| Sustaining proliferative signaling |
Cell division starts when intercellular proliferative signals are released (only when needed) |
Proliferative signals constantly being used to form rapidly growing tumor structures |
EGFR inhibitors |
| Evading growth suppressors |
Use growth suppression signals to inhibit unwanted proliferation |
Suppressors are repressed and continue to grow out of control |
Cyclin-dependent kinase inhibitors |
| Inducing angiogenesis |
Vascular endothelial growth factor (VEGF) is released to generate new vessels but only if more nutrients are needed |
Unlimited growth implicates a high increase on nutrient demands, and VEGF release is increased |
Inhibitors of VEGF signaling |
| Enabling replicative immortality |
Limited replication is done by progressive and accumulative loss of telomeres in each cell division |
Telomerase production allows telomere replication, which in turn results in infinite replication |
Telomerase Inhibitors |
| Resisting cell death |
Programmed (apoptosis) and necrotic cell death, eliminates cells with a damaged DNA |
Apoptosis is attenuated, producing increased cell proliferation, cancer progression and resistance to therapy (38,39) |
Pro-Apoptotic BH3 mimetics |
| Activating invasion & metastasis |
Organized growth with differential limits |
Tissue barriers are broken and the tumor can invade other organs or vascular and lymphatic vessels (to migrate to other organs) |
Inhibitors of HGF/c-Met |
| Avoiding immune destruction |
T-lymphocytes look for surface markers to detect abnormal cells and destroy those with an aberrant behavior |
The immune system can be evaded by multiple pathways, mainly avoiding the expression of cell markers |
Immunotherapy |
| Deregulation of cellular energetics |
Oxygen obtained from blood supply is used to convert glucose to energy |
Higher and unreachable nutrient supply is needed. Anaerobic glucose metabolism occurs |
Aerobic Glycolysis Inhibitors |
| Enabling characteristics |
| Tumor-promoting inflammation |
Equilibrium between nutrients, inflammatory cells and free radicals is required to produce optimal conditions for normal cell growth and replication |
Inflammation modifies cell proliferation, survival, apoptosis and angiogenesis, facilitating the release of reactive oxygen species, promoting carcinogenesis and favoring metastasis (40-43) |
Selective anti-inflammatory drugs |
| Genome instability & mutation |
Progressive addition of different hallmarks |
Gain susceptibility to both genomic alterations and the appearance of driver mutations. These genomic changes contribute to the multi-step (or multi-hit) process of carcinogenesis (44,45) |
PARP inhibitors |
