutrients from the underlying host vasculature and the surrounding peritoneal fluid. However, neovascularization clearly occurred in some intraperitoneal tumors, particularly the large solid tumors that formed on the pelvic organs. Thus, intraperitoneal carcinomatosis appears to have angiogenesis-independent and -dependent components; ie, formation and growth of the thin layers of tumor and some of the smaller solid buds would be independent of angiogenesis and be maintained by the pre-existing vasculature, whereas the larger solid intraperitoneal tumors would require neovascularization for continued growth. If this concept is correct, then inhibition of angiogenesis would only inhibit the development and growth of the larger intraperitoneal tumors. Consistent with this notion, we found that A4.6.1 did not inhibit the formation of tumor sheets on peritoneal surfaces or the formation of small solid tumor foci. However, large and presumably angiogenesis-dependent SKOV-3 tumors were detected in some A4.6.1-treated mice. It is unlikely that the dose of A4.6.1 was insufficient to inhibit SKOV-3 activity by intraperitoneal tumors, as the same dose was sufficient to act systemically and completely inhibit subcutaneous SKOV-3 tumor growth in SC mice. Furthermore, in some IP mice it was sufficient to inhibit the growth of a subcutaneous tumor that developed at the site of SKOV-3 inoculation. This indicates that VEGF-regulated angiogenesis may not be an essential factor in the growth of intraperitoneal carcinomatosis. Indeed, it is possible that other angiogenic factors, many of which have been detected in ovarian carcinoma cells, may have compensated for the lack of VEGF or may play a more prominent role in the control of intraperitoneal tumor angiogenesis. However, it is difficult to reconcile this possibility with an explanation of why such factors would not have supported angiogenesis in the subcutaneous model. It appears that the role of VEGF in tumor growth may be influenced by the site of tumor engraftment.
A4.6.1 completely inhibited ascites formation in IP mice, even though some animals had a tumor burden that was similar to that of controls that developed ascites and cachexia. When A4.6.1 treatment was stopped, IP mice rapidly developed ascites and became cachectic. VEGF is a potent stimulator of vascular permeability and is thought to play a major role in the development of malignant ascites.43 Our data support the hypothesis that ascites formation in ovarian cancer is regulated by tumor-derived VEGF via the augmentation of tumor microvessel permeability. Ascites formation, as indicated by abdominal swelling, only became apparent relatively late in disease progression when tumor burden was high. It is possible that ascites was produced earlier; however, its rate of production was likely less than its rate of clearance from the peritoneal cavity. As tumor burden increased, the rate of ascites production likely became greater than the capacity for clearance and resulted in ascites accumulation and abdominal swelling with associated cachexia. Interestingly, in the SC mice, A4.6.1 reduced the volume of existing tumor cysts, suggesting that A4.6.1 could possibly reverse ascites accumulation if administered to IP mice exhibiting abdominal swelling. This possibility has important clinical implications, as it suggests that inhibition of VEGF activity may reverse the accumulation of ascitic fluid in women with ovarian cancer, which could significantly contribute to treatment of the disease. In summary, these data suggest that tumor-derived VEGF is not an essential regulator of peritoneal ovarian cancer growth but plays a pivotal role in malignant ascites formation likely by increasing vascular permeability.
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Acknowledgements |
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Footnotes |
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Presented in part at the 43rd Annual Meeting of the Society for Gynecological Investigation, San Diego, CA, 1997.
Supported in part by National Institutes of Health grant PO1 CA64602.
SM's present address is Maternal Health Research Centre, Endocrine Unit, John Hunter Hospital, Newcastle, New South Wales, Australia.
Accepted for publication June 26, 1998.
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