fig3

Figure 3. Resistance by Hypoxia. Following anti-angiogenic treatment, the decrease in number of vessels frequently leads to increased hypoxia levels. A: Mechanism driven by p53 mutation. In the model investigated by Yu et al.^[47] the human colorectal cancer HCT116 cell line is used in its wild type and p53-/p53- versions. When a mouse carrying a xenograft produced by a mixture of HCTT16 WT and HCT116 p53-/p53- is treated with an anti VEGF antibody an initial shrinkage of the tumour occurs as most of the WT-hypoxia sensitive cells undergo apoptosis. However, the p53-/p53- cells, hypoxia resistant, continuous to growth producing eventually an even larger mass. (based on Yu et al.^[47]); B: Mechanism driven by Metabolic Symbiosis. As the number of hypoxic cells increases, following treatment-induced vascular disappearance, the hypoxic cells by releasing LDH allows the normoxic cells, which internalise it and turn it into pyruvate, to improve their Oxidative Phosphorylation, decrease their consume of glucose and therefore leave more glucose available. for the hypoxic cells which have therefore the possibility to produce more energy and survive. The same phenomenon occurs for the tumour-associated stroma. (Based on ^[51]and ^[52])