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Research ArticleExperimental Studies

Heterogeneity of Vascular Endothelial Growth Factor Receptors 1, 2, 3 in Primary Human Colorectal Carcinoma

AEJAZ NASIR, LESLIE O'NEILL REISING, DREW M. NEDDERMAN, ANGIE D. FULFORD, MARK T. UHLIK, LAURA E. BENJAMIN, ANDREW E. SCHADE and TIMOTHY R. HOLZER
Anticancer Research June 2016, 36 (6) 2683-2696;
AEJAZ NASIR
1Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
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  • For correspondence: nasirae@lilly.com
LESLIE O'NEILL REISING
1Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
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DREW M. NEDDERMAN
1Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
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ANGIE D. FULFORD
1Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
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MARK T. UHLIK
2Cancer Biology and Angiogenesis, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
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LAURA E. BENJAMIN
2Cancer Biology and Angiogenesis, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
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ANDREW E. SCHADE
1Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
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TIMOTHY R. HOLZER
1Diagnostic and Experimental Pathology, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, U.S.A.
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Abstract

Background: The vascular endothelial growth factor (VEGF) pathway plays an important role in growth and progression of human cancer, including colorectal carcinomas (CRC). The key mediators of VEGF signaling are VEGFR1, VEGFR2, and VEGFR3, part of a family of related receptor tyrosine kinases. The relative expression, activity, or interplay among these receptors may determine the response of CRC patients to anti-angiogenic therapies. Materials and Methods: We developed technically sound immunohistochemical (IHC) assays to quantify VEGFR1, 2 and 3, and using a well-annotated CRC tissue microarray (TMA), we carried out comprehensive comparative evaluation of the three VEGFRs in archival primary CRC tissues (n=84). For each TMA core, tumor cell VEGFR1 expression was reported as H-score (range=0-300); vascular VEGFR2/VEGFR3 expression was manually scored as the number of receptor-positive tumor stromal vessels. Each case was defined as VEGFR1/ VEGFR2/VEGFR3-negative, low, medium or high. Results: Based on the differential expression of the three VEGFRs, eight VEGFR staining profiles were observed: Triple VEGFR positive (n=12, 14%), VEGFR1 predominant (n=17, 20%), VEGFR2 predominant (n=7, 8%), VEGFR3 predominant (n=1, 1%), VEGFR1/2 predominant (n=39, 46%), VEGFR1/3 predominant (n=2, 2%), VEGFR2/3 predominant (n=3, 4%), and triple-VEGFR-negative (n=3, 4%). Conclusion: Herein we demonstrated heterogeneity of expression of VEGFRs in human CRC stromal vessels and tumor cells. The observed VEGFR expression-based subsets of human CRCs may reflect differences in biology of pathologic angiogenesis in primary CRC tissues. Furthermore, the heterogeneity of expression of VEGFRs unraveled in this analysis merits independent validation in larger cohorts of primary and metastatic human CRC tissues and in pertinent experimental models treated with various anti-angiogenic therapies.

  • VEGFR
  • VEGFR1
  • VEGFR2
  • VEGFR3
  • colorectal cancer
  • IHC
  • Received March 9, 2016.
  • Revision received May 5, 2016.
  • Accepted May 11, 2016.
  • Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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Anticancer Research: 36 (6)
Anticancer Research
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June 2016
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Heterogeneity of Vascular Endothelial Growth Factor Receptors 1, 2, 3 in Primary Human Colorectal Carcinoma
AEJAZ NASIR, LESLIE O'NEILL REISING, DREW M. NEDDERMAN, ANGIE D. FULFORD, MARK T. UHLIK, LAURA E. BENJAMIN, ANDREW E. SCHADE, TIMOTHY R. HOLZER
Anticancer Research Jun 2016, 36 (6) 2683-2696;

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Heterogeneity of Vascular Endothelial Growth Factor Receptors 1, 2, 3 in Primary Human Colorectal Carcinoma
AEJAZ NASIR, LESLIE O'NEILL REISING, DREW M. NEDDERMAN, ANGIE D. FULFORD, MARK T. UHLIK, LAURA E. BENJAMIN, ANDREW E. SCHADE, TIMOTHY R. HOLZER
Anticancer Research Jun 2016, 36 (6) 2683-2696;
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Keywords

  • VEGFR
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  • VEGFR2
  • VEGFR3
  • Colorectal cancer
  • IHC
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