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Angiogenesis in brain tumours

Key Points

  • The growth of both primary and metastatic brain tumours depends on their ability to recruit blood vessels by co-opting the host vessels (co-option), forming new vessels by sprouting (angiogenesis) and/or by recruiting bone-marrow-derived cells (vasculogenesis).

  • Of primary malignant brain tumours, glioblastoma is the most common and is uniformly fatal.

  • Malignant glioma vessels are highly abnormal, both structurally and functionally. This abnormality contributes to high interstitial fluid pressure, hypoxia and brain oedema.

  • Vascular endothelial growth factor (VEGF) has a major role in neovascularization, but other molecules are also involved and might be important therapeutic targets.

  • In preclinical models of brain tumours, anti-angiogenesis therapy can transiently prune and normalize the tumour vasculature and improve the outcome of radiation and/or chemotherapy given during the normalization window. This window has also been demonstrated in patients with recurrent glioblastoma using new MRI techniques that allow structural and functional evaluation of blood vessels during tumour growth and treatment.

  • Anti-VEGF therapy has so far shown promising results in small clinical trials, with increased response rates and alleviation of oedema. Larger trials of anti-VEGF agents and other therapeutics (for example, rapamycin or blockers of αvβ3 integrin) are ongoing or being planned.

  • A number of randomized phase II and III trials are examining the effect of anti-angiogenic therapy in combination with radiation and chemotherapy in patients with brain tumours. Imaging and blood biomarkers may be helpful in evaluating tumour response to, and toxicity from, these agents. It should be noted that anti-VEGF agents have rare but serious side effects on the CNS, such as intracerebral haemorrhage.

Abstract

Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumours stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma — the most frequent primary brain tumour — and can transiently normalize tumour vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.

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Figure 1: Structural and functional differences between normal and tumour vasculature.
Figure 2: Schematic representation of the mechanisms of vessel formation and the associated molecular components.
Figure 3: Mechanisms of anti-angiogenic therapy.
Figure 4: Molecules targeted by angiogenesis inhibitors currently in clinical trials.

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Acknowledgements

We would like to thank the members of the Steele Laboratory, especially, Y. Boucher, D. Fukumura, I. Garkavstev, L. Munn, L. Xu and F. Yuan, who contributed to studies summarized in this review article. We also thank P. Carmeliet, W. Cavenee, S.-S. Chae, I. J. Fidler, D. Fukumura, M. Kieran, K. Plate, G. Plowman, M. Tessier-Lavigne and P. Wen for helpful comments, and L.L. Munn for figure 2. R.K.J.'s research on tumour biology has been supported by the US National Cancer Institute since 1980; D.G.D. is an American Association for Cancer Research grantee and E.d.T. a Claflin Fellow.

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Supplementary information

Supplementary information S1 (movie)

Angiography of glioma vessels. Multiphoton laser–scanning intravital microscopy of a U87 glioma xenografted in the brain of an immunodeficient mouse (cancer cells are labelled with green fluorescence protein, shown in green). Glioma vasculature is imaged after rhodamine–dextran M.W. 2,000,000 injection (shown in red). (AVI 3530 kb)

Supplementary information S2 (movie)

Angiography in normal brain vessels. Multiphoton laser–scanning intravital microscopy of brain vessels in a mouse through a cranial window. Vasculature is imaged after rhodamine–dextran M.W/ 2,000,000 injection (shown in red). (AVI 3530 kb)

Supplementary information S3 (movie)

Three–dimensional reconstruction of white–matter tracks using MRI in a recurrent glioblastoma patient. Left, image of the brain prior to AZD2171 (cediranib) treat–ment. Right, image of the brain 28 days after daily AZD2171 therapy. Note the re-emergence of the white-matter tracks following tumour response to AZD2171 therapy. Reproduced, with permission, from Ref. 13 © (2007) Elsevier Science. (MP4 3289 kb)

Supplementary information S4 (Table)

Angiogenesis activators and inhibitors (updated from 37) (PDF 166 kb)

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FURTHER INFORMATION

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Glossary

Glioblastoma

Also known as glioblastoma multiforme or grade IV astrocytoma, is the most prevalent and aggressive malignant primary brain tumour. Other malignant gliomas include anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma and anaplastic ependymoma.

Vasogenic oedema

The specific form of oedema in which increased extracellular fluid accumulates in the brain parenchyma as a result of breakdown of the blood–brain barrier.

Angiogenesis

The process of new blood vessel formation by endothelial cells from pre-existing adjacent vessels.

Glioma

Primary CNS tumour that arises from glial cells.

Permselectivity

The property of the vasculature that allows only molecules of a certain size to enter and pass through the capillaries' endothelium.

Pia

(Pia mater). The fine vascular membrane that closely envelops the brain and spinal cord under the arachnoid and the dura mater.

Blood–brain barrier

An anatomical and physiological barrier that alters the permeability of brain capillaries, so that some substances, such as certain drugs, are prevented from entering brain tissue, whereas other substances are allowed to enter freely.

Diffusion tensor MRI

Diffusion tensor imaging of brain structures measures diffusion properties through the self-motion of water molecules.

Aptamers

Oligonucleic acids or peptide molecules that bind a specific target molecule.

Vascular Co-option

Tumour growth along pre-existing blood vessels.

Vasculogenesis

The formation of a de novo vascular system from endothelial precursor cells.

Intussusception

A mechanism of tumour vessel remodelling and expansion by the insertion of interstitial tissue columns into the lumen of pre-existing vessels.

Pseudopalisading cells

Rows of viable cells surrounding areas of necrosis, which are a histopathological characteristic of glioblastoma.

Tip cell

A specialized endothelial cell that leads the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth during angiogenesis.

Orthotopic brain tumour model

A brain tumour model in which the tumour is grafted into the location that corresponds to the normal pattern of human primary or metastatic cancer.

Biomarkers

A specific physical or chemical entity used to measure or indicate the effects or progress of a disease or condition.

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Jain, R., di Tomaso, E., Duda, D. et al. Angiogenesis in brain tumours. Nat Rev Neurosci 8, 610–622 (2007). https://doi.org/10.1038/nrn2175

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