Hallmarks of cancer + enabling factors
Hallmarks
1. Self-sufficiency in growth signals
Tumors have the capacity to proliferate without external stimuli, usually as a consequence of
oncogene activation
Oncogenes are created by mutations in proto-oncogenes and encode proteins called
oncoproteins that have the ability to promote cell growth in the absence of normal growth-
promoting signals
Fight with EGFR inhibitors
2. Insensitivity to growth-inhibitory signals
Tumors may not respond to molecules that inhibit the proliferation of normal cells, usually
because of inactivation of tumor suppressor genes than encode components of these growth
inhibitory pathways
Fight with cyclin-dependent kinase inhibitors
3. Altered cellular metabolism
Tumor cells undergo a metabolic switch to aerobic glycolysis Warburg effect enables the
synthesis of macromolecules and organelles that are needed for rapid cell growth
o Aerobic glycolysis used to visualize tumors by PET scanning
Fight with aerobic glycolysis inhibitors
4. Evasion of apoptosis
Tumors are resistant to programmed cell death
Intrinsic and extrinsic
o Activation of protease (normally inactive) initiates proteolytic cascade
Fight with proapoptotic BH3 mimetrics
5. Limitless replicative potential (immortality)
Tumors have unrestricted proliferative capacity, a stem cell-like property that permits tumor
cells to avoid cellular senescence and mitotic catastrophe
Reactivation of telomerase telomere maintenance
Fight with telomerase inhibitors
6. Sustained angiogenesis
Tumors, like normal cells, are not able to grow without a vascular supply to bring nutrients
and oxygen and remove waste products tumors must induce angiogenesis
o Vascular endothelial growth factor (VEGF) and thrombosponding-1 (TSP-1)
o Increased productions of angiogenic factors/loss of angiogenic inhibitors tumor
cells/inflammatory cells
o Hypoxia relative lack of oxygen stimulates production of pro-angiogenic
cytokines
Fight with VEGF signaling inhibitors
7. Ability to invade and metastasize
Arise from the interplay of processes that are intrinsic to tumor cells and signals that are
initiated by the tissue environment
Complex invasion-metastasis cascade
i. Loosening of cell-cell contacts by inactivation of E-cadherin several pathways
ii. Degradation of ECM proteolytic enzymes secreted by tumor/stromal cells
1. MMPs/cathepsins
iii. Attachment to novel ECM components proteolytic enzymes growth factors
iv. Migration of tumor cells prediction by primary site of tumor
Fight with HCF/c-MET inhibitors
8. Ability to evade host immune system
Cancer cells exhibit a number of alterations that allow them to evade the host immune
response
Fight with immune activating anti-CRLA4 mAb
Hallmarks
1. Self-sufficiency in growth signals
Tumors have the capacity to proliferate without external stimuli, usually as a consequence of
oncogene activation
Oncogenes are created by mutations in proto-oncogenes and encode proteins called
oncoproteins that have the ability to promote cell growth in the absence of normal growth-
promoting signals
Fight with EGFR inhibitors
2. Insensitivity to growth-inhibitory signals
Tumors may not respond to molecules that inhibit the proliferation of normal cells, usually
because of inactivation of tumor suppressor genes than encode components of these growth
inhibitory pathways
Fight with cyclin-dependent kinase inhibitors
3. Altered cellular metabolism
Tumor cells undergo a metabolic switch to aerobic glycolysis Warburg effect enables the
synthesis of macromolecules and organelles that are needed for rapid cell growth
o Aerobic glycolysis used to visualize tumors by PET scanning
Fight with aerobic glycolysis inhibitors
4. Evasion of apoptosis
Tumors are resistant to programmed cell death
Intrinsic and extrinsic
o Activation of protease (normally inactive) initiates proteolytic cascade
Fight with proapoptotic BH3 mimetrics
5. Limitless replicative potential (immortality)
Tumors have unrestricted proliferative capacity, a stem cell-like property that permits tumor
cells to avoid cellular senescence and mitotic catastrophe
Reactivation of telomerase telomere maintenance
Fight with telomerase inhibitors
6. Sustained angiogenesis
Tumors, like normal cells, are not able to grow without a vascular supply to bring nutrients
and oxygen and remove waste products tumors must induce angiogenesis
o Vascular endothelial growth factor (VEGF) and thrombosponding-1 (TSP-1)
o Increased productions of angiogenic factors/loss of angiogenic inhibitors tumor
cells/inflammatory cells
o Hypoxia relative lack of oxygen stimulates production of pro-angiogenic
cytokines
Fight with VEGF signaling inhibitors
7. Ability to invade and metastasize
Arise from the interplay of processes that are intrinsic to tumor cells and signals that are
initiated by the tissue environment
Complex invasion-metastasis cascade
i. Loosening of cell-cell contacts by inactivation of E-cadherin several pathways
ii. Degradation of ECM proteolytic enzymes secreted by tumor/stromal cells
1. MMPs/cathepsins
iii. Attachment to novel ECM components proteolytic enzymes growth factors
iv. Migration of tumor cells prediction by primary site of tumor
Fight with HCF/c-MET inhibitors
8. Ability to evade host immune system
Cancer cells exhibit a number of alterations that allow them to evade the host immune
response
Fight with immune activating anti-CRLA4 mAb
