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Anticancer strategies involving the vasculature

Abstract

The growth and metastasis of solid tumors critically depends on their ability to develop their own blood supply, a process known as tumor angiogenesis. Over the past decade much work has been performed to understand this process, and modifying this process provides a key point of therapeutic intervention in the fight against cancer. This Review explores the development of anti-VEGF-based antiangiogenic therapies, of which there are currently three licensed for clinical use worldwide. Although originally anticipated to inhibit the growth of tumor vessels, the induction of vascular normalization caused by these approved agents has provided a novel means of effective delivery of known chemotherapeutic agents. The development of small molecules that target VEGF receptors has resulted in the generation of inhibitors with not only vascular activity but antitumor activity in certain cancers. This Review will address the current status of vascular-disrupting strategies, such as therapies designed to induce tumor collapse by selectively destroying existing tumor vessels. These therapies can be broadly divided into small-molecular-weight vascular-disrupting agents and ligand-directed approaches. We discuss the current status of development, drug mechanisms of actions, combination with conventional chemotherapy and radiotherapy, and potential future targets for therapeutic intervention.

Key Points

  • Blockade of VEGF signaling results in vascular normalization, and the use of bevacizumab, an anti-VEGF agent, is effective only when combined with chemotherapy

  • Small-molecular-weight VEGF receptor inhibitors such as sorafenib and sunitinib inhibit a range of receptor tyrosine kinases

  • Sorafenib and sunitinib cause vascular normalization and additionally target stromal cells and certain tumor-cell types; they are currently being used as monotherapies

  • Microtubule-disrupting agents selectively destroy the tumor vasculature, leading to hemorrhagic necrosis of the tumor

  • The distinctive tumor microenvironment results in the differential expression of cell-surface and extracellular matrix molecules; these distinctive expression profiles can be used for imaging and targeting therapeutics specifically to the tumor

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Figure 1: The development of the tumor vasculature, and the effect of therapies that target it.
Figure 2: Structure and alternative splicing of fibronectin and tenascin-C.

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Heath, V., Bicknell, R. Anticancer strategies involving the vasculature. Nat Rev Clin Oncol 6, 395–404 (2009). https://doi.org/10.1038/nrclinonc.2009.52

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