Figure 2

Dual microenviromental adaptive response against antiangiogenic therapies and its clinical implications. Tumours can exhibit a dual different adaptive response, vascular ‘normalisation’ (associated to hypoxia correction) or vascular pruning (associated to increased hypoxia), that would be determined by the type of antiangiogenic agent, dynamic changes in the concentrations of pro- and antiangiogenic factors, administration timing, and tumour type. Vascular normalisation corrects oxygenation leading to a metabolic switch. This metabolic reprogramming requires the interaction of several specialised cell lineages in the tumour microenvironment and it is characterised by an increased in dependence on mitochondrial metabolism. Upon this situation tumours become vulnerable to mitochondrial inhibitors inducing the phenomenon of metabolic synthetic lethality. The process may not be homogeneous: some tumour areas may experience hypoxia correction and others hypoxia increase. In this case, an alternative model proposes a metabolic compartmentalisation of tumours. In hypoxic regions cells import and metabolise glucose, whereas in normoxic regions tumour cells activate lactate catabolism leading to the upregulation of mTOR signalling. The resulting upregulation of mTOR signalling could be disrupted by the administration of mTOR inhibitors. Finally, the reprogramming may not be limited to cancer metabolism: vascular pruning and increased hypoxia as response against antiangiogenics can be associated with an immunosuppressive phenotype opening an opportunity for the novel immunotherapies.