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Department of Nuclear Medicine (J.S., C.E.), University of Regensburg, 93042 Regensburg, Germany; Departments of Clinical Pharmacology and Toxicology (D.G., P.K., E.K.) and Trauma and Reconstructive Surgery (M.I.), Charité-University Medical School, Benjamin Franklin Medical Center, 12200 Berlin, Germany
Address all correspondence and requests for reprints to: Johann Schoenberger, M.D., Department of Nuclear Medicine, University of Regensburg, 93042 Regensburg, Germany. E-mail: johann.schoenberger{at}klinik.uni-regensburg.de.
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Abstract |
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Introduction |
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Today many factors that influence angiogenesis have been identified: Induction occurs via vascular endothelial growth factors (VEGFs), fibroblast growth factors, and TGF
and -ß and inhibition via thrombospondins, angiostatins, endostatins, and others. The VEGF gene family appears to play a fundamental role in neoangiogenesis (1). This family includes several members: VEGF-A, -B, -C, -D and two VEGF-like proteins. The major factor seems to be VEGF, referred also as VEGF-A (2). VEGF induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability. The expression of VEGF is controlled by differentiation, transformation, and oxygen supply. The effect of VEGF is regulated by two receptor tyrosine kinases VEGFR-1/Flt-1 (fms-like tyrosine kinase-1) and VEGFR-2/kinase insert domain-containing receptor (KDR), which are almost exclusively located on endothelial cells (3, 4, 5). The density of Flt-1 and KDR is low in endothelial cells of normal tissue. The expression of Flt-1 and KDR in or next to tumor tissue is strongly up-regulated in situations with neoangiogenesis and/or enhanced vascular permeability such as tumor angiogenesis (6). Plate et al. (7) could demonstrate that VEGF itself is an important factor leading to VEGF receptor up-regulation.
In the thyroid gland, neoangiogenesis occurs in hyperplastic goiters, Graves disease, thyroiditis, and cancer. Usually differentiated thyroid carcinomas of the follicular and papillary type have an excellent prognosis because of their high grade of differentiation and the use of radioiodine therapy. However, there is a small but significant number of patients who will ultimately die of this disease such as those with radioiodine-resistant cancer. The reason for this is a progressive dedifferentiation of the tumor with loss of the expression of sodium-iodine symporters. In these cases other effective therapeutic options are rare. Alternative treatment, including chemotherapy or external radiotherapy, can be considered, but the responses are poor and mostly without any benefit for survival.
Therefore, new therapeutic tools for the treatment of poorly or dedifferentiated thyroid tumors and tumors without iodine uptake are necessary. Normal thyroid tissue shows only a minimum expression of VEGF, compared with thyroid cancers. Moreover, the overexpression of VEGF in thyroid tumors is associated with the risk of recurrence in papillary thyroid carcinomas (8). Based on these data, it was hypothesized that blockade of VEGF function may be an ideal target for treatment of poorly or dedifferentiated thyroid carcinomas.
Oral-active protein kinase inhibitors that potently and selectively block the VEGF/VEGF receptor system are now available for long-term treatment of these patients. PTK787/ZK222584 (PTK/ZK) (a codevelopment of Novartis, Basel, Switzerland, and Schering, Berlin, Germany) is a synthetic inhibitor of the VEGF receptor tyrosine kinases that can be given orally. In several human carcinomas (pancreas carcinoma, renal cell carcinoma, colon cancer) grown sc in nude mice, VEGF receptor blockade induced a significant inhibition of tumor growth (9, 10, 11, 12).
On the basis of the results of these studies, the principal aim of this investigation was to evaluate the effects of PTK/ZK on poorly differentiated follicular thyroid carcinoma xenografts in nude mice.
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Materials and Methods |
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ML-1 cell line
The human follicular thyroid carcinoma ML-1 cell line (passage 15) was used for these experiments (13). Doubling time was 4 d. The cells were established from a recurrent tumor of a poorly differentiated thyroid carcinoma (stage pT4) of a 50-yr-old woman. The cells take up glucose and/or iodine and secrete thyroglobulin, chondroitin sulfate, fibronectin, and T3. In addition, they are tumorigenic in nude mice.
Tumor implantation and drug treatment
Initially, 2 x 106 tumor cells in 0.1 ml PBS from monolayer cultures were inoculated subcutaneously into the right flank of 8-wk-old NMRI (
/) mice. They developed solid tumors within 1–2 months. For serial transplantation the solid tumors were cut into 2-mm3 pieces and implanted with a trocar (13G) into the right flank of another 25 8-wk-old male mice. Eight days after tumor inoculation, 20 mice were randomized into two groups and drug treatment was initiated. One group of animals received PTK/ZK (75 mg/kg). The other group (control) was treated with sodium chloride (NaCl 0.9%) by a gastric tube each day.
Animal weights and tumor surface area, measured in two dimensions, were determined weekly in each living animal. Growth rate is given in Fig. 1
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). Volumes of tumors were evaluated macroscopically by measuring their extensions in three orthogonal dimensions. Tumor volume (cubic millimeters) was calculated based on the formula: (length x width x width)/2.
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Compounds
PTK/ZK, a codevelopment of Schering and Novartis was provided by Schering. The preparation was done according to the instructions of the company. To guarantee a correct preparation of the compound, a probe was sent to the manufacturer for quality control.
The final concentration for daily application was 75 mg/kg according to the paper by Wood et al. (12). The effective dose range of PTK/ZK was between 50 and 100 mg/kg daily, and the compound was well tolerated after at least 1 month of chronic therapy.
Histochemistry
Specimens of xenograft tumors were surgically removed from the nude mice. After blocking, sectioning, and preparation of slices for histological analysis, hematoxylin and eosin staining was performed. The extent of perivascular and interstitial fibrous tissue was visualized according to the Sirius red staining procedure (collagen type I and type III) (14, 15). All samples were embedded in paraffin, cut into 3-µm sections, and subjected to Sirius red staining as a specific dye for connective structures. Collagen density was quantified after Sirius red staining by morphometry using a video camera combined with a video control system (Sony MC-3255, AVT-Horn GmbH, Aalen, Germany) adapted to a Axiophot microscope (Zeiss, Oberkochen, Germany). Image analysis was performed using a freely available software (Scion image 1.62 a, Scion Co., Frederick, MD) on a Power Macintosh 8200/120 computer (Macintosh, Saarbrücken, Germany). After digitalization, gray scale images were transformed into binary images and the relation of Sirius red stained area (connective tissue) to total area of the tumor section was determined (15, 16). Moreover, polarization microscopy was performed to determine the differential staining of collagen I and III. According to Junqueira et al. (14), collagen type I is presented in a yellow, orange or red color, whereas collagen type III appears in green.
Immunofluorescence of CD 31 (PECAM-1)
Platelet endothelial cell adhesion molecule-1 (PECAM-1), also called CD 31 or EndoCAM, is a member of the immunoglobulin superfamily. PECAM-1 is a transmembrane glycoprotein with a molecular mass of 130 kDa, depending on the degree of glycosylation. CD 31 is constitutively expressed on all vascular cells and is an important immunohistochemical marker of blood vessels, particularly in the setting of angiogenesis. For this purpose, we performed indirect immunofluorescence staining to detect CD 31-positive blood vessels. Cryo-sections (5 µm) were fixed with ice-cold acetone (-20 C, 10 min) and treated with monoclonal antibodies at optimal concentrations (CD 31, dilution 1:50 in PBS, PharMingen, Heidelberg, Germany) for 4 h at room temperature. After repeated washing with PBS, the specimens were incubated with FITC-labeled rat immunoglobulin (Dako, Hamburg, Germany, dilution: 1:10 in PBS) for another 4 h. After washing the specimens were embedded in Vectashield (Vector, Burlingame, CA) and investigated by fluorescence microscopy (magnification: x200, Zeiss). Negative controls were performed. CD 31 immunofluorescence was performed to detect vessels in the tumors of both groups with the aim to measure the amount of vessels using automatic image analysis (17).
Immunohistochemistry
Frozen specimens were sectioned at 5 µm and fixed with acetone (-20 C) for 10 min. Sections were selected to visualize antigen antibody complexes using the indirect peroxidase technique (16). Incubation with the first antibody [vimentin, collagen IV, and laminin (Sigma), thyroglobulin (Dako) and VEGF-A (Santa Cruz, Heidelberg, Germany)] was followed by incubation with the second antibody, which was peroxidase labeled. After repeated washing with PBS, the slices were exposed to diaminobenzidine and H2O2 (Sigma), generating a brown color. Finally, the specimens were dehydrated and embedded with entellan (Merck, Darmstadt, Germany). Negative controls were performed. As positive control for the VEGF-A staining, we used the VEGF-A-positive primary tumor of the ML-1 cell line (Fig. 2H). All sections were visualized by light microscopy using an oil immersion objective with a calibrated magnification (x200). Control specimens exposed to the secondary antibody alone showed no specific staining.
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Control of side effects and toxicology
To evaluate side effects such as bleeding or thrombotic events, thyroid, lung, liver, and kidney samples of animals were taken and stained with hematoxylin and eosin for histological examination. In addition, clinical chemical and hematological parameters were determined.
Thyroglobulin
The quantities of thyroglobulin of the tumor xenografts were determined using a RIA developed by demeditec (Kiel-Wellsee, Kiel, Germany). For the measurement of thyroglobulin, we used a specific antibody against human thyroglobulin developed in mice. Due to this origin, cross-reactivity with mouse thyroglobulin can be excluded. In previous tests using blood samples from nude mice without thyroid tumors, we did not find any cross-reactivity in all measured samples.
For this purpose 40 µl serum of nude mice (dilution 1:100) was filled into coated tubes with antibodies specific to human thyroglobulin. Subsequently, a second antibody also specific to the antigen, but labeled with 125I, was added. After overnight incubation at room temperature, the supernatant was discarded and each tube was washed three times with PBS. Then the radioactivity bound specifically to the walls of the tubes was determined by a 
-counter (Berthold, Nuremberg, Germany).
Statistics
Statistical analysis was performed using SPSS 10.0 (SPSS Inc., Chicago, IL). Results are expressed as mean ± SEM. Comparisons between multiple groups were assessed by one-way ANOVA, including a modified least-significant difference (Bonferroni) multiple range test to detect significant differences between two distinct groups, which were further analyzed using the Mann-Whitney U test. The strength of the relationship between two variables was assessed by calculation of the product-moment correlation coefficient (r). Statistical significance was accepted at the level of P < 0.05.
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Results |
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Tumor volumes
At the end of the experiment, volumes of the tumor xenografts of both groups were measured. Oral administration of the tyrosine kinase inhibitor significantly decreased the mean tumor volumes. Treatment with 75 mg/kg PTK/ZK for 4 wk resulted in a significant 41.4% inhibition of tumor volume (Table 1
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The course of the tumor sizes, measured weekly, is shown in Fig. 1. Tumor size of the control group increased steadily during the experiment, whereas size of the tumors of the PTK/ZK-treated group increased significantly slower, beginning the second week after tumor implantation. Statistical significance was reached at d 21 after the beginning of treatment. Figure 2A shows microscopic pictures of control tumors and of tumors treated with PTK/ZK. Furthermore, animals of the PTK/ZK group developed necrosis of the tumor xenografts earlier, whereas in the control group tumors reached dimensions up to 2 cm2 without necrosis.
Expression of VEGF
ML-1 tumor cells expressed VEGF-A when grown as tumor xenografts in nude mice. To identify VEGF-A expression in tumor xenografts, we chose specific antibodies to detect whether blockade of VEGF receptors would lead to an overexpression of VEGF-A. Compared with controls, we observed no up-regulation of VEGF in the PTK/ZK-treated group. Figure 2, F and G, demonstrates the expression of VEGF in the PTK/ZK-treated and control group. The staining intensity was similar in both tumors, whereas the primary tumor of the patient exerted a clear expression of VEGF-A (Fig. 2H).
Neoangiogenesis
Tumor xenografts were stained with hematoxylin and eosin to determine general tumor morphology in mice. The xenograft tumors revealed follicular structures and colloid-like areas. To date, only tumors at the implantation site were observed in the nude mice with no metastases. For histological examination of tumor vasculature, tumor tissues were stained for CD 31. As illustrated in Fig. 3, daily treatment with PTK/ZK significantly suppressed tumor angiogenesis and vascularization. The dense network of tumor vessel density in tumor xenografts treated with control contrasts with the microvessels seen in animals treated with PTK/ZK. Compared with controls, tumor vessel density in treated tumors was significantly reduced.
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, A and C). Polarization microscopy revealed a clear accumulation of collagen type I (yellow, orange, and red color), whereas collagen type III (green color) was only slightly demonstrated using Sirius red staining (Fig. 4, B and D).
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Collagen IV was found at the basement membranes of the vessels as well as in the interstitial space between the tumor cells. Collagen IV was strongly expressed by control tumor xenografts (Fig. 4G). Increased layers of collagen type IV positive material were found in the interstitial and perivascular areas (Fig. 4G). PTK/ZK attenuated the accumulation of collagen IV (Fig. 4F). Moreover, the cell adhesion molecule laminin (Fig. 4, H and I) mainly characterized the basement membranes of the newly formed vessels and was decreased after tyrosine kinase inhibition (Fig. 4H).
Furthermore, the expression of the intermediate filament vimentin was unchanged in both groups (Fig. 4, J and K).
Side effects and toxicology
In addition to the pathological mechanisms associated with tumor-mediated increase in thrombotic events, cancer therapies especially coadministration of chemotherapy and anti-VEGF therapies might be additional risk factors for venous thromboembolism and bleeding events. To control the possibility of thrombosis, samples of lung, liver, and kidney tissue were examined. No histological alterations characteristic for thromboembolism were detectable. Especially in the lungs, there was no evidence for recurrent pulmonary embolism. The normal thyroid glands in these adult animals showed no histological alterations. There was no direct and specific toxic effect of PTK/ZK on normal thyroid tissue. Hematology and electrolytes (potassium, sodium, calcium, chloride, phosphorous), values of liver enzymes (aspartate aminotransferase, glutamic-pyruvic transaminase, bilirubin, cholinesterase), and parameters of renal function (creatinine and urea) were within the normal range in both animal groups.
Thyroglobulin
Thyroglobulin is a glycoprotein that is produced exclusively by normal or neoplastic thyroid cells. The levels of thyroglobulin correlate with the extent of the disease and the number of functioning thyroglobulin-producing cells. Comparing both groups, controls showed a significantly higher thyroglobulin level than the PTK/ZK-treated group (Table 1). Furthermore, immunostaining of thyroglobulin revealed a more intense staining in controls (Fig. 2D), compared with PTK/ZK-treated mice (Fig. 2B).
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Discussion |
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New therapeutic strategies for the treatment of cancer are currently being developed, targeting the vasculature and inhibiting tumor angiogenesis. Antiangiogenesis, a new concept in the treatment of cancer, may offer a therapy with fewer side effects. Blockade of the VEGF receptor kinases with PTK/ZK was very effective in inhibiting tumor growth, metastases formation, and tumor vascularization in the murine renal cell carcinoma model (12).
Therefore, the aim of our study was to investigate PTK/ZK, a selective inhibitor of the VEGF receptors 1 and 2 tyrosine kinases, for its anticancer and antiangiogenic effects in the model of poorly differentiated follicular thyroid carcinoma xenografts in nude mice.
Poorly differentiated thyroid carcinomas are characterized by local invasive growth, occurrence of distant metastases, and lack of therapeutic options. Oncogene activation, tumor suppressor gene inactivation, and various growth factors are responsible for thyroid cancer development and growth modulation. Some of these factors are essential for the nutrition of the growing tumor or its metastases by stimulating angiogenesis. Although angiogenesis also plays a role in the growth of benign thyroid tissue, cancer tissue may stimulate angiogenesis in a higher amount. Segal et al. (18) demonstrated that microinvasive follicular thyroid neoplasms with pleomorphic areas and areas adjacent to capsular penetration by the tumor exerted an increase of microvessels.
In this study, we demonstrated for the first time that PTK/ZK also has antitumoral and antineoangiogenic activities in the in vivo thyroid carcinoma model. Blockade of VEGF receptors by oral application of the tyrosine kinase inhibitor induced an inhibition of growth of xenografts from human thyroid tumor cells of the ML-1 cell line implanted into nude mice. Mean xenograft tumor volume was significantly reduced in PTK/ZK-treated mice, compared with control animals.
Moreover, VEGF also seems to play a key role in the growth of thyroid tumors. Bunone et al. (19) reported an overexpression of VEGF in thyroid cancers, compared with normal tissue. The authors suggest that factors inducing neoangiogenesis were involved in the neoplastic growth and aggressiveness of thyroid cancers and that VEGF might be an initial angiogenic signal followed by tumor growth and local invasiveness. Recently it was shown that the intensity of VEGF expression is associated with an increased risk of recurrence and decreased disease-free survival in papillary thyroid carcinomas (8).
Other tumors such as bladder cancer, breast cancer, or ovarian neoplasms showed similar relations (20, 21, 22). Moreover, renal cell carcinomas exerting an overexpression of VEGF were combined with a poor prognosis (23). Concerning their resistance to radiotherapy, chemotherapy, or other therapeutic options, this tumor type is comparable with poorly differentiated thyroid neoplasms. In addition, blockade of VEGF with PTK/ZK was very effective in renal cell carcinomas. The drug primarily reduced the number of tumor microvessels (24). A principal finding of our study was the significant reduction of xenograft microvessels as determined by CD31 immunohistochemical staining.
Simultaneously we investigated possible changes of extracellular matrix proteins in treated and untreated tumor xenografts. The extracellular matrix and basement membranes greatly influence proliferation, differentiation, and function of cells and the structure of tissues. Extracellular matrix proteins are up-regulated in different tumor xenografts (25). We showed that the interstitium of untreated tumor xenografts revealed an abundance of collagens, mainly of collagen I and laminin, whereas tyrosine kinase inhibition significantly reduced the abundance of these extracellular matrix proteins in the interstitial space as well as the perivascular areas. This finding is paralleled by an increase in necrosis in the center of the tumor xenograft and the reduction of tumor size. Recently it was shown that the enhanced tumorigenicity of glioma cells overexpressing membrane type 1 matrix metalloproteinase, which is critical for pericellular degradation of the extracellular matrix, involves stimulation of angiogenesis through the up-regulation of VEGF (26).
It is known that cancer patients have a higher risk for developing venous thrombotic events. A significant correlation among VEGF levels, platelet count, and increased risk of thrombotic complications was found in chronic myeloproliferative disorders (27). In thyroid cancer, thromboembolism caused by tumor cell interactions is a rare event. One case was reported in 1995 by Raveh et al. (28). This circumstance is very important because coadministration of cytotoxic agents and kinase inhibitor SU5416 or VEGF antibody avastin seems to be associated with bleeding and thrombotic events. In our study, we could not see any thrombotic events.
In humans PTK/ZK is currently studied in phase III trials in combination with standard chemotherapy for first- and second-line treatment of patients with colorectal cancer. Phase I/II showed that PTK/ZK was well tolerated and led to a reduction of tumor perfusion and vascular permeability measured by dynamic contrast-enhanced magnetic resonance imaging. Moreover, Thomas et al. reported an impressive stabilization in patients with advanced cancer (29). The results of phase I/II trials and the findings in our study are promising. Both together should be the basis for testing PTK/ZK in patients with advanced thyroid neoplasms.
In summary, we demonstrated, for the first time, that inhibition of protein tyrosine kinases by PTK/ZK significantly reduced the growth, vessel formation, and expression of extracellular matrix proteins of poorly differentiated thyroid cancer xenografts in nude mice.
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Acknowledgments |
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Footnotes |
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Abbreviations: Flt-1, fms-Like tyrosine kinase-1; KDR, kinase insert domain-containing receptor; PECAM-1, platelet endothelial cell adhesion molecule-1; PTK/ZK, PTK787/ZK222584; VEGF, vascular endothelial growth factor.
Received September 15, 2003.
Accepted for publication October 30, 2003.
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