microenvironment is in animmunosuppressive state where the suppressed immune cells benefit the tumour bypromoting angiogenesis, tumour survival and metastasis. Afterthe monocytes are actively recruited into tumours along defined chemotacticgradients which are chemotactic ligandsthat create chemical concentration gradients that organisms move towards oraway , they reside and differentiateinto tumour-associated macrophages ( TAMs). TAMs constitute the major portion of the immune cells in the tumour stroma. TAMsappear to be preferentially attracted to and retained in areas of necrosis (unprogrammed cell death caused due to external factors suchas infection,trauma and unregulated digestion of cellular components), and hypoxia ( deficiency of oxygen reachingthe tissues) where they become phenotypically altered and upregulatehypoxia-induced transcription factors. TAMs rather than being tumoricidal alsoadopt a protumoral phenotype at both primary and metastatic sites.Macrophages also release VEGF, HGF,MMP2 and IL-8 that influence endothelial cell behaviour and ultimatelystimulate the formation of blood vessels.
Neutrophils are also stimulators ofangiogenesis. Additional immune cells do not play much important role incarcinogenesis . They are not consistent residents of the stroma and they are restricted to only specifictypes of cancer. VASCULAR ENDOTHELIALCELLSAngiogenesis is the physiological processthrough which new blood vessels form from pre-existing vessels. For cancer cellgrowth angiogenesis is important because it supplies nutrients and oxygen whichis needed for tumour growth. Many components of stroma are responsible forinitiation of angiogenesis out of CAFs play an important role in synchronizingevents of angiogenesis by secretion of many ECM molecules and growth factorssuch as TGF-?,VEGF, fibroblast growth factor. It also secretes SDF-1 where SDF-1 signallingis responsible for recruiting endothelial progenitor cells (EPCs) into thetumour stroma to form new blood vessels known as vascular mimicry. CAFs alsoproduce a significant amount of SPARC ( secreted protein and rich in cysteine)responsible for the regulation of angiogenesis.
CAFs also secrete many MMPswhich causes the initiation of angiogenesis by the degradationof the basement membrane, sprouting ofendothelial cells, regulation of pericyte attachment. As the tumour growsrapidly there are increased chances of intratumoral hypoxia which promotesangiogenesis by the production of many secreted factors such ashypoxia-inducible factors , angiopoietin 1, angiopoietin 4, placental growthfactor, platelet-derived growth factor B. However, these neoangiogenic vesselsare non-uniformly distributed, irregularly shaped, inappropriately branched,tortuous often ending blindly.
These do not have the classical hierarchy ofarterioles, capillaries, venules and oten have arteriovenous