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Expression of stromal genes associated with the angiogenic response are not differentiated between human tumour xenografts with divergent vascular morphologies

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Abstract

Human tumour xenografts have commonly been used to explore the mechanisms of tumour angiogenesis and the interaction of tumour cells with their microenvironment, as well as predict potential utility of anti-angiogenic inhibitors across different tumour types. To investigate how well human tumour xenografts can be used to differentiate the effects of stromal targeting agents we performed a comparative assessment of the murine angiogenic response across a panel of pre-clinical tumour xenografts. By analysing a panel of 22 tumour xenografts with a range of vascular morphologies, micro-vessel densities and levels of fibroblast and inflammatory infiltrate, we have examined the relationship between angiogenic stroma and human tumour models. These models were studied using a combination of immunohistochemistry and species specific mRNA profiling to differentiate the tumour and stromal transcript mRNA profiles. Principal Component Analysis (PCA) and regression analysis was used to investigate the transcriptional relationships between the individual models and the correlation with the stromal architecture. We found the human tumour cell expressed factors to be independent of the murine host responses such as microvessel density, and fibroblast or macrophage cellular infiltrate. Moreover mRNA profiling of the mouse stroma suggested that the host response to the different tumours was relatively uniform despite differences in stromal structures within the tumour. Supporting this, models with different stromal compositions responded similarly to cediranib, a small molecule inhibitor of VEGF signalling. The data indicate that although the angiogenic response to the tumour results in reproducible stromal architectures, these responses are not differentiated at the level of gene expression.

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References

  1. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307

    Article  PubMed  CAS  Google Scholar 

  2. Huang H, Bhat A, Woodnutt G, Lappe R (2010) Targeting the ANGPT-TIE2 pathway in malignancy. Nat Rev Cancer 10:575–585

    Article  PubMed  CAS  Google Scholar 

  3. Thurston G, Kitajewski J (2008) VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br J Cancer 99:1204–1209

    Article  PubMed  CAS  Google Scholar 

  4. Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmgren E, Hambleton J, Novotny WF, Kabbinavar F (2005) Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 23:3502–3508

    Article  PubMed  CAS  Google Scholar 

  5. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W et al (2004) Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  PubMed  CAS  Google Scholar 

  6. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C et al (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111

    Article  PubMed  Google Scholar 

  7. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S et al (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27:3584–3590

    Article  PubMed  CAS  Google Scholar 

  8. Ivy SP, Wick JY, Kaufman BM (2009) An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol 6:569–579

    Article  PubMed  CAS  Google Scholar 

  9. Muramatsu M, Yamamoto S, Osawa T, Shibuya M (2010) Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth. Cancer Res 70:8211–8221

    Article  PubMed  CAS  Google Scholar 

  10. Welti JC, Gourlaouen M, Powles T, Kudahetti SC, Wilson P, Berney DM, Reynolds AR (2011) Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib. Oncogene 30:1183–1193

    Article  PubMed  CAS  Google Scholar 

  11. Cascone T, Herynk MH, Xu L, Du Z, Kadara H, Nilsson MB, Oborn CJ et al (2011) Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma. J Clin Invest 121:1313–1328

    Article  PubMed  CAS  Google Scholar 

  12. Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8(4):299–309

    Article  PubMed  CAS  Google Scholar 

  13. Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S et al (2007) Tumor refractoriness to anti-VEGF treatment is mediated by CD11b + Gr1 + myeloid cells. Nat Biotechnol 25:911–920

    Article  PubMed  CAS  Google Scholar 

  14. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J et al (2007) Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450:825–831

    Article  PubMed  CAS  Google Scholar 

  15. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M et al (2009) G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. PNAS 106:6742–6747

    Article  PubMed  CAS  Google Scholar 

  16. Kitadai Y, Sasaki T, Kuwai T, Nakamura T, Bucana CD, Fidler IJ (2006) Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma. Am J Pathol 169:2054–2065

    Article  PubMed  CAS  Google Scholar 

  17. Pietras K, Pahler J, Bergers G, Hanahan D (2008) Functions of paracrine PDGF signaling in the pro-angiogenic tumor stroma revealed by pharmacological targeting. PLoS Med 5(1):e19

    Article  PubMed  Google Scholar 

  18. Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, Kaminker J, Ferrara N (2009) PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell 15:21–34

    Article  PubMed  CAS  Google Scholar 

  19. Anderberg C, Li H, Fredriksson L, Andrae J, Betsholtz C, Li X et al (2009) Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res 69:369–378

    Article  PubMed  CAS  Google Scholar 

  20. Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR et al (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400

    Article  PubMed  CAS  Google Scholar 

  21. Smith NR, Baker D, James NH, Ratcliffe K, Jenkins M, Ashton SE, Sproat G, Swann R, Gray N, Ryan A, Jürgensmeier JM, Womack C (2010) Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers. Clin Cancer Res 16:3548–3561

    Article  PubMed  CAS  Google Scholar 

  22. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239

    Article  PubMed  CAS  Google Scholar 

  23. Brave SR, Ratcliffe K, Wilson Z, James NH, Ashton S, Wainwright A et al (2011) Assessing the activity of cediranib, a VEGFR-2/3 tyrosine kinase inhibitor, against VEGFR-1 and members of the structurally related PDGFR family. Mol Cancer Ther 10:861–873

    Article  PubMed  CAS  Google Scholar 

  24. Brown JL, Cao ZA, Pinzon-Ortiz M, Kendrew J, Reimer C, Wen S et al (2010) A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models. Mol Cancer Ther 9:145–156

    Article  PubMed  CAS  Google Scholar 

  25. Bagri A, Berry L, Gunter B, Singh M, Kasman I, Damico LA et al (2010) Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy. Clin Cancer Res 16:3887–3900

    Article  PubMed  CAS  Google Scholar 

  26. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L et al (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131:463–475

    Article  PubMed  CAS  Google Scholar 

  27. Bais C, Wu X, Yao J, Yang S, Crawford Y, McCutcheon K et al (2010) PlGF blockade does not inhibit angiogenesis during primary tumor growth. Cell 141:166–177

    Article  PubMed  CAS  Google Scholar 

  28. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295

    PubMed  CAS  Google Scholar 

  29. Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP et al (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18:338–340

    PubMed  CAS  Google Scholar 

  30. Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A et al (2011) Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19:512–526

    Article  PubMed  CAS  Google Scholar 

  31. Nisancioglu MH, Betsholtz C, Genové G (2010) The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-A blockade. Cancer Res 70:5109–5115

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Simon T. Barry.

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Farren, M., Weston, S., Brown, H. et al. Expression of stromal genes associated with the angiogenic response are not differentiated between human tumour xenografts with divergent vascular morphologies. Angiogenesis 15, 555–568 (2012). https://doi.org/10.1007/s10456-012-9280-2

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  • DOI: https://doi.org/10.1007/s10456-012-9280-2

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