Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts
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Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts. / Bockhorn, Maximilian; Tsuzuki, Yoshikazu; Xu, Lei; Frilling, Andreja; Broelsch, Christoph E; Fukumura, Dai.
In: CLIN CANCER RES, Vol. 9, No. 11, 15.09.2003, p. 4221-6.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Differential vascular and transcriptional responses to anti-vascular endothelial growth factor antibody in orthotopic human pancreatic cancer xenografts
AU - Bockhorn, Maximilian
AU - Tsuzuki, Yoshikazu
AU - Xu, Lei
AU - Frilling, Andreja
AU - Broelsch, Christoph E
AU - Fukumura, Dai
PY - 2003/9/15
Y1 - 2003/9/15
N2 - PURPOSE: The objectives of this study were to investigate the effects of anti-vascular endothelial growth factor (VEGF) treatment on various vascular functions, gene expression, and growth of orthotopic human pancreatic cancer xenografts and thus to provide useful preclinical data for novel cancer treatments.EXPERIMENTAL DESIGN: Small pieces of a human pancreatic carcinoma, PANC-1, were implanted into the pancreas of male severe combined immunodeficient mice. The animals were treated with anti-human VEGF antibody A.4.6.1 (300 micro g, every 3 days i.p.) or a nonspecific IgG between 4 and 8 weeks after tumor implantation. Then, vascular density, diameter, permeability, and tumor growth were determined by intravital microscopy. Subsequently, tumors were harvested, and angiogenic gene expression profile was determined by a microarray kit including 96 genes involved in tumor angiogenesis.RESULTS: Anti-VEGF antibody significantly reduced angiogenesis and growth of orthotopic PANC-1 tumors. In the anti-VEGF treatment group, the vessel density was significantly smaller (67.8 +/- 10.6 cm/cm(2)) than that seen in the control group (146.7 +/- 10.0 cm/cm(2)). However, vessel diameter and permeability were not altered significantly by anti-VEGF antibody treatment. The pancreatic tumors in the treated group were significantly smaller than those in the control group. Microarray and subsequent Northern blot and semiquantitative reverse transcription-PCR analyses revealed both a decrease (fibroblast growth factor 1, transforming growth factor beta1, platelet-derived growth factor alpha, erbB2, and c-ets1,) and an increase (placenta growth factor, hypoxia-inducible factor alpha, and endoglin) in expression of angiogenesis-related genes in the PANC-1 tumors by anti-VEGF treatment.CONCLUSIONS: Anti-VEGF antibody treatment has differential effects on vessel functions as well as angiogenic gene expression and inhibitory effects on angiogenesis and growth of the orthotopic pancreatic tumor. Anti-VEGF strategy appears promising for pancreatic cancer treatment.
AB - PURPOSE: The objectives of this study were to investigate the effects of anti-vascular endothelial growth factor (VEGF) treatment on various vascular functions, gene expression, and growth of orthotopic human pancreatic cancer xenografts and thus to provide useful preclinical data for novel cancer treatments.EXPERIMENTAL DESIGN: Small pieces of a human pancreatic carcinoma, PANC-1, were implanted into the pancreas of male severe combined immunodeficient mice. The animals were treated with anti-human VEGF antibody A.4.6.1 (300 micro g, every 3 days i.p.) or a nonspecific IgG between 4 and 8 weeks after tumor implantation. Then, vascular density, diameter, permeability, and tumor growth were determined by intravital microscopy. Subsequently, tumors were harvested, and angiogenic gene expression profile was determined by a microarray kit including 96 genes involved in tumor angiogenesis.RESULTS: Anti-VEGF antibody significantly reduced angiogenesis and growth of orthotopic PANC-1 tumors. In the anti-VEGF treatment group, the vessel density was significantly smaller (67.8 +/- 10.6 cm/cm(2)) than that seen in the control group (146.7 +/- 10.0 cm/cm(2)). However, vessel diameter and permeability were not altered significantly by anti-VEGF antibody treatment. The pancreatic tumors in the treated group were significantly smaller than those in the control group. Microarray and subsequent Northern blot and semiquantitative reverse transcription-PCR analyses revealed both a decrease (fibroblast growth factor 1, transforming growth factor beta1, platelet-derived growth factor alpha, erbB2, and c-ets1,) and an increase (placenta growth factor, hypoxia-inducible factor alpha, and endoglin) in expression of angiogenesis-related genes in the PANC-1 tumors by anti-VEGF treatment.CONCLUSIONS: Anti-VEGF antibody treatment has differential effects on vessel functions as well as angiogenic gene expression and inhibitory effects on angiogenesis and growth of the orthotopic pancreatic tumor. Anti-VEGF strategy appears promising for pancreatic cancer treatment.
KW - Animals
KW - Antibodies
KW - Base Sequence
KW - Capillary Permeability
KW - Cell Division
KW - DNA Primers
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Male
KW - Mice
KW - Mice, SCID
KW - Neovascularization, Pathologic
KW - Neutralization Tests
KW - Oligonucleotide Array Sequence Analysis
KW - Pancreatic Neoplasms
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Transcription, Genetic
KW - Transplantation, Heterologous
KW - Vascular Endothelial Growth Factor A
M3 - SCORING: Journal article
C2 - 14519649
VL - 9
SP - 4221
EP - 4226
JO - CLIN CANCER RES
JF - CLIN CANCER RES
SN - 1078-0432
IS - 11
ER -