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The Rip1Tag2 Transgenic Mouse Model

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Tumor Angiogenesis Assays

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1464))

Abstract

The Rip1Tag2 transgenic mouse model of β-cell carcinogenesis has been instrumental in studying various aspects of tumor angiogenesis and in investigating the response to anti-angiogenic therapeutics. Thereby, the in-depth assessment of blood and lymphatic vessel phenotypes and functionality represents key experimental analyses. In this chapter, we describe basic protocols to assess tumor blood vessel morphology (pericyte coverage), functionality (perfusion, leakiness, and hypoxia), lymphatic tumor coverage, and tumor cell proliferation and apoptosis based on immunofluorescence microscopy analysis.

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References

  1. Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115–122

    Article  CAS  PubMed  Google Scholar 

  2. Christofori G, Naik P, Hanahan D (1994) A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 369:414–418

    Article  CAS  PubMed  Google Scholar 

  3. Bill R, Fagiani E, Zumsteg A et al (2015) Nintedanib is a highly effective therapeutic for neuroendocrine carcinoma of the pancreas (PNET) in the Rip1Tag2 transgenic mouse model. Clin Cancer Res 21:4856–4867

    Article  CAS  PubMed  Google Scholar 

  4. Folkman J, Watson K, Ingber D et al (1989) Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339:58–61

    Article  CAS  PubMed  Google Scholar 

  5. Inoue M, Hager JH, Ferrara N et al (2002) VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 1:193–202

    Article  CAS  PubMed  Google Scholar 

  6. Albrecht I, Kopfstein L, Strittmatter K et al (2010) Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis. PLoS One 5:e14109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bergers G, Brekken R, McMahon G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fagiani E, Lorentz P, Kopfstein L et al (2011) Angiopoietin-1 and -2 exert antagonistic functions in tumor angiogenesis, yet both induce lymphangiogenesis. Cancer Res 71:5717–5727

    Article  CAS  PubMed  Google Scholar 

  9. Gannon G, Mandriota SJ, Cui L et al (2002) Overexpression of vascular endothelial growth factor-A165 enhances tumor angiogenesis but not metastasis during beta-cell carcinogenesis. Cancer Res 62:603–608

    CAS  PubMed  Google Scholar 

  10. Mandriota SJ, Jussila L, Jeltsch M et al (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Paez-Ribes M, Allen E, Hudock J et al (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schomber T, Kopfstein L, Djonov V et al (2007) Placental growth factor-1 attenuates vascular endothelial growth factor-A-dependent tumor angiogenesis during beta cell carcinogenesis. Cancer Res 67:10840–10848

    Article  CAS  PubMed  Google Scholar 

  13. Tuveson D, Hanahan D (2011) Translational medicine: cancer lessons from mice to humans. Nature 471:316–317

    Article  CAS  PubMed  Google Scholar 

  14. Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10:417–427

    Article  CAS  PubMed  Google Scholar 

  15. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    Article  CAS  PubMed  Google Scholar 

  16. Mazzone M, Dettori D, Leite de Oliveira R et al (2009) Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136:839–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215

    Article  CAS  PubMed  Google Scholar 

  18. Kopfstein L, Veikkola T, Djonov VG et al (2007) Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am J Pathol 170:1348–1361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hager JH, Hodgson JG, Fridlyand J et al (2004) Oncogene expression and genetic background influence the frequency of DNA copy number abnormalities in mouse pancreatic islet cell carcinomas. Cancer Res 64:2406–2410

    Article  CAS  PubMed  Google Scholar 

  20. Kuzmanov A, Hopfer U, Marti P et al (2014) LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling. Mol Oncol 8:401–416

    Article  CAS  PubMed  Google Scholar 

  21. Maione F, Capano S, Regano D et al (2012) Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J Clin Invest 122:1832–1848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Anderberg C, Cunha SI, Zhai Z et al (2013) Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. J Exp Med 210:563–579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rigamonti N, Kadioglu E, Keklikoglou I et al (2014) Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep 8:696–706

    Article  CAS  PubMed  Google Scholar 

  24. Sennino B, Ishiguro-Oonuma T, Schriver BJ et al (2013) Inhibition of c-Met reduces lymphatic metastasis in RIP-Tag2 transgenic mice. Cancer Res 73:3692–3703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sennino B, Ishiguro-Oonuma T, Wei Y et al (2012) Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2:270–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Singh M, Couto SS, Forrest WF et al (2012) Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models. J Pathol 227:417–430

    Article  CAS  PubMed  Google Scholar 

  27. Hypoxyprobe, Inc. http://www.hypoxyprobe.com/faq.html. Accessed 27 Aug 2015

  28. Hunter KE, Quick ML, Sadanandam A et al (2013) Identification and characterization of poorly differentiated invasive carcinomas in a mouse model of pancreatic neuroendocrine tumorigenesis. PLoS One 8:e64472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgement

This work was supported by a Swiss National Science Foundation MD-PhD student fellowship to R.B.

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Authors and Affiliations

  1. Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland

    Ruben Bill & Gerhard Christofori

Authors
  1. Ruben Bill
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  2. Gerhard Christofori
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Corresponding author

Correspondence to Gerhard Christofori .

Editor information

Editors and Affiliations

  1. Neurosciences and Sensory Organs, University of Bari,School of Med Dept of Basic Med Sci, Bari, Italy

    Domenico Ribatti

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Bill, R., Christofori, G. (2016). The Rip1Tag2 Transgenic Mouse Model. In: Ribatti, D. (eds) Tumor Angiogenesis Assays. Methods in Molecular Biology, vol 1464. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3999-2_14

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  • DOI: https://doi.org/10.1007/978-1-4939-3999-2_14

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3997-8

  • Online ISBN: 978-1-4939-3999-2

  • eBook Packages: Springer Protocols

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