The Tumor Microenvironment Blood Vessel Formation

Microenvironmental vascular status also exerts a profound impact on the ability of the primary tumor to grow and metastasize. Expression of blood vessel growth-promoting molecules is generally a poor prognostic factor associated with cancer54,55 and specifically with breast cancer,56-58 cancer of the central nervous system,59-61 gynecologic cancers,62-64 gastrointestinal cancer,65-67 and prostate cancer.68,69 Proclivity for metastasis correlates with the degree of tumor-associated blood vessel formation.70-78 Such tumor-associated blood vessel formation promotes metastasis in two ways: blood vessels function to transport growth-stimulating nutrients to the burgeoning primary tumor and as a conduit by which metastasizing cells travel toward their secondary tumor destinations.

The formation of blood vessels is regulated by the cumulative effects of a variety of molecules; the roles of these mol ecules typically are defined during the period of embryonic blood vessel formation and later reprised in the context of pathologic tumor-associated vessel genesis. During embryonic development, blood vessels arise via a number of distinct mechanisms including vasculogenesis, angiogenesis, and vessel intussusception.

Vasculogenesis is the de novo construction of the vascu-lature. During this process, embryonal mesoderm is stimulated to differentiate into precursor hemangioblasts and then endothelial cells. Fibroblast growth factors (FGFs)79 and vascular endothelial growth factor (VEGF)80 provide key differentiation signals initiating the mesodermal to endothelial transition. VEGF, together with other molecular factors, cue endothelial cells to proliferate further and assemble into linear aggregates that subsequently reorganize to form a tubular vascular reticulum.81-83 Additional molecules play more specialized roles; for example, the integrins induce lumen formation,84 and angiopoietin 1 acts to promote the entrenchment and stabilization of the nascent vasculature by modulating endothelial cell adherence to nearby tissue and extracellular components.85-87

Following incipient vasculogenic establishment of the original blood vessel system, the vasculature may continue to expand via ancillary mechanisms including angiogenesis or vessel intussusception. Angiogenesis entails proliferation of the previously established endothelial cell population, permitting collateral expansion from the nascent vascular reticulum. VEGF is a primary molecular promoter of angiogenesis. However, for efficient collateral expansion to occur, angiopoietin 1-mediated fortification of the vasculature must be abrogated. Such reversal is mediated through the antagonistic actions of angiopoietin 2, which inhibits the actions of angiopoietin 1 at the Tie 2 receptor, permitting the disruption of endothelial cell-extracellular matrix stabilizing interactions.88 An additional mechanism that may allow expansion of the extant blood vessel system is the process of intussusception in which blood vessels are split by VEGF-stimulated growth and interposition of an endothelial tissue barrier across the lumen of the vessel.89-92

The pathologic formation of blood vessels during tumor growth and metastasis reactivates many of the mechanisms operating during embryonic blood vessel formation. Reminiscent of embryonic vasculogenesis, endothelial precursor hemangioblastic cells are activated from the bone marrow. These cells incorporate into the newly forming tumor vascu-lature,93-96 frequently comprising more than one-third of the blood vessels.97 Both FGF and VEGF have been demonstrated to function as molecular mediators of tumor-associated vas-culogenesis.98-102 Angiogenic sprouting, as well, contributes to pathologic blood vessel formation, and this mechanism is also modulated by FGFs and VEGF103 in addition to angiopoietin

2.104

Tumors may also achieve vascularization via specialized mechanisms. Tumors may "co-opt" existing blood vessels by associating with previously established vasculature and, in so doing, satisfying their own metabolic needs by allowing themselves access to the nutrients and oxygen transported through these vessels. Intriguingly, in a mechanism referred to as "vascular mimicry," tumor cells may functionally imitate the endothelial cell itself by forming tumor cell-lined channels that accommodate blood flow.90,91,105

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