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Chapter 15 Vascular Growth in Health and Disease 159

Vasculogenic mimicry and endothelial differentiation of circulating blood; (7) flow perturbations and stasis; (8) indirect external
cancer stem cells are processes whereby nonendothelial cells adopt effects (e.g., indwelling catheters or administration of chemotherapy);
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endothelial-like phenotypes and line vascular channels. Vasculo- and (9) shedding of procoagulant, anticoagulant, or bioactive extracel-
9
genic mimicry occurs during normal placentation and in tumors, lular vesicles (microparticles), and soluble factors into blood. A better
such as melanoma, or mouse teratoma, and results in positioning of understanding of blood vessel–directed therapies and their capacity to
parenchymal cells (e.g., cancer cells) within the layer of endothelium modulate or exacerbate some of these events represents an emerging
or around blood-containing channels. Such cells may adopt some of challenge in hematology (see Chapter 149).
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the morphologic and antigenic attributes of proper endothelium.
In human glioblastoma, cancer stem cells were reported to undergo
a more profound endothelial or pericytic transdifferentiation, Therapeutic Inhibition and Stimulation of Angiogenesis
including the expression of corresponding lineage markers and some
contribution to the vascular wall. The scope and functional role of Excessive, protracted, or aberrant activation of vascular growth may
these processes remain unclear and controversial. 22,23,30 represent a correlative and/or a causative factor in several pathologies
1
Vascular cooption occurs when cancer cells actively adopt a (often referred to collectively as angiogenesis-related diseases). These
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growth and invasion pattern around preexisting blood vessels. This include chronic inflammation, certain forms of blindness, metabolic
1
process is observed in highly vascular organs, such as the lungs and diseases, atherosclerosis, and cancer. In some of these disorders
brain, resulting in a nonangiogenic form of tumor neovascularization. (e.g., macular degeneration, certain malignancies) antiangiogenic
Coopted vessels may undergo secondary structural alterations, which therapies, especially inhibitors of the VEGF pathway (Table 15.2),
may result in their remodeling, formation of occlusive thrombi, and already represent the standard of care. Numerous clinical trials are
regression that can lead to ischemia. 32 ongoing to explore other agents and indications. 2
Conversely, pathology may also arise due to insufficient angio-
genesis, arteriogenesis, or regulatory/repopulating activity of bone
MECHANISMS TRIGGERING ANGIOGENESIS marrow–derived cells, as is the case in the myocardium postinfarc-
tion, in limb ischemia, and in other hypovascular states, especially
Vascular growth may occur in response to hypoxia, metabolic stress, in the elderly. In these disorders, stimulation of vascular growth may
expression of growth factors, emission of inflammatory mediators, or provide a therapeutic benefit, notably through delivery of angiogenic
after activation of the coagulation system or malignant transforma- cells (EPCs), growth factors (VEGF, FGF), or gene therapy vectors
tion. These mechanisms are interdependent and often converge upon into the affected site. Several such (proangiogenic) strategies are
2
the regulation of the VEGF gene, but may also involve additional under investigation. 2
(or alternative) complex networks of molecular effectors. Although
angiogenic responses may be morphologically similar, they exhibit
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context-dependent degrees of regulatory and functional redundancy. Tumor Angiogenesis and Antiangiogenesis
The most studied in this regard is the regulation of VEGF, which is
transcriptionally controlled by dimeric hypoxia-inducible factors 1 The disorganized signaling cues during tumor angiogenesis may
and 2 (HIFs). Normally, the HIF alpha subunit (HIF-1α) is consti- produce highly abnormal, leaky, tortuous, prothrombotic, and poorly
tutively degraded by a pathway involving oxygen-dependent prolyl perfused vasculature (vessel “abnormalization”), which may contrib-
2
and aspargyl hydroxylases, von Hippel–Lindau (VHL) ubiquitin ute to aberrant hemostasis. Antiangiogenic agents may cause further
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ligase, and the proteasome. Hypoxia blocks this process, resulting perturbations by selective destruction of tumor-associated endothelial
1
in elevated HIF activity and VEGF production by parenchymal, cells or by inhibition of their stimulatory circuitry. Several classes of
stromal, and inflammatory cells. Several other mechanisms of pro- antiangiogenic compounds have been evaluated to date, including
angiogenic, hypoxic responses have also been described (e.g., NFκB, derivatives of natural angiogenesis inhibitors (e.g., endostatin or
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EGR1). Likewise, the exposure of cells to growth factors (EGF, FGF, tumstatin), inhibitors of proangiogenic signaling pathways (antibod-
HGF) and inflammatory cytokines (IL-6) may upregulate VEGF, and ies, small-molecule agents), and agents that block proangiogenic
2
some of these effectors may also directly stimulate endothelial cells. inflammatory pathways (e.g., thalidomide analogs). Anticancer drugs
Activation of oncogenes (e.g., ras) and loss of tumor suppressors may also be administered in low but frequent doses (metronomic
(VHL) lead to upregulation of VEGF and may also affect other chemotherapy) to target endothelial immune and regulatory cells
angiogenic growth factors in cancer cells, even under conditions preferentially (Table 15.2). 1,4,34
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of normoxia. Oncogenic transformation also shuts down some of Bevacizumab (Avastin), a humanized monoclonal anti-VEGF
the angiogenic inhibitors, contributes to coagulopathy (through antibody, was the first antiangiogenic agent to be approved (in 2004)
upregulation of tissue factor and thrombin receptors), and enhances for cancer treatment, and the drug is now used to treat colorectal,
proangiogenic cellular vesiculation (biogenesis and emission of extra- lung, kidney, and recurrent brain tumors. 2,34 Several tyrosine kinase
cellular vesicles loaded with vascular mediators). Indeed, oncogenic inhibitors (TKIs) with anti-VEGFR or multikinase activity (sunitinib,
pathways often mimic, distort, or exacerbate the effects of hypoxia, sorafenib, pazopanib) are also in common use, as are inhibitors of
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inflammation, or microenvironmental stress. 9 oncogenic pathways that drive the production of VEGF. The latter
include inhibitors of epidermal growth factor receptor (EGFR) and
THERAPEUTIC IMPLICATIONS OF ANGIOGENESIS IN HER2 (cetuximab and transtuzumab, respectively), and other onco-
9
gene inhibitors. These VEGF/VEGFR antagonists are mostly used
HEMATOLOGY in combination with chemotherapy, which suggests that they serve
2,4
as chemosensitizers or mediators of vascular normalization. Studies
Vascular events associated with cancer, hemangioma, or vascular mal- are underway to develop drugs that specifically target pathologic
formations have the potential to trigger hematologic consequences, angiogenesis (e.g., blockers of PlFG), or established tumor blood
either spontaneously or during therapeutic angiogenesis or antian- vessels (e.g., vascular disrupting agents [VDAs]). 4
giogenesis. These linkages are poorly understood, but often include The overall objectives of antiangiogenic therapy in cancer are at
one or more of the following factors: (1) endothelial cell activation least threefold: (1) to induce tumor hypovascularity, thereby causing
associated with intravascular upregulation of procoagulant tissue factor, hypoxic damage to cancer cells; (2) to deprive cancer (stem) cells of
adhesion molecules, and other mediators; (2) disruption of vascular the paracrine growth stimulation and support rendered by angiogenic
wall continuity; (3) recruitment of inflammatory cells; (4) enhanced endothelial cells (anti-angiocrine effect) 9,10 ; and (3) at lower doses,
vascular permeability resulting in the extravasation and activation to induce vessel “normalization,” resulting in the improved tumor
of circulating coagulation factors; (5) platelet activation; (6) contact perfusion associated with increased sensitivity to chemotherapy and
between procoagulant cell surfaces (e.g., metastatic cancer cells) and radiation. 2