A role for TSP in the inhibition of ang iogenesis is supported by several obse rvations.It ispresent adjacent to ma tu re qu iescent vesse ls and is ab sent from Hematoxylin actively growing sp rou ts bo th in vivo and in vitro. There are several poss ib le exp lanations for th is appa rent functionaldicho tomy.The ang iogen icpotential of mac rophages in vivo may be the result of the ba lanced production of bo th positive and negative regulators of ang iogenes is.The po tential significance ofthese observations to in vivo wound neovascularization is just beginning to emerge.First, it was shown that tumo rs, imp lan ted into isolated perfused organs, whereblood vesse ls did not grow or when introduced intoei ther sub cutan eoustranspa rent chambe rs in mice or the avascular cornea of the rabbit eye, grew ever so slowly, as small mm sphe res or as thin wafers, by absorb ing nutr ien ts diffusing from the surround ingtissues. The tumo rs were ab le to survive in th is dormantst a te for an ex tended period oftime but were unab le to grow progressively.However, as the advancing edge of the tumor app roached adjacent microvessels, diffusible angiogen ic factors, re leased fromthe tumor,st imu la ted endo thelial cells to grow andmigra te directionally towardthe tumor and organize into a capillary network.This switch from the prevascular to vascular ph a se was accomp anied by expon enti al growth ofthe tum or. There are nume rous examples where these observations have been validated in humantumor s.For examp le, hum anretinobl ast om as th at me tas tas ize to the vitreous or the an ter ior chamber of the eye remain avascular until they sett le on the richly vascu lar iris or retina andbecome vascu lar ized.Carcinoma of the ovary me tas tas izes to the peri toneum as avascular sphe res th at fail to grow until they become vascularized.The appea rance of neovascularization at the ba se of me lanomas that en ter the vertical growth phase, the red blush that is assoc ia ted with cervical and oral carcinoma, hera lds the onset of rapid growth and increased me tastatic po tentia l.An increase in the number of new capillaries in certain types ofbreast andprosta te carcinoma has been shown to correlate with malignant and me tastatic po tential and thus is of prognostic significance. Tumor cells Levomilnacipran recruit newblood vesse ls by several different mechan isms.They produce diffusible angiogenic factors that directly activate endo thelial cells,st imu la ting them to sprout and grow toward the developing tumor.Theyelabo ra te cytokines, which attract and activate mac rophages, and neutrophils, which in turnelabo ra te angiogenic factors.They produce enzymes that release angiogenic factors sequestered in the extracellular matrix, and they stimulate adjacent normal tissues to make enzymes such as stromelysin that can be activated to promote angiogenesis.The onset of angiogenic activity in tumor cells may occur at any time during neoplastic transformation.How and where tumor angiogenesis fits into the multistep carcinogenic process and what its relationship is to other phenotypic traits that define the transformed phenotype are discussed below.