REVIEWTumours can adapt to anti-angiogenic therapy depending on the stromal context: Lessons from endothelial cell biology
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is dispensable, whereas VEGFR2 is crucial to the development of a tumour vascular bed (Leenders et al., 2002b; and unpublished data).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.
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