Oncogenesis Week 1
Lecture 1
Second messengers are produced inside of
the cell.
Kinases phosphorylate substrates to
activate them. It uses ATP → ADP for this
reaction.
GTPase bound to GDP is inactive/off,
GTPase bound to GTP is active/on.
G-protein receptor, phospholipase-C,
calcium, activation of protein kinases.
→ See PLC.
Nf-kb is an important transcription factor
that can go into the nucleus.
Receptor tyrosine kinases need
dimerization for their activation. They
undergo a conformational change and they
start to cross-phosphorylate.
Phosphorylated tyrosine residues →
activated receptor (ligand is a growth
factor).
SH2 domains → high affinity for
phosphorylated tyrosine residues.
RAS is active if it’s bound to GTP rather than GDP (inactive). GTP Exange Protein (GEP) activates RAS.
GAP = GTPase (GTP → GDP hydrolysis) activating protein → helps Ras to become inactive. Grb2 x SOS
molecule has 1 SH2 and 2 SH3 domains → this recruits Ras. Ras recruits Raf. Raf phosphorylates MEK
and MEK phosphorylates MAPK.
Raf = MAP-kinase-kinase-kinase, MEK = MAP-kinase-kinase, MAPK =MAP-kinase
, Grb2xSOS recruits
inactive RAS
Phospholipase C (PLC) is activated
by both G-protein coupled receptors
AND by Receptor tyrosine kinases
→ cross-talk between the pathways.
PLC catalyses:
PIP2 → IP3 + DG (DiacylGlycerol).
PI3K is another kinase → PIP3 (phospholipid) production in the membrane → recruits PH domains of
PDK1 and PKB. PBK can phosphorylate BAD → inhibition of apoptosis ➔ Survival pathway.
,Src = sarc/sarcoma. This src gene is highly similar to the human gene for a protein kinase (tyrosine).
Proto-oncogenes are normal genes that can become oncogenes by gene mutations / amplification /
translocation / insertional mutagenesis.
Bcr/abl gene is constantly active (fusion protein → chromosomal translocation). Bcr gene on
chromosome 22, abl gene on chromosome 9.
Overexpression of Bcl-2 = anti-apoptotic.
Oncogene = gain of function. Tumor suppressor gene = loss of function.
Retinoblastoma (eye cancer, Rb) controls the cell cycle and it is a tumor suppressor gene. Loss of
function (mutated in both alleles) results in an uncontrolled cell cycle.
Colorectal cancer due to defects in Wnt signalling. B-catenin is an oncogene. If it’s not degraded it
will be present in high numbers. Hereditary mutations in APC (TSG in Wnt signaling pathway) results
in FAP (polyps).
NF-1 deactivates RAS (tumor suppressor gene). Small molecule inhibitors and antibody therapy are
two cancer therapies that are used often lately.
Hereditary cancer: almost exclusively TSG mutations (oncogenic mutations are embryonic lethal).
P53 blocks initiation of DNA synthesis and/or initiates apoptosis and is therefore both an TSG as an
oncogene.
Lecture 2 Hallmarks of Cancer
1. Self-sufficiency of growth signals (sustaining proliferative signalling)
cell proliferation without the need of external growth factors.
2. Insensitivity to anti-growth signals (evading growth-suppressors)
Loss of cadherins or … → Loss of tumor suppressors (2-hit event) → continued proliferation
Anti-growth signals: oncogenic signalling, glucose, DNA damage, ROS, lack of nucleotides.
These signals go through TP53 (tumor suppressor gene P53).
3. Evading apoptosis
Loss of pro-apoptotic proteins and increased survival signals → Survival.
4. Limitless replicative potential
Telomeres are ends of chromosomes. End replication problem. Loss of DNA. Anytime you have a
cell division you’ll lose a bit of your chromosome. Telomere shortening. Eventually you’ll damage
your DNA.
Telomere extension by telomerase. Reverse transcription with a RNA primer. Especially within
germ line cells.
Telomerase reactivation → immortality
5. Sustained angiogenesis
Cancer doesn’t naturally have this. New vessels to the tumour. VEGF is a ligand for a receptor
tyrosine kinase that activates this process. Pro-angiogenic signals → vascularization (formation of
new blood vessels).
, 6. Invasion/Metastasis
Epithelial-mesenchymal transition (MET) → increased motility (?).
Bonus hallmarks:
7. Deregulating cellular energetics
Glucose and especially Glutamine are taken up by tumors. Increased lactate secretion, reduced
need for oxygen, and increased production of nucleotides.
8. Immune evasion
Most of the tumors are killed by the immune system. Tumor cells may escape immune detection
by secreting immunosuppressive factors, downregulating antigen presentation, expression of
inhibitory immune checkpoint ligands.
Enabling characteristics:
9. Genomic instability
10. Tumor-promoting inflammation
Secrete growth factors to promote tumor growth, secrete immunosuppressive factors, open up
the Extracellular Matrix, etc.
Lecture 1
Second messengers are produced inside of
the cell.
Kinases phosphorylate substrates to
activate them. It uses ATP → ADP for this
reaction.
GTPase bound to GDP is inactive/off,
GTPase bound to GTP is active/on.
G-protein receptor, phospholipase-C,
calcium, activation of protein kinases.
→ See PLC.
Nf-kb is an important transcription factor
that can go into the nucleus.
Receptor tyrosine kinases need
dimerization for their activation. They
undergo a conformational change and they
start to cross-phosphorylate.
Phosphorylated tyrosine residues →
activated receptor (ligand is a growth
factor).
SH2 domains → high affinity for
phosphorylated tyrosine residues.
RAS is active if it’s bound to GTP rather than GDP (inactive). GTP Exange Protein (GEP) activates RAS.
GAP = GTPase (GTP → GDP hydrolysis) activating protein → helps Ras to become inactive. Grb2 x SOS
molecule has 1 SH2 and 2 SH3 domains → this recruits Ras. Ras recruits Raf. Raf phosphorylates MEK
and MEK phosphorylates MAPK.
Raf = MAP-kinase-kinase-kinase, MEK = MAP-kinase-kinase, MAPK =MAP-kinase
, Grb2xSOS recruits
inactive RAS
Phospholipase C (PLC) is activated
by both G-protein coupled receptors
AND by Receptor tyrosine kinases
→ cross-talk between the pathways.
PLC catalyses:
PIP2 → IP3 + DG (DiacylGlycerol).
PI3K is another kinase → PIP3 (phospholipid) production in the membrane → recruits PH domains of
PDK1 and PKB. PBK can phosphorylate BAD → inhibition of apoptosis ➔ Survival pathway.
,Src = sarc/sarcoma. This src gene is highly similar to the human gene for a protein kinase (tyrosine).
Proto-oncogenes are normal genes that can become oncogenes by gene mutations / amplification /
translocation / insertional mutagenesis.
Bcr/abl gene is constantly active (fusion protein → chromosomal translocation). Bcr gene on
chromosome 22, abl gene on chromosome 9.
Overexpression of Bcl-2 = anti-apoptotic.
Oncogene = gain of function. Tumor suppressor gene = loss of function.
Retinoblastoma (eye cancer, Rb) controls the cell cycle and it is a tumor suppressor gene. Loss of
function (mutated in both alleles) results in an uncontrolled cell cycle.
Colorectal cancer due to defects in Wnt signalling. B-catenin is an oncogene. If it’s not degraded it
will be present in high numbers. Hereditary mutations in APC (TSG in Wnt signaling pathway) results
in FAP (polyps).
NF-1 deactivates RAS (tumor suppressor gene). Small molecule inhibitors and antibody therapy are
two cancer therapies that are used often lately.
Hereditary cancer: almost exclusively TSG mutations (oncogenic mutations are embryonic lethal).
P53 blocks initiation of DNA synthesis and/or initiates apoptosis and is therefore both an TSG as an
oncogene.
Lecture 2 Hallmarks of Cancer
1. Self-sufficiency of growth signals (sustaining proliferative signalling)
cell proliferation without the need of external growth factors.
2. Insensitivity to anti-growth signals (evading growth-suppressors)
Loss of cadherins or … → Loss of tumor suppressors (2-hit event) → continued proliferation
Anti-growth signals: oncogenic signalling, glucose, DNA damage, ROS, lack of nucleotides.
These signals go through TP53 (tumor suppressor gene P53).
3. Evading apoptosis
Loss of pro-apoptotic proteins and increased survival signals → Survival.
4. Limitless replicative potential
Telomeres are ends of chromosomes. End replication problem. Loss of DNA. Anytime you have a
cell division you’ll lose a bit of your chromosome. Telomere shortening. Eventually you’ll damage
your DNA.
Telomere extension by telomerase. Reverse transcription with a RNA primer. Especially within
germ line cells.
Telomerase reactivation → immortality
5. Sustained angiogenesis
Cancer doesn’t naturally have this. New vessels to the tumour. VEGF is a ligand for a receptor
tyrosine kinase that activates this process. Pro-angiogenic signals → vascularization (formation of
new blood vessels).
, 6. Invasion/Metastasis
Epithelial-mesenchymal transition (MET) → increased motility (?).
Bonus hallmarks:
7. Deregulating cellular energetics
Glucose and especially Glutamine are taken up by tumors. Increased lactate secretion, reduced
need for oxygen, and increased production of nucleotides.
8. Immune evasion
Most of the tumors are killed by the immune system. Tumor cells may escape immune detection
by secreting immunosuppressive factors, downregulating antigen presentation, expression of
inhibitory immune checkpoint ligands.
Enabling characteristics:
9. Genomic instability
10. Tumor-promoting inflammation
Secrete growth factors to promote tumor growth, secrete immunosuppressive factors, open up
the Extracellular Matrix, etc.
