Biologia Tumoral

Review

Tumor Angiogenesis: Cause or Consequence of Cancer?
Ksenya Shchors and Gerard Evan
Cancer Research Institute and Department of Cellular and Molecular Pharmacology, UCSF Comprehensive Cancer Center, San Francisco, California

Abstract
Both tumors and normal tissues need a blood supply for oxygen, nutrients, and waste removal. However, whereas normal vasculature is hierarchicallyassembled into efficient networks of arteries, capillaries, and veins, the blood vessels of tumors are a mess—chaotic, leaky, inefficient, and barely making do. Why the difference? Do tumor vessels lack the signals to mature or, instead, is their maturation actively suppressed? What triggers and maintains tumor vasculature? In a recent study using a switchable Myc-driven mouse tumor model, weaddressed these fundamental questions. We identified the inflammatory cytokine interleukin-1B as an essential initiating trigger of vascular endothelial growth factor–dependent angiogenesis. Here, we consider how kinetic studies using regulatable forms of Myc or other oncogenes can shed new light on the way tumors initiate and maintain their aberrant blood supplies. [Cancer Res 2007;67(15):7059–61]Introduction
Macroscopic expansion of tissues, both normal and neoplastic, requires the concomitant growth, infiltration, and elaboration of a supporting vasculature network to maintain oxygenation and provide nutrients. As normal tissues become established, their incipient vasculature matures into a highly structured, hierarchical network of arteries, capillaries, and veins that maintainsefficient tissue perfusion. By contrast, tumor vasculature typically lacks hierarchy and retains the disordered, tortuous, and leaky characteristics of incipient vasculature. However, the relationship between normal and tumor vasculature remains uncertain. One possibility is that the maturation of vasculature in normal tissues is actively driven by signals that appear when tissues mature and stabilize,although the nature and source of such signals are unexplained. Alternatively, vascular maturation may be a default program that is actively suppressed by the regenerative programs that build normal tissues during ontogeny and repair, programs that are constitutively active in tumors. It is also possible that tumor vasculature is an aberrant monster assembled piecemeal from sporadic mutations inangiogenic pathways and with no direct mechanistic counterpart in normal tissue biology. The key to understanding tumor angiogenesis is to identify the mechanisms that cause it. However, in this regard there is no clear consensus. One plausible candidate mechanism is hypoxia, a potent trigger of neovascularization in normal tissues that is an expected consequence of the relentless and untowardexpansion of tumor cells (1). Hypoxia triggers a wide variety of adaptive responses that are coordinated transcriptionally by the hypoxiainducible factors HIF1, HIF2, and HIF3, heterodimeric bHLH-PAS

transcription factors (2, 3). Stability of the obligate HIF-a subunits is regulated by the pVHL E3-ubiquitin ligase according to oxygen availability (4). The HIFs have many target genes that governdiverse functions such as oxygen transport, glycolysis, glucose uptake, metabolism, inflammation, and angiogenesis. Prominent examples of the latter are vascular endothelial growth factor-A (VEGFA), a potent inducer of endothelial cell proliferation and remodeling, placental growth factor (PIGF), and basic fibroblast growth factor (bFGF; refs. 5–7). In other instances, however, evidence suggests thatearly-stage tumors are not competent for angiogenesis and acquire the capacity only sporadically, a transition dubbed ‘‘the angiogenic switch’’ that presumably involves accumulation of additional angiogenic mutations. More recently, evidence has accumulated that certain types of oncogenic mutation can directly instruct angiogenesis as well as stromal modeling in general. Indeed, Ras and Myc,...