Fibroblast growth factors are heparin binding mitogens.Basic fibroblast growth factor on endothelial cells.The binding activates the MAPK signalling pathway leading to endothelial cell proliferation has not attracted as much interest as VEGF or bFGF, but evidence is accumulating that it has a role in tumor angiogenesis as well.Some tumors secrete PDGF that can upregulate its own receptor on endothelial cells. The combination of VEGFVEGFR inhibitors and PDGFPDGFR antagonists is an attractive concept for the inhibition of tumor angiogenesis, as pericytes seem to be able to survive VEGF inhibition, and possibly pericytes might confer resistance to VEGFVEGFR antagonists. Angiopoietin can facilitate angiogenesis and lymphangiogenesis by increasing basement membrane degradation and endothelial cell migration. The ECM is not just a passive storage and sequestering place for vascular growth factors; the ECM components as such play an important role in tumor angiogenesis.Many of them, including Argatroban collagen I, III, XV, fibronectin, fibulin, perlecan, laminin and promote angiogenesis, and stabilize blood vessels during angiogenesis.Particularly fibronectin seems to play an important role in these processes.Fibronectin promotes endothelial cell survival and migration.Interestingly, fibronectin might also control ECM remodelling events, as the inhibition of fibronectin matrix deposition also inhibits the deposition and retention of other ECM components that affect angiogenesis, such as thrombospondin and collagen I and III. The backbone of basement membranes, collagen IV also regulates angiogenesis.The parent molecules usually are not antiangiogenic or they might even promote vascular growth, as discussed in the previous chapter. Thrombospondin was the first protein to be recognized as a naturally occurring endogenous inhibitor of angiogenesis. Thrombospondin has antiangiogenic activity as well. Implanted melanoma and testicular teratocarcinoma tumors grow faster in thrombospondin null mice, showing that also endogenous levels are sufficient to inhibit angiogenesis. Many other endogenous inhibitors of angiogenesis are cryptic fragments from larger molecules.These inhibitors can be divided into two major classes: matrix derived and nonmatrix derived inhibitors.Endostatin is a matrix derived antiangiogenic fragment from collagen XVIII.The noncollagenous endostatinlike fragment of collagen XV also possesses similar antiangiogenic activity.Arresten, canstatin and Entecavir hydrate tumstatin are angiogenesis inhibitors cleaved from collagen IV. Other matrix derived endogenous inhibitors of angiogenesis include endorepellin from perlecan, and the fibronectin derived fragment anastellin. Angiostatin is a nonmatrix inhibitor of angiogenesis derived from plasminogen, and the first cryptic fragment of a larger parent molecule possessing novel antiangiogenic properties that the intact molecule does not have. Although they are not directly cleaved from ECM molecules, many of them are stored within the ECM or otherwise regulated by it.Endostatin is probably the most studied cryptic endogenous inhibitor of angiogenesis.The discovery of endostatin in raised high hopes for cancer cure and a lot of hype in the media as well.The idea of the crucial importance of angiogenesis in cancer growth was indeed revolutionary. Endostatin has the broadest anticancer spectrum of the endogenous angiogenesis inhibitors.It affects over of the angiogenesis regulatory human genes, and has shown no toxicity in human patients even in longterm use.There are growing numbers of tumor types whose growth is inhibited by endostatin. In fact, it has recently been discovered in some clinical studies that overexpression of collagen XVIII, and thus elevated levels of circulating serum endostatin, is actually associated with poor outcome in nonsmall cell lung cancer.