molecular basis or cancer biology abnormalities in neoplastic cell behaviour tumour angiogenesis

 What angiogenesis means

Angiogenesis is the establishment of new blood vessels from a pre­-existing vascular bed. This neovasculariztion  is essential for tumor growth and metastasis. Tumors develop an angiogenic phenotype a. as a result of accumulated genetic alterations and in response to local selection pressures such as hypoxia. Many of the common oncogenes and tumor suppressor genes have been shown to play a role in inducing angiogenesis. including ras, myc. HER2/neu. and mutations in p53
In response to the angiogenic switch. pericytes retract and the endothelium secretes several growth factors such as basic fibroblast growth factor (FGF), platelet-derived growth factor (pDGF). and insulin-like growth factor (FGF). The basement membrane and stroma around the capillary are proteolytically degraded, which is mediated in most part by uPA. The endothelium then migrates through the degraded matrix, initially as a solid cord, then forming lumina. Finally. sprouting tips anastomose to form a vascular network surrounded by a basement membrane

Angiogenesis is mediated by factors produced by various cells

including tumor cells, endothelial cells. stromal cells, and inflamma­tory cells

The first proangiogenic factor was identified by Folkman and colleagues in 1971. Since then. several other factors have been shown to be proangiogenic or antiangiogenic Of the angiogenic stimulators. the best studied are the vascular en­dothelial growth factors (VEGF). The VEGF family consists of six growth factors (VEGF-A. VEGF-B. VEGF-C, VEGF-D, VEGF-E, and placental growth factor) and three recepto (VEGFRI or Flt-1. VEGFR2 or KDR/FLK-l. and VEGfR3 or FLT4).Neuropilin 1 and 2 also may act as receptors induced by by ­hypoxia and by different growth factors and cytokines, including EGF, PDGF. TNF-alpha. TGF-beta and interleukin 1 beta VFGF has various functions including increasing vascular permeability. induc­ ing endothelial cell proliferation and tube formation, and inducing
endothelial cell synthesis of proteolytic enzymes such as uPA. PAI­- l UPAR. and MMP Furthermore. VEGF may mediate blood flow by its effects on the vasodilator nitric oxide and act as an endothelial survival factor. thus protecting the integrity of the vasculature. The proliferation of new lymphatic vessels. Iymphan­ giogenesis. is also thought to be controlled by the VEGF family. Sig­naling in lymphatic cells is thought to be modulated by VEGFR3

PDGFs A. B. C. and D also play important roles in angiogenesis. PDGFs can not only enhance endothelial cell proliferation directly but also upregulate VEGF expression in vascular smooth muscle cells. promoting endothelial cell survival via a paracrine effect.
The angiopoietins, angiopoietin I (Ang-I) and angiopoietin 2 (Ang-2). In return. are thought to regulate blood vessel maturation. Ang-I and Ang-2 both bind endothelial cell receptor Tie-2 but only the binding of Ang-I activates signal transduction; thus Ang-2 is an Ang-l antagonist." Ang-l , via the Tie-2 receptor, induces remodel­ mgand stabilization of blood vessels. Upregulation of Ang-2 by hypoxic induction of VEGF inhibits Ang-1-induced Tie-2 signaling. resulting in destabilization of vessels and making endothelial cells responsive to angiogenic signals. thus promoting angiogenesis in the presence of VEGF. Therefore the balance between these factors determines the angiogenetic capacity of a tumor.

Tumor angiogenesis is regulated by several factors in a coordinated fashion. In addition to upregulation of proangiogenic

molecules. angiogenesis also can be encouraged by suppression of naturally occurring inhibitors. Such Inhibitors of angiogenesis include thrombospondin I and angiostarin, It has been proposed that the generation of inhibitors of angiogenesis by primary tu­mors results in the accumulation of inhibitors at distant sites. sup­ pressing metastasis. and with resection of the primary tumor. the source of the inhibitors is removed. occasionally leading to growth of metastases.
Indeed, angiogenesis is a prerequisite I.not only for primary tumor growth but also for metastasis. Angiogenesis in the primary tumor. as determined by microvessel density. has been demonstrated to be an independent predictor of distant metastatic disease and survival in several cancers. Expression of angiogenic factors such as VEGFs has had prognostic value in many studies. These findings further emphasize the importance of angiogenesis in cancer biology.

what are the angiogenic switch means

 It means tumours recruit endothelial cells from surrounding vessels and from progenitor cells in the circulation. These cells are stimulated to grow into the tumour from the outside. When this stage is called 'the angiogenic switch. The angiogenic phenotype of a tumour depends on the net between pro-angiogenic and anti-angiogenic growth factors in the region of the These growth factors may be produced by the tumour itself or by stromal or
immune cells in the tumour vicinity

some summary of promoters of angiogensis and inhibitors of angiogenesis

promotors of angiogenesis

angiogenic factors are secreted by tumour cells and tumour-associated macrophages. The most important naturally occurring angiogenesis promoters include
fibroblast growth factors CFGFs)
vascular endothelial growth factor (VEGF angiopoietins Ang-l and Ang-2; the ratio between them is likely to be important
Inhibitors of angiogenesis
naturally occurring proteins like 
Angiostatin  Endostatin and Thrombostatin

NB.physiological angiogenesis in adult occurs only as a response to trauma and tissue repair at certain times eg the menstrual cycle but the pathological angiogenesis occurs when there is persistent proliferation of endothelial cells in response to a stimulus eg from a tumour


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