Tumor Angiogenesis

For tumors to grow and metastasize, they must secure an expanded blood supply by taking over existing blood vessels and promoting angiogenesis, i.e., the sprouting of new blood vessels from existing vessels.2,3 Except in wound healing or in the female reproductive tissues, only 0.01% of normal endothelial cells are involved in angiogenesis.24,25 In contrast, angiogenesis is both essential for tumor growth beyond 1-2 mm size and is highly specific for neoplasia.26,27 Indeed, a highly significant statistical correlation has been shown between microvessel density and clinical stage, histopathology stage, and disease-specific survival.28,29

The induction of angiogenesis—the angiogenic switch—is an important early event in tumor progression and propagation.30,31 The switch to an angiogenic phenotype is tightly regulated by a balance between endogenous anti-angiogenic32-34 and pro-angiogenic35,36 molecules. Studies in transgenic mice suggest that the switch occurs early in tumor development as a response to local stresses such as hypoxia and low pH.37,38 Hypoxia increases levels of hypoxia-inducible factors (HIF) in tumor cells and in surrounding stromal cells. HIF then promotes the transcription of genes for VEGF and several other pro-angiogenic factors.38,39

During normal angiogenesis such as during reproduction, development, and wound healing, new vessels rapidly mature and stabilize.2,4 By contrast, tumor blood vessels often fail to mature and are characterized by structures that are leaky, tortuous, and irregular in shape.40 The high levels of growth factors within a tumor support a continual state of vascular growth, regression, and regrowth. Many lack functional pericytes and are exceptionally permeable because of the presence of fenestrae, transcellular holes, and a lack of a complete basement membrane.40-44 These ultrastructural changes lead to substantial leaks of tissue fluids into the tumor microenvironment and increased interstitial fluid pressure (IFP). Tumor IFP begins to increase as soon as the host vessels become leaky in response to angiogenic molecules such as VEGF. The importance of this transvascular flux is compounded by the impaired lymphatic system characteristic of cancer tissues. Hence, hyperpermeable angiogenic tumor vessels allow preferential extravasation of circulating macromolecules, and once in the interstitium, they are retained there by a lack of intratumoral lymphatic drainage. This enhanced permeability and retention (EPR) effect22 results in intratumoral penetration and retention of macromolecules. It is one important factor explaining the delivery of macromolecular anti-cancer agents to the tumor microenvironment.

In addition to the angiogenic factors that enhance the passive delivery of macromolecules via the EPR effect, angiogenic tumor vessels also display a variety of markers (Table 9.1) that can be the focus of active molecular targeting. These markers provide several targeting advantages relative to direct targeting of tumor cell.45,46 First, endothelial cells are immediately accessible to intravenously delivered ligands. In contrast, the increased interstitial pressure associated with the tumor microenvironment can limit the access of macromolecular agents to tumor-associated targets. Second, endothelial cells are derived from normal, genetically stable host vessels. Hence, they present a target with characteristics that do not fluctuate unlike the genomic instability of most cancer tissues. Third, because large numbers of tumor cells rely on each blood vessel, antitumor effects will be amplified by vascular bed injury. Endothelial cell damage leads to vascular coagulation and downstream hypoxic death of approximately 100-fold more cancer cells. Fourth, endothelial targets are common to all solid tumors, whereas most other tumor cell associated markers are cancer phenotype specific.

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