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• _2 value "In transgenic mice in which the large T-antigen was expressed in all -cells of the pancreatic islets, carcinomas appeared at approximately 4 weeks of life and the angiogenic switch occurred at approximately 7 weeks in 4-10% of islets [8,9]. The angiogenic switch occurred slightly later in fibrosarcomas arising in transgenic mice carrying the bovine papilloma virus oncogenes [10], or when squamous cell carcinomas arose in mice carrying the human papillovirus type 16 oncogenes targeted to basal cells of the epidermis [11]. The spontaneous angiogenic switch [9] in human tumors can be driven by: (1) angiogenic oncogenes [12] which up-regulate expression of pro-angiogenic proteins (i.e. VEGF, bFGF etc.), and/or down-regulate expression of angiogenesis inhibitors, such as thrombospondin); (2) tumor-associated hypoxic conditions which activate hypoxia-inducible factor-1 (HIF-1) [13], which itself up-regulates angiogenic proteins; (3) fibroblasts in the tumor bed which can be induced by tumor cells to elaborate pro-angiogenic proteins [14]; and (4) bone marrow derived progenitor endothelial cells which traffic to tumors [15]. Of interest is that not all cells in a non-angiogenic dormant human tumor must switch to the angiogenic phenotype for a tumor itself to become neovascularized. Experiments in which human cancer cells both non-angiogenic and angiogenic, are mixed at different ratios before implantation into SCID immunodeficient mice reveal that as few as 1% angiogenic cells will lead to a neovascularized tumor [7]. However, the latent period before a detectable tumor appears is longer with a lower percentage of angiogenic cells (e.g. months with 1% angiogenic cells versus weeks with 50% angiogenic cells). While pre-existing microvessels, are surrounded by normal cells, under some conditions such as in brain metastasis, tumor cells can displace normal cells around a microvessel, a process of vessel cooption [16]. However, new tissue mass requires the recruitment of new microvessels. This principle applies to tumors as well as to normal tissue (such as fat) [17]. Neoplastic tissue usually exceeds the oxygen diffusion limit when tumor cell layers accumulate to a thickness of approximately 150-200 um from a nearest open microvessel. Tumor cells beyond this limit undergo apoptosis (Fig. 1). Therefore, almost any tumor that has reached a diameter of >10-100 mm, is probably already neovascularized. After the angiogenic switch, new microvessels converge on the dormant in situ tumor and tumor cells cluster around each microvessel in a cylindrical configuration. The radius of the microcylinder of tumor cells is limited by the oxygen diffusion requirements for that particular tumor, but it would be rare to find layers of viable tumor cells beyond 200 m (Fig. 1) [18]. The angiogenic switch is associated with a marked decrease (3- to 4-fold) in overall tumor cell apoptosis [5]. In contrast to apoptosis, the proliferation rate of tumor cells may remain at the same level and in many angiogenic tumors appears to be relatively independent of the onset of angiogenesis or its intensity [19]. The mechanisms of increased tumor cell survival and decreased tumor cell apoptosis after the onset of angiogenesis, depend not only on delivery of oxygen and nutrients and the removal of catabolites by new microvessels, but also on a paracrine release of anti-apoptotic factors from the endothelial cells in these new vessels. Microvascular endothelial cells recruited into a tumor bed supply at least 20 mitogens, anti-apoptotic factors, and survival factors (including among others, bFGF, HB-EGF, IL-6, G-CSF, IGF-1 and PDGF) for those tumor cells apposed to the new microvessels [20-22]. It is unclear whether angiogenesis inhibitors also directly decrease endothelial cell production of paracrine factors, but this could be tested in vitro. 3. Antiangiogenic therapy increases apoptosis of endothelial cells and tumor..." provenance.
• _2 wasQuotedFrom 12654259 provenance.