16 - Hallmarks of Cancer Flashcards
Hallmark 1
Sustaining proliferative signalling
Sustaining proliferative signalling
- Normal tissues control the production and release of growth-promoting signals that govern cell growth and division
- Cancer cells deregulate these signals
- Enabling signals are conveyed by growth factors
Ways of sustaining proliferative signalling
- Autocrine proliferative signalling
- Elevated levels of receptor proteins
- Signalling to normal cells within associated stroma
- Growth factor independence by constitutive activation of downstream signalling pathways
Disruptions of negative-feedback mechanisms that
attenuate proliferative signalling
RAS mutations
Hallmark 2
Evading growth suppressors
Evading growth suppressors
Evasion of RB and TP53
Evasion of RB effects
- Metastasis
- Angiogenesis
- Senescence
- Genome stability
- Cell death
- Differentiation
- g1-s Cell cycle
Hallmark 3
Resisting cell death
How do tumour cells avoid cell death
- Loss of TP53 tumor suppressor function
- Increasing expression of antiapoptotic regulators (Bcl-2, Bcl-xl)
- Short-circuiting the extrinsic ligand-induced death pathway
How do Bcl-2 family regulator proteins (Bcl-2, Bcl-x) inhibit apoptosis
Bind to and suppress Bax and Bak
Necrotic pathway
- Cell enlargement
- Loss of membrane integrity
- Leakage of cell contents
- Inflammation (recruitment of immune cells)
- Nuclear degeneration
Hallmark 4
Enabling replicative immortality
Enabling replicative immortality
Through telomerase
Additional functions of telomerase (TERT) in
tumorigenesis
- Amplify signalling by the Wnt pathway
- Enhancement of cell proliferation and/or
- Resistance to apoptosis
- Involvement in DNA-damage repair
Hallmark 5
Inducing angiogenesis
Angiogenic regulator
Signalling proteins that bind to stimulatory or inhibitory cell-surface receptors
Examples of angiogenic regulators
- Vascular endothelial growth factor (VEGF-A)
- Thromboplastin-1 (TSP-1) (inhibitory)
Hallmark 6
Activating invasion and metastasis
Multistep process of metastasis
- Local invasion
- Intravasation
- Extravasation
- Micro-metastases
- Colonisation
E cadherin
- Mediates Contact Inhibition of Proliferation
- Normal cells stop proliferating once they reach confluence upon homophilic E-cadherin binding
- When cells either lose E-cadherin, they continue proliferating, grow on top of each other and lose CIP
Loss of E cadherin
Key characteristic of EMT
Hallmark 7
Evading immune destruction
Reprogramming energy metabolism
- Upregulation of glucose transporters (eg GLUT1) to
increase glucose transport into the cytoplasm - Associated with activation of oncogenes
- Hypoxia can also upregulate glucose transporters
Aerobic glycolysis / warburg effect
Cancer cells have increased rates of glucose uptake and lactate production, even in the presence of sufficient oxygen and low rate of oxidative phosphorylation
Hallmark 8
Reprogramming energy metabolism
TGFβ
Significant role in inhibiting T helper cell differentiation and promoting antitumor immunity
Enabling characteristics
- Genome instability and mutation
- Tumour-promoting inflammation
Genomic instability and mutation
- Characteristic of almost all human cancers
- The most common is chromosomal instability (CIN)
Hereditary cancer genomic instability
The presence of both CIN and non-CIN forms of genomic instability have been linked to mutations in DNA repair genes
Sporadic cancer genomic instability
not due to mutations in DNA repair genes or mitotic checkpoint gene
Tumour promoting inflammation
- Linked to transformation, proliferation, angiogenesis, and metastasis
- Supplying bioactive molecules such as growth factors and survival factors
- Immune cells, through the production of inflammatory mediators (e.g. cytokines) contribute to the survival of the tumor in its microenvironment
- The aberrant expression and secretion of proinflammatory by the tumor cells result in the recruitment of immune cells, thus creating a mutual
crosstalk
