REVIEW
Tumours can adapt to anti-angiogenic therapy depending on the stromal context: Lessons from endothelial cell biology

https://doi.org/10.1016/j.ejcb.2005.10.003Get rights and content

Abstract

It has long been recognized that interference with the blood supply of a tumour is an effective way to halt tumour progression, and even induce tumour regression. This can be accomplished by anti-angiogenic treatment which prevents the formation of a tumour neovasculature, or anti-vascular treatment, which aims at destruction of existent tumour vessels. The latter has received relatively little attention because there is a lack of specific tumour-endothelial markers. Instead, the current detailed knowledge on the factors and mechanisms, involved in angiogenesis, has enabled the development of a variety of angiogenesis inhibitors, especially those that target cellular signalling by vascular endothelial growth factor-A (VEGF-A), the most potent angiogenic factor known. These inhibitors have received lots of attention because they effectively inhibit tumour growth in pre-clinical models. However, in clinical trials these same inhibitors showed very poor anti-tumour activity. In this review we discuss this discrepancy, and we show that the tumour microenvironment is crucial to the sensitivity of tumours to anti-angiogenic therapy.

Section snippets

Tumour angiogenesis

Like any tissue in the body, tumours need an ongoing blood supply to grow beyond a minimum size of 2–3 mm3 (Folkman, 1971). Tumours start as avascular masses which can initially thrive on pre-existent vasculature in the microenvironment (Holash et al., 1999b). However, when during the initial stages of growth, proliferating tumour cells become localized beyond the maximum oxygen diffusion distance from neighbouring vessels (approximately 200 μm), hypoxia will arise. This results in attenuated

VEGF-A

The VEGF-A gene is expressed as multiple splice variants, among them isoforms counting 121, 145, 165, and 189 amino acids, respectively, and of which VEGF-A121 is the only freely diffusible isoform (Neufeld et al., 1999; Robinson and Stringer, 2001). This isoform lacks exons 6 and 7, which are contained in VEGF-A189 (both exons) and VEGF-165 (exon 7 only). Other isoforms of 183 and 209 amino acids have also been described, but these are rare and their functions are poorly understood. A VEGF165b

VEGF-A signalling cascades that elicit blood vessel growth

Whereas studies with knock-out mice revealed that both receptors are crucial for embryonic angiogenesis (Fong et al., 1995; Millauer et al., 1996), studies in our lab with VEGFR-selective VEGF-A mutants revealed that during tumour angiogenesis the activity of VEGFR1 is dispensable, whereas VEGFR2 is crucial to the development of a tumour vascular bed (Leenders et al., 2002b; and unpublished data). VEGF-A-mediated signal transduction via VEGFR2 results in a multitude of effects. PLCγ is

Blood vessel maturation

Mature and functional blood vessels are composed of more than tubularly arranged endothelial cells on a basement membrane. Perivascular cells (pericytes in capillaries and smooth muscle cells in larger vessels) are needed to stabilize blood vessels and prevent them from rupture at physiological blood pressure. Cross-talk between vascular endothelial cells and pericytes is critical for proper vessel development and maturation. The regulation of pericyte detachment during angiogenesis and

Inhibitors of angiogenesis

The current detailed knowledge on the process of angiogenesis has enabled the development of numerous inhibitors of the process. Most of these compounds aim at interference with signal transduction by VEGFR2. An important example that recently was put in the spotlights is bevacizumab (Avastin), a neutralizing humanized antibody against VEGF-A, developed by Genentech (Presta et al., 1997). Other inhibitors consist of antibodies against VEGFR2 (IMC-1-11, developed by Imclone Systems (Sweeney et

Angiogenesis inhibitors in clinical setting versus pre-clinical tumour models

These results provided the first indication that anti-angiogenic therapy might not be the miracle therapy that was initially hoped for. It showed that inhibiting angiogenesis may not be sufficient to regress established tumours. Yet, the results from pre-clinical studies with a wide range of angiogenesis inhibitors, all showing very potent anti-tumour activity in subcutaneous tumour models, primed an enormous enthusiasm and resulted in a number of clinical trials. Unfortunately, most of these

Combination therapy

Structural abnormalities of tumour vessels and high interstitial pressure, due to vascular leakage, compromise blood flow and interfere with drug delivery to tumour cells (Padera et al., 2004). It has been shown that anti-VEGF therapy can normalize tumour vessels and, paradoxically, improve blood flow to tumours (Winkler et al., 2004). Therefore, it is predicted that the efficacy of adjuvant chemotherapy is enhanced when given in combination with anti-VEGF therapies. On the other hand, in brain

Vascular targeting

The blood-brain barrier poses a big problem for drug delivery to brain tumours, especially when anti-angiogenic therapy carries a risk of closure of the blood-brain barrier. In general, tumour-specific delivery of therapeutic agents is a challenge. Targeting the existent tumour-associated vasculature, instead of preventing the formation of new vasculature, is now considered a potentially powerful approach for tumour therapy. This approach makes use of vascular targeting agents, antibodies or

Concluding remarks

Whereas anti-angiogenic research has taught us its limitations in a clinical setting, it is simultaneously an inspiration for designing effective anti-tumour therapies. Vascular targeting agents that recognize all tumour vessels is a potential new avenue for anti-tumour therapy in order to induce thrombosis within and occlusion of (co-opted) tumour blood vessels, or aid in specific drug delivery. However, when disruption of the tumour vasculature selects for tumour cells that grow within the

Acknowledgements

The authors were supported by grants from the Dutch Cancer Society (KUN2004-3195, LCLvK, KUN 2000-2302 (WL)), The Netherlands Organisation for Scientific Research (016.056.933, LCLvK) and the Hersenstichting Nederland (12F04(2), WL). The authors thank AstraZeneca for providing ZD6474.

References (63)

  • W. Leenders et al.

    Design of a variant of vascular endothelial growth factor-A (VEGF-A) antagonizing KDR/Flk-1 and Flt-1

    Lab. Invest.

    (2002)
  • R. Mamluk et al.

    Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2 and heparin via its b1b2 domain

    J. Biol. Chem.

    (2002)
  • S. Morikawa et al.

    Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors

    Am. J. Pathol.

    (2002)
  • D. Mukhopadhyay et al.

    Multiple regulatory pathways of vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) expression in tumors

    Semin. Cancer Biol.

    (2004)
  • J. Plouet et al.

    Extracellular cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect

    J. Biol. Chem.

    (1997)
  • F. Winkler et al.

    Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases

    Cancer Cell

    (2004)
  • A. Abramsson et al.

    Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors

    J. Clin. Invest.

    (2003)
  • W. Arap et al.

    Targeting the prostate for destruction through a vascular address

    Proc. Natl. Acad. Sci. USA

    (2002)
  • D.O. Bates et al.

    VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma

    Cancer Res.

    (2002)
  • F.M. Belgore et al.

    sFlt-1, a potential antagonist for exogenous VEGF

    Circulation

    (2000)
  • G. Bergers et al.

    Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

    Nat. Cell Biol.

    (2000)
  • G. Bergers et al.

    Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors

    J. Clin. Invest.

    (2003)
  • C. Blancher et al.

    Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3′-kinase/Akt signaling pathway

    Cancer Res.

    (2001)
  • A. Dienst et al.

    Specific occlusion of murine and human tumor vasculature by VCAM-1-targeted recombinant fusion proteins

    J. Natl. Cancer Inst.

    (2005)
  • H.F. Dvorak et al.

    Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis

    Am. J. Pathol.

    (1995)
  • J. Folkman

    Tumor angiogenesis: therapeutic implications

    N. Engl. J. Med.

    (1971)
  • G.H. Fong et al.

    Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium

    Nature

    (1995)
  • T.A. Fong et al.

    SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types

    Cancer Res.

    (1999)
  • D. Hanahan

    Signaling vascular morphogenesis and maintenance

    Science

    (1997)
  • A.L. Harris

    von Hippel-Lindau syndrome: target for anti-vascular endothelial growth factor (VEGF) receptor therapy

    Oncologist

    (2000)
  • A.L. Harris

    Hypoxia – a key regulatory factor in tumour growth

    Nat. Rev. Cancer

    (2002)
  • Cited by (28)

    • Divergent roles of Plexin D1 in cancer

      2019, Biochimica et Biophysica Acta - Reviews on Cancer
      Citation Excerpt :

      Thus, these tumors are relatively less susceptible to antiangiogenic therapies. Furthermore, antiangiogenic therapies could promote the tumor microenvironment to adapt or continue tumor growth, or both, by co-option of an existing capillary bed [61–63]. Therefore, we think that markers that specifically differentiate tumor vasculature from normal vasculature must be found for effective vascular targeting.

    • Fixed-interval versus OCT-guided variable dosing of intravitreal bevacizumab in the management of neovascular age-related macular degeneration: A 12-month randomized prospective study

      2012, American Journal of Ophthalmology
      Citation Excerpt :

      Since CATT considered sub-RPE fluid as “fluid on OCT,” it is not clear how many eyes had only sub-RPE fluid with no subretinal or intraretinal fluid. It seems that partial responders can appear at the onset of treatment, in which case this may be attributable to some intrinsic resistance of the CNV to anti-VEGF therapy.20–23 Partial responders in our study tended to have greater baseline CRT in the form of large intraretinal cysts, indicating chronic CNV with mature VEGF-independent vessels.

    • Intravitreal Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: The Second Year of a Prospective Study

      2009, American Journal of Ophthalmology
      Citation Excerpt :

      Perhaps CNV in partial responders were somewhat resistant to anti-VEGF therapy, which is why they did not show the same reduction in lesion size as complete responders. Possible mechanisms for resistance to anti-VEGF therapy include a change to alternative pathways of angiogenesis that do not rely on VEGF-A or a change in the CNV to more mature VEGF-independent vessels.19–22 There is evidence that the basement membrane of endothelial cells persists after endothelial cell death, which acts as a scaffold for rapid regrowth of vessels during gaps in treatment.21

    • Pilot study of anti-angiogenic vaccine using fixed whole endothelium in patients with progressive malignancy after failure of conventional therapy

      2008, European Journal of Cancer
      Citation Excerpt :

      In contrast, with the three responding malignant brain tumour patients, neither tumour response nor other improvement of the clinical outcome could be observed in the other patients. The reason for the discrepancy between the immune response to vaccination and tumour response in these patients is not yet known, but we can speculate that it might be caused by either strong immunosuppression in the tumour microenvironment ,30–32 or by possible adaptation of some tumour cells to the consequences of anti-angiogenic therapy, as was recently described by others.33 Discrepancy between the immunological and anti-tumour effects was also reported by many other authors clinically investigating cancer vaccines,24,34 and therefore we suppose that there is a strong need for studies searching for factors that make cancer patients responsive or resistant to active immunotherapy.

    View all citing articles on Scopus
    View full text