Advertisement

Tumor Biology

, Volume 33, Issue 5, pp 1709–1717 | Cite as

Vascular density and endothelial cell expression of integrin alpha v beta 3 and E-selectin in murine tumours

  • Johanne Seguin
  • Céline Nicolazzi
  • Nathalie Mignet
  • Daniel Scherman
  • Guy G. Chabot
Research Article

Abstract

The endothelial cell adhesion molecules, including the integrin alpha v beta 3 (αvβ3) and E-selectin, are involved in the process of angiogenesis required for tumour growth, cell migration and metastasis. The purpose of this study was to assess and compare widely used tumour models to select the ones most suitable for angiogenesis research. Fifteen murine tumours were selected including melanoma (B16), colon (C26, C38, C51), mammary (MA13, MA16, MA16/Adr, MA17, MA17/Adr, MA25, MA44), pancreatic (PO2, PO3), Glasgow osteogenic sarcoma (GOS) and Lewis lung carcinoma (LLC). The tumour vascular density, assessed using the platelet endothelial cell adhesion molecule 1 (PECAM-1; CD31) immunostaining, revealed that B16 melanoma was poorly vascularized (<5 %), whereas the colon and mammary tumours were well vascularized (5–15 %). The most vascularized tumours (>15 %) were the pancreatic tumours (PO2 and PO3), the sarcoma (GOS) and the lung tumour (LLC). The integrin αvβ3 and E-selectin, evaluated by immunohistology, showed that 7/15 tumours expressed the αvβ3 integrin which was homogeneously distributed on all tumour sections (B16, C26, MA17/Adr, MA25, MA44, PO2, LLC). E-selectin was expressed in 4/15 tumours and its expression was restricted to the tumour periphery. Only 2/15 tumours (B16 and C26) were shown to express both integrin αvβ3 and E-selectin. In conclusion, these data not only contribute to a better understanding of the tumour biology of murine tumours but can also guide the choice of appropriate models for antiangiogenic therapy, for selective drug delivery to tumours and the validation of tumour imaging modalities targeting these endothelial cell adhesion molecules.

Keywords

Mouse tumours Vascularization Integrin alpha v beta 3 E-selectin Melanoma Colon Mammary Pancreas Sarcoma Lung 

Abbreviation

CAM

Endothelial cell adhesion molecule

Notes

Acknowledgments

We are grateful to the Oncology Department of Aventis Pharma, S.A. (now Sanofi, S.A.), for providing the murine tumour samples. This work was supported in part by Gencell S.A., the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Ecole Nationale Supérieure de Chimie Paris (ENSCP). We also thank the Institut National du Cancer for grant support to GGC (INCa, Boulogne Billancourt, France).

References

  1. 1.
    Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29:15–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Nussenbaum F, Herman IM. Tumor angiogenesis: insights and innovations. J Oncol. 2010;2010:132641.Google Scholar
  3. 3.
    Bischoff J. Cell adhesion and angiogenesis. J Clin Invest. 1997;100:S37–9.PubMedGoogle Scholar
  4. 4.
    O. I, Otvos L, Kieber-Emmons T, Blaszczyk-Thurin M. Role of SA-Le(a) and E-selectin in metastasis assessed with peptide antagonist. Peptides. 2002;23:999–1010.Google Scholar
  5. 5.
    Hosotani R, Kawaguchi M, Masui T, Koshiba T, Ida J, Fujimoto K, Wada M, Doi R, Imamura M. Expression of integrin alphaVbeta3 in pancreatic carcinoma: relation to MMP-2 activation and lymph node metastasis. Pancreas. 2002;25:e30–5.CrossRefPubMedGoogle Scholar
  6. 6.
    Langley RR, Russell J, Eppihimer MJ, Alexander SJ, Gerritsen M, Specian RD, Granger DN. Quantification of murine endothelial cell adhesion molecules in solid tumors. Am J Physiol. 1999;277:H1156–66.PubMedGoogle Scholar
  7. 7.
    Varner JA, Cheresh DA. Tumor angiogenesis and the role of vascular cell integrin alpha v beta 3. Important Adv Oncol. 1996;1996:69-87.Google Scholar
  8. 8.
    Kraling BM, Razon MJ, Boon LM, Zurakowski D, Seachord C, Darveau RP, Mulliken JB, Corless CL, Bischoff J. E-selectin is present in proliferating endothelial cells in human hemangiomas. Am J Pathol. 1996;148:1181–91.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Friedlander M, Theesfeld CL, Sugita M, Fruttiger M, Thomas MA, Chang S, Cheresh DA. Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases. Proc Natl Acad Sci U S A. 1996;93:9764–9.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ruoslahti E. Specialization of tumour vasculature. Nat Rev Cancer. 2002;2:83–90.CrossRefPubMedGoogle Scholar
  11. 11.
    Max R, Gerritsen RR, Nooijen PT, Goodman SL, Sutter A, Keilholz U, Ruiter DJ, De Waal RM. Immunohistochemical analysis of integrin alpha vbeta3 expression on tumor-associated vessels of human carcinomas. Int J Cancer. 1997;71:320–4.CrossRefPubMedGoogle Scholar
  12. 12.
    Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994;79:1157–64.CrossRefPubMedGoogle Scholar
  13. 13.
    Eliceiri BP, Cheresh DA. The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J Clin Invest. 1999;103:1227–30.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Weis SM, Cheresh DA. Alpha v Integrins in Angiogenesis and Cancer. Cold Spring Harb Perspect Med. 2011;1:a006478.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Haviv YS, Curiel DT. Conditional gene targeting for cancer gene therapy. Adv Drug Deliv Rev. 2001;53:135–54.CrossRefPubMedGoogle Scholar
  16. 16.
    Nguyen M, Eilber FR, Defrees S. Novel synthetic analogs of sialyl Lewis X can inhibit angiogenesis in vitro and in vivo. Biochem Biophys Res Commun. 1996;228:716–23.CrossRefPubMedGoogle Scholar
  17. 17.
    Yasuda M, Shimizu S, Ohhinata K, Naito S, Tokuyama S, Mori Y, Kiuchi Y, Yamamoto T. Differential roles of ICAM-1 and E-selectin in polymorphonuclear leukocyte-induced angiogenesis. Am J Physiol Cell Physiol. 2002;282:C917–25.CrossRefPubMedGoogle Scholar
  18. 18.
    Mannori G, Santoro D, Carter L, Corless C, Nelson RM, Bevilacqua MP. Inhibition of colon carcinoma cell lung colony formation by a soluble form of E-selectin. Am J Pathol. 1997;151:233–43.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Vonlaufen A, Wiedle G, Borisch B, Birrer S, Luder P, Imhof BA. Integrin alpha(v)beta(3) expression in colon carcinoma correlates with survival. Mod Pathol. 2001;14:1126–32.CrossRefPubMedGoogle Scholar
  20. 20.
    Polin L, Corbett TH, Roberts BJ, Lawson AJ, Leopold III WR, White K, Kushner J, Hazeldine S, Moore R, Rake J, Horwitz JP. Transplantable syngeneic rodent tumors: Solid tumors of mice. In: Teicher BA, editor. Tumors models in cancer research, Cancer Drug Discovery and Development. New York: Springer Science & Business Media LLC; 2011. p. 43–78.CrossRefGoogle Scholar
  21. 21.
    Fidler IJ. Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res. 1975;35:218–24.PubMedGoogle Scholar
  22. 22.
    Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM. Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res. 1975;35:2434–9.PubMedGoogle Scholar
  23. 23.
    Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM. Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas. Cancer. 1977;40:2660–80.CrossRefPubMedGoogle Scholar
  24. 24.
    Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM. Biology and therapeutic response of a mouse mammary adenocarcinoma (16/C) and its potential as a model for surgical adjuvant chemotherapy. Cancer Treat Rep. 1978;62:1471–88.PubMedGoogle Scholar
  25. 25.
    Schabel Jr FM, Skipper HE, Trader MW, Laster Jr WR, Griswold Jr DP, Corbett TH. Establishment of cross-resistance profiles for new agents. Cancer Treat Rep. 1983;67:905–22.PubMedGoogle Scholar
  26. 26.
    Liang J, Moore RE, Moher ED, Munroe JE, Al-awar RS, Hay DA, Varie DL, Zhang TY, Aikins JA, Martinelli MJ, Shih C, Ray JE, Gibson LL, Vasudevan V, Polin L, White K, Kushner J, Simpson C, Pugh S, Corbett TH. Cryptophycins-309, 249 and other cryptophycin analogs: preclinical efficacy studies with mouse and human tumors. Invest New Drugs. 2005;23:213–24.CrossRefPubMedGoogle Scholar
  27. 27.
    Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold Jr DP, Schabel Jr FM. Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res. 1984;44:717–26.PubMedGoogle Scholar
  28. 28.
    Glasgow LA, Crane Jr JL, Kern ER, Youngner JS. Antitumor activity of interferon against murine osteogenic sarcoma in vitro and in vivo. Cancer Treat Rep. 1978;62:1881–8.PubMedGoogle Scholar
  29. 29.
    Bertram JS, Janik P. Establishment of a cloned line of Lewis Lung Carcinoma cells adapted to cell culture. Cancer Lett. 1980;11:63–73.CrossRefPubMedGoogle Scholar
  30. 30.
    Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med. 1998;49:407–24.CrossRefPubMedGoogle Scholar
  31. 31.
    Rofstad EK, Danielsen T. Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis. Br J Cancer. 1999;80:1697–707.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Strohmeyer D. Pathophysiology of tumor angiogenesis and its relevance in renal cell cancer. Anticancer Res. 1999;19:1557–61.PubMedGoogle Scholar
  33. 33.
    Hasan J, Byers R, Jayson GC. Intra-tumoural microvessel density in human solid tumours. Br J Cancer. 2002;86:1566–77.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Boles KS, Schmieder AH, Koch AW, Carano RA, Wu Y, Caruthers SD, Tong RK, Stawicki S, Hu G, Scott MJ, Zhang H, Reynolds BA, Wickline SA, Lanza GM. MR angiogenesis imaging with Robo4- vs. alphaVbeta3-targeted nanoparticles in a B16/F10 mouse melanoma model. FASEB J. 2010;24:4262–70.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Felding-Habermann B, Fransvea E, O'Toole TE, Manzuk L, Faha B, Hensler M. Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells. Clin Exp Metastasis. 2002;19:427–36.CrossRefPubMedGoogle Scholar
  36. 36.
    Desgrosellier JS, Barnes LA, Shields DJ, Huang M, Lau SK, Prevost N, Tarin D, Shattil SJ, Cheresh DA. An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat Med. 2009;15:1163–9.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Nelson H, Ramsey PS, Donohue JH, Wold LE. Cell adhesion molecule expression within the microvasculature of human colorectal malignancies. Clin Immunol Immunopathol. 1994;72:129–36.CrossRefPubMedGoogle Scholar
  38. 38.
    Fox SB, Turner GD, Gatter KC, Harris AL. The increased expression of adhesion molecules ICAM-3, E- and P-selectins on breast cancer endothelium. J Pathol. 1995;177:369–76.CrossRefPubMedGoogle Scholar
  39. 39.
    Barthel SR, Gavino JD, Descheny L, Dimitroff CJ. Targeting selectins and selectin ligands in inflammation and cancer. Expert Opin Ther Targets. 2007;11:1473–91.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Jubeli E, Moine L, Vergnaud-Gauduchon J, Barratt G. E-selectin as a target for drug delivery and molecular imaging. J Control Release. 2012;158:194–206.CrossRefPubMedGoogle Scholar
  41. 41.
    Senger DR, Perruzzi CA, Streit M, Koteliansky VE, de Fougerolles AR, Detmar M. The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am J Pathol. 2002;160:195–204.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Reynolds LE, Wyder L, Lively JC, Taverna D, Robinson SD, Huang X, Sheppard D, Hynes RO, Hodivala-Dilke KM. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med. 2002;8:27–34.CrossRefPubMedGoogle Scholar
  43. 43.
    Tucker GC. Inhibitors of integrins. Curr Opin Pharmacol. 2002;2:394–402.CrossRefPubMedGoogle Scholar
  44. 44.
    Parkes RJ, Hart SL. Adhesion molecules and gene transfer. Adv Drug Deliv Rev. 2000;44:135–52.CrossRefPubMedGoogle Scholar
  45. 45.
    Wesseling JG, Bosma PJ, Krasnykh V, Kashentseva EA, Blackwell JL, Reynolds PN, Li H, Parameshwar M, Vickers SM, Jaffee EM, Huibregtse K, Curiel DT, Dmitriev I. Improved gene transfer efficiency to primary and established human pancreatic carcinoma target cells via epidermal growth factor receptor and integrin-targeted adenoviral vectors. Gene Ther. 2001;8:969–76.CrossRefPubMedGoogle Scholar
  46. 46.
    Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R, Cheresh DA. Tumor regression by targeted gene delivery to the neovasculature. Science. 2002;296:2404–7.CrossRefPubMedGoogle Scholar
  47. 47.
    Spragg DD, Alford DR, Greferath R, Larsen CE, Lee KD, Gurtner GC, Cybulsky MI, Tosi PF, Nicolau C, Gimbrone Jr MA. Immunotargeting of liposomes to activated vascular endothelial cells: a strategy for site-selective delivery in the cardiovascular system. Proc Natl Acad Sci U S A. 1997;94:8795–800.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, Bodkin DJ, Cheresh DA. Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. Clin Cancer Res. 2000;6:3056–61.PubMedGoogle Scholar
  49. 49.
    Kumar CC, Malkowski M, Yin Z, Tanghetti E, Yaremko B, Nechuta T, Varner J, Liu M, Smith EM, Neustadt B, Presta M, Armstrong L. Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha(v)beta3 and alpha(v)beta5 integrin receptor antagonist. Cancer Res. 2001;61:2232–8.PubMedGoogle Scholar
  50. 50.
    Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10:9–22.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Mas-Moruno C, Rechenmacher F, Kessler H. Cilengitide: the first anti-angiogenic small molecule drug candidate design, synthesis and clinical evaluation. Anticancer Agents Med Chem. 2010;10:753–68.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Ye Y, Chen X. Integrin targeting for tumor optical imaging. Theranostics. 2011;1:102–26.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Liu ZJ, Tian R, Li Y, An W, Zhuge Y, Livingstone AS, Velazquez OC. Inhibition of tumor angiogenesis and melanoma growth by targeting vascular E-selectin. Ann Surg. 2011;254:450–6.CrossRefPubMedGoogle Scholar
  54. 54.
    Formelli F, Rossi C, Supino R, Parmiani G. In vivo characterization of a doxorubicin resistant B16 melanoma cell line. Br J Cancer. 1986;54:223–33.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Bissery MC, Nguyen CH, Bisagni E, Vrignaud P, Lavelle F. Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice. Invest New Drugs. 1993;11:263–77.CrossRefPubMedGoogle Scholar
  56. 56.
    Bissery MC, Guenard D, Gueritte-Voegelein F, Lavelle F. Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue. Cancer Res. 1991;51:4845–52.PubMedGoogle Scholar
  57. 57.
    Corbett TH, Leopold WR, Dykes DJ, Roberts BJ, Griswold Jr DP, Schabel Jr FM. Toxicity and anticancer activity of a new triazine antifolate (NSC 127755). Cancer Res. 1982;42:1707–15.PubMedGoogle Scholar
  58. 58.
    LoRusso PM, Demchik L, Foster B, Knight J, Bissery MC, Polin LM, Leopold III WR, Corbett TH. Preclinical antitumor activity of CI-994. Invest New Drugs. 1996;14:349–56.PubMedGoogle Scholar
  59. 59.
    DeWys WD. Studies correlating the growth rate of a tumor and its metastases and providing evidence for tumor-related systemic growth-retarding factors. Cancer Res. 1972;32:374–9.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Johanne Seguin
    • 1
  • Céline Nicolazzi
    • 1
  • Nathalie Mignet
    • 1
  • Daniel Scherman
    • 1
  • Guy G. Chabot
    • 1
  1. 1.Chemical, Genetic and Imaging Pharmacology Laboratory (INSERM U1022—CNRS UMR 8151), Faculty of PharmacyParis Descartes UniversityParisFrance

Personalised recommendations