Skip to main content
SpringerLink
Log in
Book cover

Cancer Drug Resistance pp 3–19Cite as

The Cycle Between Angiogenesis, Perfusion, and Hypoxia in Tumors

  • Chapter

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

This chapter will present a pathophysiologic paradigm that occurs in solid tumors that is characterized by a self-propagating cycle of abnormally regulated angiogenesis, instability in perfusion, and hypoxia. Interactions between tumor and endothelial cells occur during tumor growth and in response to therapy. These interactions are of central importance in establishing codependence that contributes to promotion of cell survival, treatment resistance, enhanced invasion, and metastasis. Results indicate that concurrent targeting of both tumor and endothelial cells may be of central importance in improving treatment responses to both radiation and chemotherapy.

This is a preview of subscription content, 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   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
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

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Kraus RM, Stallings HW III, Yeager RC, Gavin, TP. Circulating plasma VEGF response to exercise in sedentary and endurance-trained men. J Appl Physiol 2004; 96:1445–1450.

    Article  PubMed  CAS  Google Scholar 

  2. Wilkinson-Berka JL. Vasoactive factors and diabetic retinopathy: vascular endothelial growth factor, cycoloxygenase-2 and nitric oxide. Curr Pharm Des 2004; 10:3331–3348.

    Article  PubMed  CAS  Google Scholar 

  3. Folkman J, Hanahan D. Switch to the angiogenic phenotype during tumorigenesis. Princess Takamatsu Symp 1991; 22:339–347.

    PubMed  CAS  Google Scholar 

  4. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3:721–732.

    Article  PubMed  CAS  Google Scholar 

  5. Rak J, Mitsuhashi Y, Bayko L, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 1995; 55:4575–580.

    PubMed  CAS  Google Scholar 

  6. Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000; 2:423–27.

    Article  PubMed  CAS  Google Scholar 

  7. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1 alpha (HIF-1 alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001; 21:3995–1004.

    Article  PubMed  CAS  Google Scholar 

  8. Zundel W, Schindler C, Haas-Kogan D, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 2000; 14:391–396.

    PubMed  CAS  Google Scholar 

  9. Arany Z, Huang LE, Eckner R, et al. An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci U S A 1996; 93:12,969–12,973.

    Article  PubMed  CAS  Google Scholar 

  10. Zhou J, Fandrey J, Schumann J, Tiegs G, Brune B. NO and TNF-alpha released from activated macrophages stabilize HIF-1alpha in resting tubular LLC-PK1 cells. Am J Physiol 2003; 284:C439–C446.

    CAS  Google Scholar 

  11. Yang ZZ, Zhang AY, Yi FX, Li PL, Zou AP. Redox regulation of HIF-1 alpha levels and HO-1 expression in renal medullary interstitial cells. Am J Physiol Renal Physiol 2003; 284: F1207–F1215.

    PubMed  CAS  Google Scholar 

  12. Kuppusamy P, Li H, Ilangovan G, et al. Noninvasive imaging of tumorredox status and its modification by tissue glutathione levels. Cancer Res 2002; 62:307–312.

    PubMed  CAS  Google Scholar 

  13. Kimura H, Braun RD, Ong ET, et al. Fluctuations in red cell flux in tumor micro vessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 1996; 56:5522–5528.

    PubMed  CAS  Google Scholar 

  14. Braun RD, Lanzen JL, Dewhirst MW. Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am J Physiol 1999; 277(2 Pt 2):H551–H568.

    PubMed  CAS  Google Scholar 

  15. Patan S, Munn LL, Jain RK. Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis. Microvasc Res 1996; 51:260–272.

    Article  PubMed  CAS  Google Scholar 

  16. Burri PH, Hlushchuk R, Djonov V. Intussusceptive angiogenesis: its emergence, its characteristics, and its significance. Dev Dyn 2004; 231:474-488.

    Google Scholar 

  17. Folkman J. Angiogenesis and angiogenesis inhibition: an overview. EXS 1997; 79:1–8.

    PubMed  CAS  Google Scholar 

  18. Holash J, Wiegand SJ, Yancopoulos GD. New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 1999; 18:5356–5362.

    Article  PubMed  CAS  Google Scholar 

  19. Dewhirst MW. Concepts of oxygen transport at the microcirculatory level. Semin Radiat Onco, 1998; 8:143–150.

    Article  CAS  Google Scholar 

  20. Gulledge CJ, Dewhirst MW. Tumor oxygenation: amatterof supply and demand. Anticancer Res 1996; 16:741–749.

    PubMed  CAS  Google Scholar 

  21. Kim ES, Serur A, Huang J, et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. Proc Natl Acad Sci U S A 2002; 99:11,399–11,404.

    Article  PubMed  CAS  Google Scholar 

  22. Passalidou E, Trivella M, Singh N, et al. Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas. Br J Cancer 2002; 86:244–249.

    Article  PubMed  CAS  Google Scholar 

  23. Stessels F, Van den Eynden G, Van der Auwera I, et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br J Cancer 2004; 90:1429–1436.

    Article  PubMed  CAS  Google Scholar 

  24. Kunkel P, Ulbricht U, Bohlen P, et al. Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2. Cancer Res 2001; 61:6624–6628.

    PubMed  CAS  Google Scholar 

  25. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A 2002; 99:11,393–11,398.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Peoch M, Farion R, Hiou A, Le Bas JF, Pasquier B, Remy, C. Immunohistochemical study of VEGF, angiopoietin 2 and their receptors in the neovascularization following microinjection of C6 glioma cells into rat brain. Anticancer Res 2002; 22:2147–2151.

    PubMed  CAS  Google Scholar 

  28. Kimura H, Esumi H. Reciprocal regulation between nitric oxide and vascular endothelial growth factor in angiogenesis. Acta Biochim Pol 2003; 50:49–59.

    PubMed  CAS  Google Scholar 

  29. Brekken RA, Thorpe PE. VEGF-VEGF receptor complexes as markers of tumor vascular endothelium. J Control Release 2001; 74:173–181.

    Article  PubMed  CAS  Google Scholar 

  30. Haroon ZA, Lai TS, Hettasch JM, Lindberg RA, Dewhirst MW, Greenberg CS. Tissue transglutaminase is expressed as a host response to tumor invasion and inhibits tumor growth. Lab Invest 1999; 79:1679–1686.

    PubMed  CAS  Google Scholar 

  31. Hettasch JM, Bandarenko N, Burchette JL, et al. Tissue transglutaminase expression in human breast cancer. Lab Invest 1996; 75:637–645.

    PubMed  CAS  Google Scholar 

  32. Iacobuzio-Donahue CA, Ashfaq R, Maitra A, et al. Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies. Cancer Res 2003; 63:8614–8622.

    PubMed  CAS  Google Scholar 

  33. Mehta K, Fok J, Miller FR, Koul D, Sahin AA. Prognostic significance of tissue transglutaminase in drug resistant and metastatic breast cancer. Clin Cancer Res 2004; 10:8068–8076.

    Article  PubMed  CAS  Google Scholar 

  34. Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 1996; 87:1161–1169.

    Article  PubMed  CAS  Google Scholar 

  35. Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277:55–60.

    Article  PubMed  CAS  Google Scholar 

  36. Papapetropoulos A, Garcia-Cardena G, Dengler TJ, Maisonpierre PC, Yancopoulos GD, Sessa WC. Direct actions of angiopoietin-1 on human endothelium: evidence for network stabilization, cell survival, and interaction with other angiogenic growth factors. Lab Invest 1999; 79:213–223.

    PubMed  CAS  Google Scholar 

  37. Thurston G, Rudge JS, Ioffe E, et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 2000; 6:460–463.

    Article  PubMed  CAS  Google Scholar 

  38. Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM. Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 2002; 160:985–1000.

    PubMed  Google Scholar 

  39. Enholm B, Paavonen K, Ristimaki A, et al. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRN A regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 1997; 14:2475–2483.

    Article  PubMed  CAS  Google Scholar 

  40. Mandriota SJ, Pepper MS. Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ Res 1998; 83:852–859.

    PubMed  CAS  Google Scholar 

  41. Oh H, Takagi H, Suzuma K, Otani A, Matsumura M, Honda Y. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 1999; 274:15,732–15,739.

    Article  PubMed  CAS  Google Scholar 

  42. Zakrzewicz A, Secomb TW, Pries AR. Angioadaptation: keeping the vascular system in shape. News Physiol Sci 2002; 17:197–201.

    PubMed  Google Scholar 

  43. Tong S, Yuan F. Numerical simulations of angiogenesis in the cornea. MicrovascRes 2001; 61:14–27.

    Article  CAS  Google Scholar 

  44. Li CY, Shan S, Cao Y, Dewhirst MW. Role of incipient angiogenesis in cancer metastasis. Cancer Metastasis Rev 2000; 19:7–11.

    Article  PubMed  CAS  Google Scholar 

  45. Shan S, Robson ND, Cao Y, et al. Responses of vascular endothelial cells to angiogenic signaling are important for tumor cell survival. FASEB J 2004; 18:326–328.

    PubMed  CAS  Google Scholar 

  46. Krishnamachary B, Berg-Dixon S, Kelly B, et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res 2003; 63:1138–1143.

    PubMed  CAS  Google Scholar 

  47. Wong CW, Song C, Grimes MM, et al. Intravascular location of breast cancer cells after spontaneous metastasis to the lung. Am J Pathol 2002; 161:749–753.

    PubMed  Google Scholar 

  48. Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med 2000; 6:100–102.

    Article  PubMed  CAS  Google Scholar 

  49. Burri PH, Djonov, V. Intussusceptive angiogenesis-the alternative to capillary sprouting. Mol Aspects Med 2002; 23(Suppl):S1–S27.

    Article  PubMed  Google Scholar 

  50. Djonov V, Andres AC, Ziemiecki A. Vascular remodelling during the normal and malignant life cycle of the mammary gland. Microsc Res Tech 2001; 52:182–189.

    Article  PubMed  CAS  Google Scholar 

  51. Djonov VG, Kurz H, Burri PH. Optimality in the developing vascular system: branching remodeling by means of intussusception as an efficient adaptation mechanism. Dev Dyn 2002; 224:391–402.

    Article  PubMed  Google Scholar 

  52. Djonov V, Baum O, Burri PH. Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res 2003; 314:107–117.

    Article  PubMed  Google Scholar 

  53. Pries AR, Reglin B, Secomb TW.Structural response of microcirculatory networks to changes in demand: information transfer by shear stress. Am J Physiol 2003; 284:H2204–2212.

    CAS  Google Scholar 

  54. Dewhirst MW, Ong ET, Klitzman B, et al. Perivascular oxygen tensions in a transplantable mammary tumor growing in a dorsal flap window chamber. Radiat Res 1992; 130:171–182.

    Article  PubMed  CAS  Google Scholar 

  55. Helmlinger G, Yuan F, Dellian M, Jain RK. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med 1997; 3:177–182.

    Article  PubMed  CAS  Google Scholar 

  56. Dewhirst MW, Ong ET, Braun RD, et al. Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia. Br J Cancer 1999; 79:1717–1722.

    Article  PubMed  CAS  Google Scholar 

  57. Secomb TW, Hsu R, Braun RD, Ross JR, Gross JF, Dewhirst MW. Theoretical simulation of oxygen transport to tumors by three-dimensional networks of microvessels. Adv Exp Med Biol 1998; 454:629–634.

    PubMed  CAS  Google Scholar 

  58. Dewhirst MW, Secomb TW, Ong ET, Hsu R, Gross JF. Determination of local oxygen consumption rates in tumors. Cancer Res 1994; 54:3333–3336.

    PubMed  CAS  Google Scholar 

  59. Kavanagh BD, Coffey BE, Needham D, Hochmuth RM, Dewhirst MW The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment. Br J Cancer 1993; 67:734–741.

    PubMed  CAS  Google Scholar 

  60. Haroon ZA, Raleigh JA, Greenberg CS, Dewhirst MW. Early wound healing exhibits cytokine surge without evidence of hypoxia. Ann Surg 2000; 231:137–147.

    Article  PubMed  CAS  Google Scholar 

  61. Graeber TG, Osmanian C, Jacks T, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996; 379:88–91.

    Article  PubMed  CAS  Google Scholar 

  62. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986; 315:1650–1659.

    Article  PubMed  CAS  Google Scholar 

  63. Teicher BA, Sotomayor EA, Huang ZD. Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res 1992; 52:6702–6704.

    PubMed  CAS  Google Scholar 

  64. Teicher BA, Holden SA, Ara G, et al. Influence of an anti-angiogenic treatment on 9L gliosarcoma: oxygenation and response to therapy. Int J Cancer 1995; 61:732–737.

    Article  PubMed  CAS  Google Scholar 

  65. Denekamp J. Review article: Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. Br J Radiol 1993; 66:181–196.

    Article  PubMed  CAS  Google Scholar 

  66. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumorresponse to radiotherapy regulated by endothelial cell apoptosis. Science 2003; 300:1155–1159.

    Article  PubMed  CAS  Google Scholar 

  67. Brown M, Bristow R, Glazer P, et al. Comment on &quote;Tumor response to radiotherapy regulated by endothelial cell apoptosis&quote; (II). Science 2003; 302:1894; author reply 1894.

    Article  PubMed  CAS  Google Scholar 

  68. Rubin P, Casarett G. Microcirculation of tumors. II. The supervascularized state of irradiated regressing tumors. Clin Radiol 1966; 17:346–355.

    Article  PubMed  CAS  Google Scholar 

  69. Hilmas DE, Gillette EL. Tumormicrovasculature following fractionated X-irradiation. Radiology 1975; 116:165–169.

    PubMed  CAS  Google Scholar 

  70. Dewhirst MW, Oliver R, Tso CY, Gustafson C, Secomb T, Gross JF. Heterogeneity in tumor micro vascular response to radiation. Int J Radiat Oncol Biol Phys 1990; 18:559–568.

    PubMed  CAS  Google Scholar 

  71. Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 2004; 5:429–41.

    Article  PubMed  CAS  Google Scholar 

  72. Gilks N, Kedersha N, Ayodele M, et al. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol Biol Cell 2004; 15:5383–5398.

    Article  PubMed  CAS  Google Scholar 

  73. Kedersha N, Anderson P. Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. Biochem Soc Trans 2002; 30(Pt 6):963–969.

    Google Scholar 

  74. Milas L, Hunter N, Mason KA, Milross C, Peters LJ. Tumor reoxygenation as a mechanism of taxolinduced enhancement of tumor radioresponse. Acta Oncol 1995; 34(3):409–412.

    Google Scholar 

  75. Vujaskovic Z, Song CW. Physiological mechanisms underlying heat-induced radiosensitization. Int J Hyperthermia 2004; 20:163–174.

    Article  PubMed  CAS  Google Scholar 

  76. Jones EL, Prosnitz LR, Dewhirst MW, et al. Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer. Clin Cancer Res 2004; 10:4287–1293.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Duke University Medical Center, Durham, NC

    Mark W. Dewhirst DVM, PhD, Yiting Cao MD, PhD, Benjamin Moeller PhD & Chuan-Yuan Li PhD

Authors
  1. Mark W. Dewhirst DVM, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yiting Cao MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benjamin Moeller PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chuan-Yuan Li PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Genzyme Corporation, Framingham, MA

    Beverly A. Teicher PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Dewhirst, M.W., Cao, Y., Moeller, B., Li, CY. (2006). The Cycle Between Angiogenesis, Perfusion, and Hypoxia in Tumors. In: Teicher, B.A. (eds) Cancer Drug Resistance. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-035-5_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-035-5_1

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-530-9

  • Online ISBN: 978-1-59745-035-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation