Angiogenesis

CRITICAL ANALYSIS OF SCIENTIFIC PUBLICATION

Angiogenesis is a process involved in the formation of new blood vessels, which occurs naturally in the body during wound healing, embryonic development, reproduction and also plays a vital role in tumour growth. Angiogenesis in tumour is the formation of new blood vessels through which the nutrients and oxygen is been supplied, which assist tumour growth 1, 2. The idea of inhibiting tumour growth by targeting angiogenesis has been proposes by researchers for more than three decades. Many signalling pathways are involved in regulating all stages of blood vessel formation and maturation, so chemotherapeutic agents are been involved, targeting angiogenic pathways to inhibit tumour growth 2. Angiogenesis is almost involved in all types of tumour but this particular article focuses mainly on breast cancer and also about various single and multitargeting agents involved in tumour growth inhibition.

Blood vessel formation, a complex process involving intercellular pro and antiangiogenic pathways. These signalling pathways aid the formation of endothelial cells, pericytes and also governing the activity of other blood vessel cells. Angiogenesis not only aids in tumour growth but also helps in metastasis that is travelling of the tumour along the blood stream. Normal layers of endothelial cells and pericytes are formed during blood vessel formation but tumour associated vasculature are irregular and unstable due to the increase in proangiogenic proteins such as Vascular Endothelial Growth Factors (VEGF). VEGF pathway is a key regulator in tumour angiogenesis as there receptors triggers endothelial cell growth, cell migration and also mobilizes endothelial cells. Thus inhibiting VEGF pathway helps in cancer therapy 3, 4. Tumours growing beyond 1-2 mm triggers proangiogenic factors and the suppression of antiangiogenic factors are expressed which leads to an angiogenic switch 2. Molecular pathways like VEGF and Platelet Derived Growth Factors (PDGF) pathway regulates the tumour vascularisation mechanism. Pro and antiangiogenic factors regulate endothelial sprouting but the detachment of pericytes is coordinated by VEGF and the enzymes activated by VEGF helps in cellular migration to form new capillary tubes 5. Blood vessel maturation takes place when angiopoietin-2 binds to its receptor, but due to hypoxia condition the tumour vasculature fails to mature completely 6. Sometimes the vessel formation is also been contributed by bone marrow derived circulating cells like Circulating Endothelial Cells (CECs) and Endothelial Progenitor Cells (EPCs) 7. An undetectable level of EPCs has been reported in peripheral blood so thus by measuring CESs and EPCs levels in blood may serve as a biomarker predicting the drug or agent response. The antiangiogenic factors aids in disassociating endothelial cells from the blood vessels which leads to increase in CEC in blood so these CEC themselves serves as a target for anti cancer treatments8.

Molecular signalling pathways involved in tumour angiogenesis have been studied extensively by identifying the ligands and the receptors. VEGF an important growth factor in tumour angiogenesis and it is usually over expressed by hypoxic tumour cells. VEGF are group of glycoproteins comprises of six members namely -A, -B, -C,-D, -E and Placenta Growth Factor (PGF). The growth factors like insulin, epidermal growth factor and transforming growth factors influences the levels of VEGF. There are three tyrosine kinase receptors VEGFR -1,-2 and -3 to which these VEGF binds and these receptors are found to be directly involved in pathological angiogenesis so they are been used as targets in drug development. Over expression of VEGF may also lead to tumour progression9. PDGF member of glycoproteins comprises of -A,-B,-AB,-C and -D plays a vital role in tumour angiogenesis. PDGF receptors (-α,-β and - αβ) helps in cell signalling, cell migration, VEGF transcription, secretion and also maintains newly formed blood vessels. When the levels of PDGF and PDGFR increase in the tumour tissues the response to the drug becomes relatively low 10. A monoclonal antibody HER2 was found to be effective by inhibiting the activity of VEGF in case of breast cancer 11.

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