Angiogenic mechanisms

Angiogenic mechanisms include ensuring EC survival, stimulating EC proliferation, and promoting EC migration. 

A particularly active area of research concerns the elucidation of the mechanisms of refractoriness or resistance to anti-VEGF therapy. Tumor cell-intrinsic or treatment-induced expression of angiogenic factors may be implicated Very recent studies have provided evidence that, at least is some murine models, refractor-inessm to anti-VEGF therapy is related to the ability of the tumor to recruit CDllb+Grl+ myeloid cells, which promote angiogenesis [5]. It remains to be established whether these findings also apply to human tumors. 

It should be noted, however, that mechanisms of action of most anti-angiogenic compounds are not well understood at present. For example, trombospondrn-1 (TSP-1) is able to inhibit tumour-associated angiogenesis, but when TSP-1 pellets were implanted into the ankles of AIA rats, it enhanced joint swelling and body weight loss in a dose- and time-dependent manner. These, possibly indirect, effects may be due to the involvement of TSP-1 in cell adhesion, as well as to its interactions with other adhesion molecules and inflammatory mediators [125]. 

The technologies described above can be used to pinpoint the mechanism(s) of action of angiogenic or angiostatic agents in specific steps in the angiogenic cascade. For instance, application of these systems revealed that IFNa and angiostatin inhibit cell migration whereas endostatin and platelet factor-4 function primarily as inhibitors of endothelial cell proliferation. 

Although much has been learned ftom in vitro assays, we do not yet fully understand the predominant migratory mechanisms used by cancer cells in vivo. It is important that any molecular mediators (or their inhibitors) identified in one assay are tested in complementary assays and validated in appropriate in vivo models before they can be assumed to play a significant role in invasion and metastasis. There are several examples where a molecule can have either positive or negative regulatory roles in key cellular functions depending on the cellular/microenvironmental context (e.g., tissue inhibitors of matrix metalloproteinases TIMPs (12)). Thus, care needs to be taken to avoid undesirable activities or, as in the example of some angiogenic inhibitors, compensatory mechanisms that result in adverse events (13). 

Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigen-esis. Cell 1996 86 353-364. 

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