Even if a solid tumor possesses all of the genetic aberrations that are required for malignant transformation, it cannot enlarge beyond 1 to 2 mm in diameter unless it has the capacity to induce angiogenesis. Like normal tissues, tumors require delivery of oxygen and nutrients and removal of waste products; presumably the 1to 2-mm zone represents the maximal distance across which oxygen, nutrients, and waste can diffuse to and from blood vessels. Growing cancers stimulate neoangiogenesis, during which vessels sprout from previously existing capillaries. Neovascularization has a dual effect on tumor growth: perfusion supplies needed nutrients and oxygen, and newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors, such as insulin-like growth factors (IGFs) and PDGF. While the resulting tumor vasculature is effective at delivering nutrients and removing wastes, it is not entirely normal; the vessels are leaky and dilated, and have a haphazard pattern of connection, features that can be appreciated on angiograms. By permitting tumor cells access to these abnormal vessels, angiogenesis also contributes to metastasis. Angiogenesis is thus an essential facet of malignancy.
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How do growing tumors develop a blood supply? The current paradigm is that angiogenesis is controlled by a balance between angiogenesis promoters and inhibitors; in angiogenic tumors this balance is skewed in favor of promoters. Early in their development, most human tumors do not induce angiogenesis. Starved of nutrients, these tumors remain small or in situ, possibly for years, until an angiogenic switch terminates this stage of vascular quiescence. The molecular basis of the angiogenic switch involves increased production of angiogenic factors and/ or loss of angiogenic inhibitors. These factors may be produced by the tumor cells themselves or by inflammatory cells (e.g., macrophages) or resident stromal cells (e.g., tumor-associated fibroblasts). Proteases, either elaborated by the tumor cells or by stromal cells in response to the tumor, are also involved in regulating the balance between angiogenic and anti-angiogenic factors. Many proteases can release proangiogenic basic fibroblast growth factors (bFGF) that are stored in the ECM; conversely, the angiogenesis inhibitors angiostatin and endostatin are produced by proteolytic cleavage of plasminogen and collagen, respectively.
The local balance of angiogenic and anti-angiogenic factors is influenced by several factors:
Relative lack of oxygen due to hypoxia stabilizes HIF1α, an oxygen-sensitive transcription factor mentioned earlier, which then activates the transcription of proangiogenic cytokines such as VEGF. These factors create an angiogenic gradient that stimulates the proliferation of endothelial cells and guides the growth of new vessels toward the tumor.
Mutations involving tumor suppressors and oncogenes in cancers also tilt the balance in favor of angiogenesis. For example, p53 stimulates expression of antiangiogenic molecules, such as thrombospondin-1, and represses expression of proangiogenic molecules, such as VEGF. Thus, loss of p53 in tumor cells provides a more permissive environment for angiogenesis.
The transcription of VEGF also is influenced by signals from the RAS-MAP kinase pathway, and gain-offunction mutations in RAS or MYC upregulate the production of VEGF. Notably, elevated levels of VEGF can be detected in the serum and urine of a significant fraction of cancer patients.