![]() A major conclusion is that a single cytokine, the 164/5 amino acid splicing variant of VEGF-A, is capable of inducing the formation of tumor-like blood vessels and connective tissue stroma. The work reported here summarizes our progress over the past 25 years toward elucidating the steps and mechanisms of tumor angiogenesis and stromagenesis. By contrast, the imperfect nature of tumor stroma suggested to us that it was generated by a simpler process, one that deviated from normal developmental stromagenesis by having fewer steps and involving fewer cytokines. 8-10 Among these are vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A), other members of the VPF/VEGF family such as placenta growth factor (PlGF), and other cytokines such as TGF-β, PDGF, ephrins, FGFs, angiopoetins-1 and -2, and their respective receptors and inhibitors. Although normal stroma generation is not completely understood, it is known to require the cooperative activities of many different cytokines and inhibitors, each expressed in appropriate amounts and temporal sequence. Given these extensive differences in composition, it seemed likely to us that tumor and normal stroma were formed by different steps and mechanisms. Other elements of tumor stroma are also abnormal: increased amounts of plasma protein-rich interstitial fluid structural proteins not normally found in mature stroma such as fibrin, tenascin, and fetal forms of fibronectin abnormal proteoglycans variable numbers of inflammatory cells, etc. They are also hyperpermeable to plasma and plasma proteins, may lack pericytes, and are lined by actively dividing endothelial cells. 2,4-7 Unlike the normal vasculature, tumor vessels are not arranged in a hierarchical pattern but are instead irregularly spaced and structurally heterogeneous. Tumor vessels differ from their normal counterparts with respect to organization, structure and function. However, tumor stroma differs strikingly from normal connective tissue. Normal tissues are also comprised of avascular parenchyma that abuts on vascularized connective tissue stroma. The discrete separation of parenchymal cells from stroma is not unique to tumors. 1,2 The quantity of stroma is highly variable from tumor to tumor but all solid tumors, regardless of type or cellular origin, require stroma for nutrition and waste disposal if they are to grow beyond minimal size. Solid tumors are composed of two distinct but interdependent compartments: the malignant cells themselves (parenchyma) and the supporting connective tissue (stroma) that they induce and in which they are dispersed.
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