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Tumor Biology |
Pharmacology Division [K. S., Y. H., H. W.] and Genetics Division [M. T.], National Cancer Center Research Institute, Tokyo 104-0045, Japan; Hitachi Medical Co.-chaired Department of Diagnostic and Interventional Imagiology, Kyoto 606-8507, Japan [H. K., S. K.]; Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [M. W. B.]; Department of Surgery, Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan [F. Ka.]; Department of Veterinary Anatomy, Hokkaido University, Sapporo 060-8638, Japan [T. I.]; and Department of Surgery, Omiya Medical Center, Jichi Medical School, Omiya 330-0834, Japan [K. S., F. Ko.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS |
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Dynamic Micro-MRA with an Intravascular Contrast Agent.
We performed dynamic micro-MRA analysis, using our newly developed intravascular macromolecular MRI contrast agent [G6D-(1B4M-Gd)256 (Mr 240,000), which consistently showed no significant leakage through the vascular wall after remaining in circulation for more than 30 min] to evaluate the physiological properties of the vascular channels in the xenografted tumors. The methods used for synthesis and preparation of the contrast agent and for obtaining dynamic MR images, along with a discussion of the agent’s properties in relation to visualizing microvasculature, have previously been published (8)
. MR angiography of the mice was performed with injection of 0.066 mmol Gd/kg of G6D-(1B4M-Gd)256, using a 1.5-tesla superconductive magnet unit (Signa; General Electric Medical System, Milwaukee, WI). We used female 8-week-old BALB/c nude mice bearing either WIBC-9 or MC-5 tumor xenografts. All of the images were obtained with dual phased-array 3-inch round surface coils, fixed at 3-cm intervals by an in-house-constructed mouse and coil holder. The mice were anesthetized with 1.15 mg of sodium pentobarbital (Dinabot, Osaka, Japan), and placed at the center of the coils. The three-dimensional-fast spoiled gradient echo technique (efgre3d; TR/TE, 10.5/2.7; flip angle, 30°) with chemical fat-suppression was used for all mice. The images were acquired before injection of the contrast agents and at 0 (immediately postinjection), 1, 2, 3, 5, 8, 10, 15, and 30 min postinjection. The coronal images were reconstructed with 1.0-mm section thickness and 0.5-mm overlap. The FOV was 8 x 4 cm, and the size of the matrix was 256 x 128. This procedure was performed with mice bearing WIBC-9 and MC-5 tumors (n = 3, for each).
Morphological Analysis and Immunohistochemistry.
In addition to dynamic micro-MRA, we performed the following analyses on the specimens, using conventional methods: H&E staining, Giemsa staining and electron microscopy. Frozen and paraffin sections of the nonresected tumor samples that had been examined by dynamic micro-MRA were embedded in O.C.T. Compound (Mile’s Sankyo, Tokyo, Japan), and assayed using the immunoperoxidase procedure. Antimurine CD31 (Pharmingen, San Diego, CA) was used as the primary antibody. The reaction was visualized using streptavidin-biotin (Pharmingen) techniques.
LCM.
Paraffin-embedded WIBC-9 and MC-5 xenograft specimens were cut into serial 5-µm sections and mounted on uncoated slides treated with diethyl pyrocarbonate. The VM in WIBC-9 and MC-5 cancer cells was examined in coverslipped H&E-stained sections. One specimen was selected for collection of 2000 individual cells for mRNA isolation and nested PCR analysis. Sections to be used for LCM were taken from 4°C storage and immediately immersed in xylene (three times, 10 min each time) and ethanol (in 100% ethanol three times, 10 min each time; and in 75% ethanol for 10 min). Slides were rinsed in H2O, stained with filtered Meyer’s hematoxylin for 30 s, rinsed in H2O again, stained with bluing reagent for 30 s, washed in 70 and 95% ethanol for 1 min each, stained with eosin Y for 30 s, and finally dehydrated in 95% ethanol (twice, for 1 min each time), 100% ethanol (over a molecular sieve three times, 1 min each time), and xylene (three times, 10 min each time). Slides were air-dried under a laminar flow for 10 min, and then immediately processed for LCM. Diethyl pyrocarbonate-treated, autoclaved, distilled water was used to prepare all of the solutions. LCM was performed with a PixCell II Microscope (Arcturus Engineering, Inc., Mountain View, CA) and a 7.5-µm laser beam at 50 mV. Target cells in the specimens were easily identified and captured; tumor cells immediately adjacent to necrotic areas and blood cells were avoided.
RT-PCR Conditions and Reagents.
Total RNA was isolated from LCM-collected cells and culture cell lines (SK-BR-3, MCF-7 and HUVEC; American Type Culture Collection, Manassas, VA, and Sankojunyaku Co., Tokyo, Japan) using the guanidinium thiocyanate-phenol-chloroform extraction method. PCR was designed to amplify specific mRNAs, using published sequences. Primer sequences for VEGF were as follows: sense, 5'-GGCCAGCACATAGGAGAG-3'; antisense, 5'-TGCAGGAACATTTACACG-3' (amplicon size, 157 bp). Primers for Flt-1 were as follows: sense, 5'-TTTTACCGAATGCCACCTC-3'; antisense, 5'-GCGTGCTAGCTGGATGTCTT-3' (amplicon size, 159 bp). Nested primers for Flt-1 were as follows: sense, 5'-GGGCGACAGCAGCACTCT-3'; antisense, 5'-GCCCCGACTCCTTACTTTT-3' (amplicon size, 122 bp). Primers for KDR were as follows: sense, 5'-GAACCAAATTATCTCCATCTT-3'; antisense, 5'-GCACTCCAATCTCTATCAGC-3' (amplicon size, 180 bp). Nested primers for KDR were as follows: sense, 5'-TGTGGCATCTGAAGGCTCAA-3'; antisense, 5'-GCACTCCAATCTCTATCAGC-3' (amplicon size, 125 bp). Primers for Ang-1 were as follows: sense, 5'-ACCGAGCCTATTCACAGTAT-3'; antisense, 5'-CAAGCATCAAACCACCATCCT-3' (amplicon size, 180 bp). Primers for Ang-2 were as follows: sense, 5'-TTCTAAACATCCCAGTCCAC-3'; antisense, 5'-CCCGTCAGCACCGAGCACAC-3' (amplicon size, 132 bp). Nested primers for Ang-2 were as follows: sense, 5'-TCTAAACATCCCAGTCCAC-3'; antisense, 5'-CCCGTCAGCACCGAGCACAC-3' (amplicon size, 131 bp). Primers for Tie-2 were as follows: sense, 5'-GTCCCGAGGTCAAGAGGTG-3'; antisense, 5'-CAAGTCATCCCGCAGTAGG-3' (amplicon size, 177 bp). Nested primers for Tie-2 were as follows: sense, 5'-TGCGCTGGATGGCCATCG-3'; antisense, 5'-CAAGTCATCCCGCAGTAGG-3' (amplicon size, 127 bp). Primers for CD31 were as follows: sense, 5'-AGTGGTTATCATCGGAGTG-3'; antisense, 5'-TCATTTATTGGTTTCATT-3' (amplicon size, 222 bp). Nested primers for CD31 were as follows: sense, 5'-AGTGGTTATCATCGGAGTG-3'; antisense, 5'-CTGCTGGCCTGGACATTTC-3' (amplicon size, 110 bp). Primers for Thrombin receptor were as follows: sense, 5'-GCCAACCGCAGCAAGAAGTC-3'; antisense, 5'-GGTGGAAGTGTGAGAAAGGA-3' (amplicon size, 129 bp). Nested primers for Thrombin receptor were as follows: sense, 5'-GCCAACCGCAGCAAGAAGTC-3'; antisense, 5'-TGGGTCCGAAGCAAATGATG-3' (amplicon size, 79 bp). Primers for Endothelin B receptor were as follows: sense, 5'-TTGTCTTTGCCCTCTGCTG-3'; antisense, 5'-GCAGTTTTTGAATCTTTTGCTC-3' (amplicon size, 200 bp). Nested primers for Endothelin B receptor were as follows: sense, 5'-GCTTCCCCTTCACCTCAG-3'; antisense, 5'-GCAGTTTTTGAATCTTTTGCTC-3' (amplicon size, 181 bp). Primers for G3PDH were as follows: sense, 5'-AATCCCATCACCATCTTCCAG-3'; antisense, 5'-AGGGGCCATCCACAGTCTTCT-3' (amplicon size, 361 bp).
PCR was performed using the following gene-specific annealing temperatures: 50°C for VEGF, Ang-1, endothelin B receptor, CD31, and Ang-2; 54°C for Flt-1 and Tie-2; 51°C for KDR; 52°C for thrombin receptor; and 57°C for G3PDH. PCR was performed with 40 cycles, as follows: 95°C for 30 s, gene-specific annealing temperature for 15 s, 72°C for 30 s. Additionally, agarose gel electrophoresis of the PCR products, followed by staining with ethidium bromide, was performed to confirm the specificity of the amplification.
Comparative Analyses.
The following analyses were performed on WIBC-9 MC-5, MC-2, MC-18, HUVEC, SK-BR3, and MCF-7, to determine patterns of VM and angiogenesis: dynamic MRA, histopathology, and post-LCM RT-PCR.
Statistical Analysis.
All data are expressed as the mean ± SD. StatView computer software (ATMS Co., Tokyo, Japan) was used for statistical analysis of results for WIBC-9 and MC-5. Two-sided Ps less than 0.05 were considered to indicate statistical significance.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, we show 2-mm-interval horizontal scans of the ventral area of anesthetized xenografted mice. To compare tumor signal intensities between mice, the amount of G6D-(1B4M-Gd)256 was normalized at 0.066 mmol Gd per kg of mouse body weight. Loupe images and high-power H&E staining images were also used for comparison, along with a side-by-side comparison of the MRA data. The tumor marginal area of WIBC-9 and MC-5 exhibited a high-intensity signal that completely surrounded the xenografted tumor, a result consistent with angiogenesis (compare Fig. 1, A–E
, with Fig. 1, F–J
). The high-power H&E staining images clearly showed neovascular vessels (compare Fig. 1, D and E
, with Fig. 1, I and J
). In the tumor center, WIBC-9 exhibited multiple high-intensity spots (*), a finding consistent with pathological VM (Figs. 1, A–C
, and 4), whereas MC-5 exhibited a low-intensity signal or a lack of signal (+), a finding consistent with central necrosis and disappearance of nuclei (Figs. 1, F–H
, and 4; compare circled areas of Fig. 1, B–E
with those of Fig. 1, G–J
).
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with those of Fig. 2, I–P
). All of the data were obtained directly from the MRA analyzer and are shown in the graphs in Fig. 3
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were obtained directly from the MRA analyzer and are expressed as the mean ± SD. To compare tumor signal intensities between mice, the amount of contrast agent per mouse was normalized, resulting in normalization of heart signal intensities between mice. The time-coursed intensity of the tumor center (which corresponded to the hemodynamics of VM, as shown in Figs. 1
and 4
) was consistent with the time-coursed intensity of the tumor margin (which corresponded to the hemodynamics of angiogenesis, as shown in Fig. 5
). Examination of the hemodynamics of VM revealed blood flow with two peaks of intensity and a statistically significant time lag relative to the hemodynamics of angiogenesis. The rate of tumor margin angiogenesis in WIBC-9 was four times as great (or more) as that observed in MC-5, a finding consistent with the microvascular intensities observed in immunohistochemical analysis (Fig. 4)
and our previously reported data, including results of immunohistochemical analysis using murine flt-1, murine tie-2, murine integrin 
vß3 and murine CD31 (1)
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. These features indicated that VM, which is associated with the absence of ECs, central necrosis, and central fibrosis of IBC, xenografted the tumors. Transmission electromicroscopy clearly visualized the tumor cell-erythrocyte interface, which did not include EC structures (Fig. 4C
; T indicates tumor cells). In contrast, H&E and Giemsa staining of MC-5 revealed a medullary growth pattern, central necrosis, rare neovasculars with ECs, and positivity for murine CD31 and infiltration by mononuclear cells (Fig. 4, H–K)
. These features are consistent with the data obtained by MRA (Figs. 1
2
3)
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In the marginal area and the overlying skin (Fig. 4F)
of WIBC-9, macroscopic examination (Fig. 4E)
and immunohistochemistry with murine CD31 (Fig. 4G)
revealed hypervascularity with a lining of ECs (angiogenesis). However, the central area of WIBC-9 rarely exhibited angiogenesis, a finding consistent with the lack of a CD31 PCR band (Fig. 5B)
and post-LCM observation of VM (Fig. 5A)
. MC-5 exhibited less angiogenesis in the marginal area of the tumor (Fig. 4N)
and the overlying skin (Fig. 4M)
than did WIBC-9 and exhibited central tumor necrosis (Fig. 4L
, *). This strongly suggests that VM of WIBC-9 involves hemodynamics that serve to feed WIBC-9 cells, and this in turn suggests a connection between VM and angiogenesis.
RT-PCR after LCM.
LCM was performed in the regions of VM (Fig. 5, A and D)
in WIBC-9 tumors (Fig. 5A)
. The regions examined did not contain stromal cells or lymphocytes (Fig. 5, B and E)
. The HUVEC cell line was used as the positive control, and interspecies primers (human-mouse) of angiogenic factors were used. All of the primers used were for EC-associated genes. For comparison of post-LCM RT-PCR results (Fig. 5B)
, we used post-LCM regions of WIBC-9 tumors (Fig. 5, C and F)
and several other breast cancer cell lines, including SK-BR3 and MCF-7. Gene expression of VEGF, Flt-1, Ang-1, Ang-2, and Tie-2 was observed in samples exhibiting VM. This finding is consistent with those of our previous study, in which we used species-specific primers (1)
. Of particular interest is the gene expression of Flt-1 and Tie-2 in the absence of CD31, thrombin receptor, and endothelin B receptor. In addition, post-LCM regions of WIBC-9 tumors and whole tumors of WIBC-9, MC-5, MC-2, and MC-18, all of which included ECs, showed expression of all of the genes assayed for. These facts suggest that VM of WIBC-9 without ECs has a vasculogenic phenotype (Flt-1 and Tie-2), and this, in turn, suggests that VM occurs in the central area of WIBC-9 and feeds WIBC-9 cells.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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As shown in Fig. 3
, examination of the hemodynamics of VM revealed blood flow with two peaks of intensity and a statistically significant time lag, relative to the hemodynamics of angiogenesis, after injection of the reagent into the tail vein of WIBC-9-xenografted mice. In addition, in the marginal area and overlying skin of WIBC-9 tumors, macroscopic examination and immunohistochemistry with murine CD31 (reported previously: murine flt-1, murine tie-2, and murine integrin vß3) revealed hypervascularity with a lining of ECs (angiogenesis). In the central area of the tumor, WIBC-9 exhibited VM in the absence of ECs, central necrosis, and fibrosis. MC-5 exhibited less angiogenesis in the marginal area of the tumor and the overlying skin than WIBC-9, and exhibited central tumor necrosis. This fact suggests that VM of WIBC-9 involves hemodynamics that serve to feed WIBC-9 cells, and this in turn suggests a connection between angiogenesis and VM.
The fact that the central area of WIBC-9 tumors rarely exhibited angiogenesis is consistent with the lack of a CD31 PCR band (Fig. 5B)
and the VM revealed by LCM (Fig. 5B)
. MC-5 exhibited less angiogenesis in the marginal area of the tumor and the overlying skin than did WIBC-9, and exhibited central tumor necrosis. Results of post-LCM RT-PCR analysis indicated that WIBC-9 had a vasculogenic phenotype, including expression of Flt-1 and Tie-2. These results suggest de novo formation of vascular channels by tumor cells in the center of the tumor as a result of putative hypoxia and induction of angiogenic factors. They also suggest that vessel regression has not been occurring in these tumors, and that the blood from ruptured vessels has not filled tumor-lined lakes or channels. WIBC-9 showed no signs of fibrosis, central necrosis, or endothelial lining, whereas non-IBC xenografts such as MC-2, MC-5, and MC-18 commonly exhibit fibrosis and central necrosis as the tumor grows (1)
. We believe these findings may be related to the expression of certain human genes in WIBC-9. As shown in Fig. 5
, LCM revealed gene expression of VEGF, Flt-1, Ang-1, Ang-2, and Tie-2 in samples exhibiting VM. These findings were consistent with those of our previous study, in which we used species-specific primers (1)
. Of particular interest is the gene expression of Flt-1 and Tie-2 in the absence of CD31, thrombin receptor and endothelin B receptor. These facts also suggest that VM of WIBC-9 results in a vasculogenic phenotype in which WIBC-9 cells are fed without ECs.
In the present study, we investigated the hemodynamics of VM and angiogenesis of WIBC-9, using time-coursed dynamic micro-MRA analysis with our newly developed intravascular macromolecular MRI contrast agent, and demonstrated the existence of a connection between VM and angiogenesis. The observed gene expression may be the cause of the observed endothelial-vascular phenotype and the putative de novo formation of vascular channels by tumor cells. We are presently conducting experiments designed to further clarify the issues addressed by this article.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Grants-in-Aid for the Second-Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare of Japan, by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare of Japan, and by Grants-in-Aid for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. 
2 To whom requests for reprints should be addressed, at National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511; Fax: 81-3-3542-1886.
3 The abbreviations used are: VM, vasculogenic mimicry; RT-PCR, reverse transcription-PCR; MRA, magnetic resonance angiography; ROI, region(s) of interest; LCM, laser-captured microdissection; VEGF, vascular endothelial growth factor; Ang, angiopoietin; MRI, magnetic resonance imaging; EC, endothelial cell; IBC, inflammatory breast cancer; HUVEC, human umbilical vein endothelial cell.
Received 6/13/01. Accepted 11/12/01.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Cancer Res., 61: 6322-6327, 2001.vß3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell, 79: 1157-1164, 1994.[Medline]
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