Skip to main content
SpringerLink
Log in

Novel Cancer Therapies Targeting Angiogenesis

  • Chapter
  • First Online:
The Molecular Basis of Human Cancer

  • 3075 Accesses

Abstract

Cancer growth is generally restricted to tissue that is approximately 2 mm in diameter. At this size, the cancer receives enough oxygen and nutrients by diffusion from nearby blood vessels to survive. Upon further growth, the proliferation of cells within the cancer is matched by the induction of apoptosis due to nutrient deprivation, resulting in a steady-state size. The way cancers adapt to these physical limits is by obtaining their own new blood supply. Only through the induction of its own blood supply, generally by the process of angiogenesis, can cancers exceed the 2 mm size limit and can continue to grow virtually unchecked. Cancer cells stimulate angiogenesis by secreting soluble factors that stimulate vessel growth and/or by suppressing factors that prevent angiogenesis. These factors act primarily upon endothelial cells to promote their proliferation and migration, resulting in the sprouting and formation of tubes, which then develop into vessels.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Vajkoczy P, Farhadi M, Gaumann A, et al. Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2. J Clin Invest. 2002;109:777–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Schmidt A, Brixius K, Bloch W. Endothelial precursor cell migration during vasculogenesis. Circ Res. 2007;101:125–36.

    Article  CAS  PubMed  Google Scholar 

  3. Hillen F, Griffioen AW. Tumour vascularization: sprouting angiogenesis and beyond. Cancer Metastasis Rev. 2007;26:489–502.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tang HS, Feng YJ, Yao LQ. Angiogenesis, vasculogenesis, and vasculogenic mimicry in ovarian cancer. Int J Gynecol Cancer. 2009;19:605–10.

    Article  PubMed  Google Scholar 

  5. Gimbrone Jr MA, Cotran RS, Leapman SB, et al. Tumor growth and neovascularization: an experimental model using the rabbit cornea. J Natl Cancer Inst. 1974;52:413–27.

    PubMed  Google Scholar 

  6. Ausprunk DH, Knighton DR, Folkman J. Vascularization of normal and neoplastic tissues grafted to the chick chorioallantois. Role of host and preexisting graft blood vessels. Am J Pathol. 1975;79:597–618.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Hanahan D. Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature. 1985;315:115–22.

    Article  CAS  PubMed  Google Scholar 

  9. Kandel J, Bossy-Wetzel E, Radvanyi F, et al. Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell. 1991;66:1095–104.

    Article  CAS  PubMed  Google Scholar 

  10. Lacey M, Alpert S, Hanahan D. Bovine papillomavirus genome elicits skin tumours in transgenic mice. Nature. 1986;322:609–12.

    Article  CAS  PubMed  Google Scholar 

  11. Smith-McCune K, Zhu YH, Hanahan D, et al. Cross-species comparison of angiogenesis during the premalignant stages of squamous carcinogenesis in the human cervix and K14-HPV16 transgenic mice. Cancer Res. 1997;57:1294–300.

    CAS  PubMed  Google Scholar 

  12. Weidner N, Folkman J, Pozza F, et al. Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. J Natl Cancer Inst. 1992;84:1875–87.

    Article  CAS  PubMed  Google Scholar 

  13. Guidi AJ, bu-Jawdeh G, Berse B, et al. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in cervical neoplasia. J Natl Cancer Inst. 1995;87:1237–45.

    Article  CAS  PubMed  Google Scholar 

  14. Smith-McCune KK, Weidner N. Demonstration and characterization of the angiogenic properties of cervical dysplasia. Cancer Res. 1994;54:800–4.

    CAS  PubMed  Google Scholar 

  15. Chiodoni C, Colombo MP, Sangaletti S. Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer Metastasis Rev. 2010;29:295–307.

    Article  CAS  PubMed  Google Scholar 

  16. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002;2:795–803.

    Article  CAS  PubMed  Google Scholar 

  17. Olofsson B, Pajusola K, Kaipainen A, et al. Vascular endothelial growth factor B, a novel growth factor for endothelial cells. Proc Natl Acad Sci U S A. 1996;93:2576–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Oklu R, Walker TG, Wicky S, et al. Angiogenesis and current antiangiogenic strategies for the treatment of cancer. J Vasc Interv Radiol. 2010;21:1791–805.

    Article  PubMed  Google Scholar 

  19. Adini A, Kornaga T, Firoozbakht F, et al. Placental growth factor is a survival factor for tumor endothelial cells and macrophages. Cancer Res. 2002;62:2749–52.

    CAS  PubMed  Google Scholar 

  20. Mazzone M, Dettori D, de Leite OR, et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell. 2009;136:839–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    Article  CAS  PubMed  Google Scholar 

  22. Korpanty G, Smyth E, Sullivan LA, et al. Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway. Exp Biol Med. 2010;235:3–9.

    Article  CAS  Google Scholar 

  23. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611.

    Article  CAS  PubMed  Google Scholar 

  24. He Y, Rajantie I, Pajusola K, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res. 2005;65:4739–46.

    Article  CAS  PubMed  Google Scholar 

  25. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.

    Article  CAS  PubMed  Google Scholar 

  26. Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol. 2009;6:507–18.

    Article  CAS  PubMed  Google Scholar 

  27. Ciulla TA, Rosenfeld PJ. Antivascular endothelial growth factor therapy for neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2009;20:158–65.

    Article  PubMed  Google Scholar 

  28. Wilhelm SM, Adnane L, Newell P, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–40.

    Article  CAS  PubMed  Google Scholar 

  29. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13.

    Article  CAS  PubMed  Google Scholar 

  30. Murakami M, Elfenbein A, Simons M. Non-canonical fibroblast growth factor signalling in angiogenesis. Cardiovasc Res. 2008;78:223–31.

    Article  CAS  PubMed  Google Scholar 

  31. Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005;16:139–49.

    Article  CAS  PubMed  Google Scholar 

  32. Partovian C, Simons M. Regulation of protein kinase B/Akt activity and Ser473 phosphorylation by protein kinase Calpha in endothelial cells. Cell Signal. 2004;16:951–7.

    Article  CAS  PubMed  Google Scholar 

  33. Li JL, Sainson RC, Shi W, et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res. 2007;67:11244–53.

    Article  CAS  PubMed  Google Scholar 

  34. Noguera-Troise I, Daly C, Papadopoulos NJ, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006;444:1032–7.

    Article  CAS  PubMed  Google Scholar 

  35. Barbara NP, Wrana JL, Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem. 1999;274:584–94.

    Article  CAS  PubMed  Google Scholar 

  36. Ferrari G, Cook BD, Terushkin V, et al. Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis. J Cell Physiol. 2009;219:449–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yingling JM, Blanchard KL, Sawyer JS. Development of TGF-beta signalling inhibitors for cancer therapy. Nat Rev Drug Discov. 2004;3:1011–22.

    Article  CAS  PubMed  Google Scholar 

  38. Yancopoulos GD, Klagsbrun M, Folkman J. Vasculogenesis, angiogenesis, and growth factors: ephrins enter the fray at the border. Cell. 1998;93:661–4.

    Article  CAS  PubMed  Google Scholar 

  39. Korhonen J, Polvi A, Partanen J, et al. The mouse tie receptor tyrosine kinase gene: expression during embryonic angiogenesis. Oncogene. 1994;9:395–403.

    CAS  PubMed  Google Scholar 

  40. Thomas M, Augustin HG. The role of the angiopoietins in vascular morphogenesis. Angiogenesis. 2009;12:125–37.

    Article  CAS  PubMed  Google Scholar 

  41. Herbst RS, Hong D, Chap L, et al. Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J Clin Oncol. 2009;27:3557–65.

    Article  CAS  PubMed  Google Scholar 

  42. Cook KM, Figg WD. Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin. 2010;60:222–43.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    Article  CAS  PubMed  Google Scholar 

  44. Perrotte P, Matsumoto T, Inoue K, et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 1999;5:257–65.

    CAS  PubMed  Google Scholar 

  45. Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer. 2003;107:873–7.

    Article  CAS  PubMed  Google Scholar 

  46. Fukuda R, Hirota K, Fan F, et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem. 2002;277:38205–11.

    Article  CAS  PubMed  Google Scholar 

  47. Weroha SJ, Haluska P. IGF-1 receptor inhibitors in clinical trials—early lessons. J Mammary Gland Biol Neoplasia. 2008;13:471–83.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Haluska P, Worden F, Olmos D, et al. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol. 2010;65:765–73.

    Article  CAS  PubMed  Google Scholar 

  49. Stupp R, Ruegg C. Integrin inhibitors reaching the clinic. J Clin Oncol. 2007;25:1637–8.

    Article  CAS  PubMed  Google Scholar 

  50. Brooks PC, Montgomery AM, Rosenfeld M, et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994;79:1157–64.

    Article  CAS  PubMed  Google Scholar 

  51. Friedlander M, Brooks PC, Shaffer RW, et al. Definition of two angiogenic pathways by distinct alpha v integrins. Science. 1995;270:1500–2.

    Article  CAS  PubMed  Google Scholar 

  52. Alghisi GC, Ruegg C. Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. Endothelium. 2006;13:113–35.

    Article  CAS  PubMed  Google Scholar 

  53. Golubovskaya VM, Cance W. Focal adhesion kinase and p53 signal transduction pathways in cancer. Front Biosci. 2010;15:901–12.

    Article  CAS  Google Scholar 

  54. Choi HS, Wang Z, Richmond W, et al. Design and synthesis of 7H-pyrrolo[2,3-d]pyrimidines as focal adhesion kinase inhibitors. Part 2. Bioorg Med Chem Lett. 2006;16:2689–92.

    Article  CAS  PubMed  Google Scholar 

  55. Slack-Davis JK, Martin KH, Tilghman RW, et al. Cellular characterization of a novel focal adhesion kinase inhibitor. J Biol Chem. 2007;282:14845–52.

    Article  CAS  PubMed  Google Scholar 

  56. Courtwright A, Siamakpour-Reihani S, Arbiser JL, et al. Secreted frizzle-related Protein 2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway. Cancer Res. 2009;69:4621–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Nilsson LM, Sun ZW, Nilsson J, et al. Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation. Am J Physiol Cell Physiol. 2007;292:C1167–78.

    Article  CAS  PubMed  Google Scholar 

  58. Minami T, Horiuchi K, Miura M, et al. Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis. J Biol Chem. 2004;279:50537–54.

    Article  CAS  PubMed  Google Scholar 

  59. Zaichuk TA, Shroff EH, Emmanuel R, et al. Nuclear factor of activated T cells balances angiogenesis activation and inhibition. J Exp Med. 2004;199:1513–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Siamakpour-Reihani S, Caster J, Bandhu ND, et al. The role of calcineurin/NFAT in SFRP2 induced angiogenesis-A rationale for breast cancer treatment with the calcineurin inhibitor tacrolimus. PLoS One. 2011;6:e20412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Armesilla AL, Lorenzo E, del Gomez AP, et al. Vascular endothelial growth factor activates nuclear factor of activated T cells in human endothelial cells: a role for tissue factor gene expression. Mol Cell Biol. 1999;19:2032–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lawler J. Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med. 2002;6:1–12.

    Article  CAS  PubMed  Google Scholar 

  63. O'Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994;79:315–28.

    Article  PubMed  Google Scholar 

  64. O'Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–85.

    Article  PubMed  Google Scholar 

  65. Klauber N, Parangi S, Flynn E, et al. Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res. 1997;57:81–6.

    CAS  PubMed  Google Scholar 

  66. St Croix B, Rago C, Velculescu V, et al. Genes expressed in human tumor endothelium. Science. 2000;289:1197–202.

    Article  CAS  PubMed  Google Scholar 

  67. Nanda A, St Croix B. Tumor endothelial markers: new targets for cancer therapy. Curr Opin Oncol. 2004;16:44–9.

    Article  CAS  PubMed  Google Scholar 

  68. Bhati R, Patterson C, Livasy CA, et al. Molecular characterization of human breast tumor vascular cells. Am J Pathol. 2008;172:1381–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Buckanovich RJ, Sasaroli D, O'brien-Jenkins A, et al. Tumor vascular proteins as biomarkers in ovarian cancer. J Clin Oncol. 2007;25:852–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    Monte S. Willis M.D., Ph.D., F.A.H.A., F.A.B.P.

  2. Department of Surgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA

    Nancy Klauber-DeMore M.D., F.A.C.S.

Authors
  1. Monte S. Willis M.D., Ph.D., F.A.H.A., F.A.B.P.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy Klauber-DeMore M.D., F.A.C.S.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancy Klauber-DeMore M.D., F.A.C.S. .

Editor information

Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Curriculum in Toxicology, UNC Program in Translational Medicine, UNC Lineberger Comprehensive Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    William B. Coleman

  2. Laboratory for Clinical Genomics and Advanced Technology (CGAT), Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, Hanover, New Hampshire, USA

    Gregory J. Tsongalis

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media New York

About this chapter

Cite this chapter

Willis, M.S., Klauber-DeMore, N. (2017). Novel Cancer Therapies Targeting Angiogenesis. In: Coleman, W., Tsongalis, G. (eds) The Molecular Basis of Human Cancer. Humana Press, New York, NY. https://doi.org/10.1007/978-1-59745-458-2_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-458-2_11

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-934115-18-3

  • Online ISBN: 978-1-59745-458-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation