Tumor growth and progression are dependent on blood vessel formation, providing vital oxygen and nutrients within the diffusion limit for oxygen (100 to 200 pm). VEGF is the most potent vascular growth factor known to date and is most closely correlated with spatial and temporal events of blood vessel growth. Besides promoting endothelial cell growth, VEGF also stimulates endothelial cell migration because of its ability to form chemotactic gradients and stimulate secretion of proteases. Specifically, the formation of primary embryonic vasculature begins with the differentiation of endothelial precursors into endothelial cells (vasculogenesis). This is followed by angiogenesis, characterized by the expansion of this primitive network by four divergent morphological pathways: (1) muscular artery/vein formation; (2) vascular bridging; (3) intussusceptive microvascular growth; and (4) sprouting angiogensis vessels (insertion of interstitial tissue columns into the lumen of preexisting vessels). The focal dissolution of endothelial basement membrane and the breakdown of the
ECM are required to release endothelial cells from anchorage, thereby allowing them to migrate into surrounding tissues and proliferate into new blood vessels. Enzymes that catalyze these events include proteolytic enzymes, secreted by activated endothelial cells and tumor cells such as plasminogen activators (e.g., the urokinase-type and tissue-type plasminogen activators, uPA and tPA)134'135 and MMPs (predominantly the family members MMP-2 (gelatinase A) and MMP-9 (gelatinase B)).136 Strings of new endothelial cells then organize into vascular tubes, dependent on the interaction between cell-associated surface proteins (hybrid i 'xn i •jq oligosaccharides, galectin-2, PECAM-1, and VE-cadherin) and the ECM. - Finally, newly formed vessels are stabilized through the recruitment of smooth muscle cells and pericytes mediated via binding of angiopoietin-1 (Ang-1) to the Tie-2 receptor.
In addition to sprouting and cooption140 of neighboring preexisting vessels, tumor-derived angiogenic factors like VEGF promote formation of the endothelial lining of tumor vessels (vasculogenesis) by recruitment of highly proliferative circulating endothelial precursors (CEPs, angioblasts) from the bone marrow, HSCs, progenitor cells, monocytes, and macrophages.141 Moreover, tumor cells (i.e., melanoma cells) can act as endothelial cells and form functional avascular blood conduits or mosaic blood vessels, which are lined partially by tumor cells and vessel walls.142-146
CEPs, but not circulating endothelial cells (CECs) sloughed from the vessel wall, are highly proliferative and contribute to tumor neoangiogenesis.141'147 HSCs and CEPs likely originate from a common precursor, the hemangioblast. Typically, CEPs express VEGFR-2, c-KIT, CD133, and CD146,77-79 whereas HSCs express VEGFR-1, Sca-1, and c-KIT; the lineage-specific differentiation of these HSCs into erythroid, myeloid, megakaryocytic, and lymphoid cells is dependent on the availability of specific cytokines including IL-3, G-CSF, GM-CSF, and TPO. Subsequently, hematopoietic progenitors and terminally differentiated precursor cells produce and secrete factors including VEGF, FGFs, brain-derived nerve growth factor (BDNF), and angiopoietin; together with ECM proteins like fibronectin and collagen, these factors promote differentiation of CEPs, thereby contributing to new vessel formation. In addition, direct cellular contact with stromal cells also regulates the expansion of undifferentiated CEPs.141 Importantly, VEGFR-1 expressing hematopoietic cells and CEPs colocalize to cooperate in the formation of functional tumor vessels.148149
Angiogenesis is tightly regulated by proangiogenic and antiangiogenic molecules. In tumorigenesis this balance is derailed,150 thereby triggering tumor growth, invasion, and metastasis.151 Specifically, a rapid phase of tumor growth occurs when the tumor switches to its angiogenic phenotype. This process has best been studied in the transgenic mouse model of multistage pancreatic islet cell carcinogenesis (Rip1-Tag2), where clonal expansion of a subset of hyperplastic cells results in tumor progression.152,153 Pro- and antiangiogenic molecules arise from cancer cells, stromal cells, endothelial cells, the ECM, and blood.154 Importantly, the relative contribution of these molecules is dependent on the tumor type and site, and their expression changes with tumor growth, regression, and relapse. The "angiogenic switch''155 is triggered by oncogene-mediated tumor expression of angiogenic proteins including VEGF, FGF, PDGF, EGF, lysophosphatic acid (LPA), and angiopoietin; as well as by metabolic stress, mechanical stress, genetic mutations, and the immune response.150,151,156-160 In contrast, inhibitors of angiogenesis including angiostatin, endostatin, interferons, platelet factor-4, thrombospondin, tissue inhibitors of metalloproteinases-1 through metalloproteinases-3, pigment epithelium-derived factor, 2-methoxy-estradiol, vasostatin, and canstatin decrease this angiogenic stimulus.161-164 The imbalance of angiogenic regulators (i.e., VEGF) accounts for an abnormal structure of tumor vessels, which in turn results in chaotic, variable blood flow and vessel leakiness, thereby lowering drug delivery and selecting for more malignant tumor cells.165-168
In the normal adult, only 0.01% of endothelial cells undergo division,150 whereas up to 25% of endothelial cells divide in tumor vessels.169 In addition, recent studies indicate that the gene expression pattern of normal endothelial cells differs from endothelial cells in tumors170: that is, 79 differentially expressed gene products were found in endothelial cells from colon cancer compared with normal endothelial cells.171 In addition, a wider array of angiogenic molecules can be produced as tumor cells grow; therefore, if one proapoptotic molecule is blocked, tumors may utilize another molecule. A cocktail of antiangiogenic therapies may therefore be required to effectively prevent angiogenesis.150
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