Molecular Markers of Tumor Endothelium
Many of the genes that are up-regulated in tumor endothelium are likely to be turned on as part of the angiogenesis process. However, some genes may be regulated in a manner independent of angiogenesis. For example, hypoxia, a hallmark of solid tumors, is known to affect the ex
Prior to recent technological advances that enabled global gene ex
As an alternative strategy to identify molecular markers differentially expressed in normal- and tumor-derived endothelium, we performed serial analysis of gene ex
From both a clinical and biological perspective, those TEMs which are located on the cell-surface are of particular interest. These TEMs are likely to be the most accessible to pharmacologic agents and may be involved in signaling pathways that regulate angiogenesis. Based on hydrophobicity and recent antibody staining, five of the TEMs (TEM1, TEM5, TEM7, TEM7R, and TEM8) appear to reside on the cell-surface (AN, unpublished data). These four genes are unrelated to each other and one of them, TEM5, appears to be most similar to genes that are uncharacterized and predicted to exist based on EST and human genomic databases. TEM5 appears to be a seven pass Gprotein-coupled transmembrane receptor, while TEM1, TEM7, and TEM8 span the membrane once. Other endothelial markers identified by SAGE, such as TEM2, TEM4, and PRL-3, though not cell-surface receptors could also prove to be useful targets therapeutically since they encode a GTPase, a guanine-nucleotide exchange factor, and a phosphatase, respectively.
Markers Of Endothelial Dysfunction
The vascular endothelium is involved in a variety of key processes important to human health and disease, including control of coagulation, fibrinolysis, vascular tone and growth, immune response and oxidative stress. Endothelial dysfunction has been found to be closely related to insulin resistance, elevated levels of inflammatory markers, impaired function of lipoprotein lipase (contributing to high triglycerides and low HDL cholesterol levels, impaired nitric oxide release58 and endothelium dependent vasodilation.
Studies suggest that endothelial dysfunction is associated with risk factors and processes associated with diabetes mellitus, such as hyperglycemia, inflammation, and insulin resistance. One of the well-known vasodilators produced in the endothelium is nitric oxide (NO) whose production is decreased due to endothelial dysfunction, resulting from reduced activity of endothelial NO (eNOS). Early stages of endothelial dysfunction are related to increased production of reactive oxygen species (ROS) which in turn can cause more damage to endothelial and vascular function. ROS are now considered to be a major risk factor in the development of insulin resistance, diabetes mellitus, hypertension, and CVD.
Endothelial dysfunction may cause hypertension by impairing the vasodilator mechanism of NO (which is also called endothelium-derived relaxing factor), subsequently causing elevated blood pressure. Endothelial dysfunction may also be related to other mechanisms involved in the development of hypertension, including insulin resistance, systemic inflammation and hyperuricemia.
Endothelial dysfunction is present in end-stage renal disease. Biomarkers of endothelial dysfunction, including circulating adhesion molecules VCAM-1, ICAM-1, and Eselectin are shown to be elevated even in less advanced stages of kidney disease. Endothelin-1 (ET-1), an endothelium-derived growth factor, of both renal mesangial and extrarenal vascular origin and its interaction with angiotensin-II are implicated in the progression of renal disease. For example, Koobi et al. showed that Angiotensin II type 1 (AT1) receptor blockade in nephrectomized rats significantly reduced the vasoconstriction response in relation to Endothelin-1 administration. Angiotensin-II, a central molecule in the initiation and progression of chronic renal disease is closely related to endothelial function and inflammation and treatment with angiotensin converting enzyme inhibitors have been shown to lower circulating biomarker levels of inflammation and endothelial dysfunction. These findings suggest that endothelial dysfunction may precede and can predict the development of CKD.
Animal studies show that endothelial dysfunction may have a causative role in the development of cardiovascular disease. The intact, healthy endothelium secretes various cardio-protective substances including nitric oxide, which diffuses to surrounding tissues and cells, relaxing smooth-muscle cells and preventing platelet adhesion and aggregation, preventing ex