Hoofdstuk 3 (wc 1)................................................................................................................. 5
§3.1 transcription factors and transcriptional regulation.....................................................5
§3.2 chromatin structure.....................................................................................................6
§3.3 epigenetic regulation of transcription..........................................................................7
Histone modification..................................................................................................... 7
DNA Methylation.......................................................................................................... 8
§3.4 evidence of a role for epigenetics in carcinogenesis..................................................8
Histone modication and cancer.................................................................................... 8
Methylation and cancer................................................................................................ 8
§3.5 long non-coding RNAs............................................................................................... 8
§3.6 microRNAs and regulation of mRNA expression....................................................... 9
§3.7 telomeren en telomerase............................................................................................9
§3.8 epigenomic and histonomic drugs............................................................................10
DNA methylation inhibitors......................................................................................... 10
Inhibitors of histone deacetylases.............................................................................. 10
§3.9 Non-coding RNAs for diagnosis............................................................................... 10
§3.10 telomerase inhibitors.............................................................................................. 10
Hoofdstuk 4 (owg 1)............................................................................................................. 10
§4.1 epidermal growth factor signaling: an important paradigm.......................................11
1. Growth factor binding..............................................................................................11
2. Dimerization............................................................................................................11
3. Autophosphorylation............................................................................................... 11
4. Translocatie van specifieke eiwitten naar het membraan.......................................12
5. RAS activation........................................................................................................ 12
6. Raf activation..........................................................................................................12
7. The MAPK kinase cascade.................................................................................... 12
8. Regulation of transcription factors..........................................................................13
The effect of cell signaling on cell behavior................................................................13
§4.2 oncogenes................................................................................................................14
Studies of retroviruses................................................................................................14
Growth factors............................................................................................................ 14
Growth factor receptors.............................................................................................. 14
Intracellular signal transducers...................................................................................15
Transcription factors................................................................................................... 15
Mechanisms of oncogenic mutations......................................................................... 15
§4.3 kinases as drug targets............................................................................................ 16
Anti-EGFR drugs........................................................................................................ 16
Strategies against Ras and Raf..................................................................................16
MEK inhibitors............................................................................................................ 16
Hoofdstuk 6 (owg 1)............................................................................................................. 17
§6.1 definitions of tumor supressor genes....................................................................... 17
§6.2 the retinoblastoma gene...........................................................................................17
§6.3 mutations in the RB pathway and cancer.................................................................17
, §6.4 the p53 pathway....................................................................................................... 18
Stucture of p53 protein............................................................................................... 18
Regulation of p53 protein by MDM2...........................................................................18
Upstream: molecular pathways van p53 activation.................................................... 19
Downstream: molecular mechanisms of p53 cellular effects......................................19
Inhibitie van de celcyclus......................................................................................19
Apoptosis..............................................................................................................20
DNA repair and angiogenesis and other emerging roles......................................21
Factors that decide downstream outcome: cell cycle arrest or apoptosis.................. 21
§6.5 mutations in the p53 pathway and cancer................................................................21
More complex than knudson’s two-hit hypothesis...................................................... 21
§6.6 interaction of DNA viral protein products with RB and p53...................................... 22
HPV causes cervical cancer.......................................................................................22
§6.7 targeting of the p53 pathway.................................................................................... 22
Strategies that aim to correct a p53 mutation.............................................................22
Hoofdstuk 2 (owg 2)............................................................................................................. 22
§2.1 gene structure.......................................................................................................... 22
§2.2 mutations..................................................................................................................23
§2.3 carcinogenic agents................................................................................................. 24
Radiation as a carcinogen..........................................................................................24
Ionizing radiation.................................................................................................. 24
Ultraviolet radiation...............................................................................................25
Chemical carcinogens.......................................................................................... 27
Infectious pathogens as carcinogens......................................................................... 28
Endogenous carcinogenic reactions.......................................................................... 28
§2.4 DNA repair and predispositions to cancer................................................................28
§2.5 conventional therapies: chemotherapy and radiation therapy..................................30
Chemotherapy............................................................................................................ 30
Alkylating agents and platinum-based drugs........................................................30
Antimetabolieten...................................................................................................31
Organische middelen............................................................................................31
Radiation therapy....................................................................................................... 31
Heterogeneous cell sensitivity and drug resistance................................................... 32
§2.6 strategies that target DNA repair pathways..............................................................32
Synthetic lethal strategies.......................................................................................... 32
Hoofdstuk 12 (owg 3)........................................................................................................... 33
§12.1 lymphocytes: B cells and T cells............................................................................ 33
§12.2 tumor suppresive roles of the immune system.......................................................34
The cancer immunity cycle......................................................................................... 34
§12.3 immune checkpoints...............................................................................................34
§12.4 cancer immunoediting and tumor promotion.......................................................... 35
§12.5 mechanisms of avoiding immune destruction........................................................ 35
§12.6 therapeutic antibodies............................................................................................ 36
§12.7 cancer vaccines......................................................................................................36
, Therapeutic vaccins................................................................................................... 36
Whole-cell vaccines..............................................................................................37
Peptide-based vaccines....................................................................................... 37
Dendritic cell vaccines.......................................................................................... 37
Vaccines for cancer prevention.................................................................................. 37
Hurdles to jump.......................................................................................................... 37
§12.8 immune checkpoint blockades............................................................................... 37
§12.9 adoptive T-cell transfer, modified T-cel receptors and chimeric antigen receptors.38
§12.10 oncolytic viruses and virotherapy......................................................................... 38
Hoofdstuk 5 (owg 4)............................................................................................................. 39
§5.1 cyclins and cyclin-dependent kinases (cdks)........................................................... 39
§5.2 mechanisms of cdk regulation..................................................................................40
§5.3 progression through the G1 checkpoint................................................................... 40
Structure of the RB protein......................................................................................... 40
Molecular mechanisms of the effects of RB............................................................... 41
§5.4 the G2 checkpoint.................................................................................................... 41
§5.5 the mitotic checkpoint...............................................................................................42
Aurora kinases........................................................................................................... 42
§5.6 the cell cycle and cancer.......................................................................................... 43
§5.7 cyclin-dependent kinase inhibitors........................................................................... 43
§5.8 other cell cycle kinase targets.................................................................................. 43
§5.9 inhibitors of the mitotic spindle................................................................................. 43
Hoofdstuk 7 (owg 4)............................................................................................................. 44
§7.1 molecular mechanisms of apoptosis........................................................................ 44
The extrinsic pathway: mediated by membrane death receptors...............................44
The intrinsic pathway: mediated by the mitochondria................................................ 45
Cross-talk between extrinsic and intrinsic pathways.................................................. 46
P53 and apoptosis......................................................................................................46
§7.2 apoptosis and cancer............................................................................................... 46
TRAIL receptors......................................................................................................... 47
Mutations that affect the extrinsic pathway.................................................................47
Mutations that affect regulators of the intrinsic pathway.............................................47
Alternative death pathways........................................................................................ 47
§7.3 Apoptosis and chemotherapy...................................................................................47
§7.4 apoptotic drugs.........................................................................................................48
Targeting TRAIL and its receptor................................................................................48
Regulation of the Bcl-2 family of proteins...................................................................48
Direct and indirect activation of caspases.................................................................. 48
Hoofdstuk 9 (hoorcollege)...................................................................................................48
9.1 How do tumors spread?............................................................................................. 49
9.2 The process of metastasis......................................................................................... 49
9.3 Invasion and epithelial-mesecnhymal transition.........................................................49
Induction of EMT........................................................................................................ 49
Tools of invasion......................................................................................................... 50
, Cell adhesion molecules.......................................................................................50
Integrins................................................................................................................50
Proteases............................................................................................................. 50
9.4 Intravasation...............................................................................................................50
9.5 Transport.................................................................................................................... 50
9.6 Extravasation..............................................................................................................51
9.7 Metastatic colonization............................................................................................... 51
The pre-metastatic niche............................................................................................ 51
Exosomes...................................................................................................................51
Metastatic suppressor genes..................................................................................... 51
9.8 metalloproteinase inhibitors (MPIs)............................................................................ 51
9.9 Strategies for restoring metastasis suppressors........................................................ 52
Hoofdstuk 10 (hoorcollege).................................................................................................52
10.1 the angiogenic switch............................................................................................... 52
Angiogenic inducers................................................................................................... 52
Angiogenic inhibitors.................................................................................................. 52
10.2 cell behavior during angiogenic sprouting................................................................ 53
10.3 other means of tumor neovascularization................................................................ 53
10.4 anti-angiogenische therapy...................................................................................... 53
Belangrijke termen:................................................................................................................ 54
§3.1 transcription factors and transcriptional regulation.....................................................5
§3.2 chromatin structure.....................................................................................................6
§3.3 epigenetic regulation of transcription..........................................................................7
Histone modification..................................................................................................... 7
DNA Methylation.......................................................................................................... 8
§3.4 evidence of a role for epigenetics in carcinogenesis..................................................8
Histone modication and cancer.................................................................................... 8
Methylation and cancer................................................................................................ 8
§3.5 long non-coding RNAs............................................................................................... 8
§3.6 microRNAs and regulation of mRNA expression....................................................... 9
§3.7 telomeren en telomerase............................................................................................9
§3.8 epigenomic and histonomic drugs............................................................................10
DNA methylation inhibitors......................................................................................... 10
Inhibitors of histone deacetylases.............................................................................. 10
§3.9 Non-coding RNAs for diagnosis............................................................................... 10
§3.10 telomerase inhibitors.............................................................................................. 10
Hoofdstuk 4 (owg 1)............................................................................................................. 10
§4.1 epidermal growth factor signaling: an important paradigm.......................................11
1. Growth factor binding..............................................................................................11
2. Dimerization............................................................................................................11
3. Autophosphorylation............................................................................................... 11
4. Translocatie van specifieke eiwitten naar het membraan.......................................12
5. RAS activation........................................................................................................ 12
6. Raf activation..........................................................................................................12
7. The MAPK kinase cascade.................................................................................... 12
8. Regulation of transcription factors..........................................................................13
The effect of cell signaling on cell behavior................................................................13
§4.2 oncogenes................................................................................................................14
Studies of retroviruses................................................................................................14
Growth factors............................................................................................................ 14
Growth factor receptors.............................................................................................. 14
Intracellular signal transducers...................................................................................15
Transcription factors................................................................................................... 15
Mechanisms of oncogenic mutations......................................................................... 15
§4.3 kinases as drug targets............................................................................................ 16
Anti-EGFR drugs........................................................................................................ 16
Strategies against Ras and Raf..................................................................................16
MEK inhibitors............................................................................................................ 16
Hoofdstuk 6 (owg 1)............................................................................................................. 17
§6.1 definitions of tumor supressor genes....................................................................... 17
§6.2 the retinoblastoma gene...........................................................................................17
§6.3 mutations in the RB pathway and cancer.................................................................17
, §6.4 the p53 pathway....................................................................................................... 18
Stucture of p53 protein............................................................................................... 18
Regulation of p53 protein by MDM2...........................................................................18
Upstream: molecular pathways van p53 activation.................................................... 19
Downstream: molecular mechanisms of p53 cellular effects......................................19
Inhibitie van de celcyclus......................................................................................19
Apoptosis..............................................................................................................20
DNA repair and angiogenesis and other emerging roles......................................21
Factors that decide downstream outcome: cell cycle arrest or apoptosis.................. 21
§6.5 mutations in the p53 pathway and cancer................................................................21
More complex than knudson’s two-hit hypothesis...................................................... 21
§6.6 interaction of DNA viral protein products with RB and p53...................................... 22
HPV causes cervical cancer.......................................................................................22
§6.7 targeting of the p53 pathway.................................................................................... 22
Strategies that aim to correct a p53 mutation.............................................................22
Hoofdstuk 2 (owg 2)............................................................................................................. 22
§2.1 gene structure.......................................................................................................... 22
§2.2 mutations..................................................................................................................23
§2.3 carcinogenic agents................................................................................................. 24
Radiation as a carcinogen..........................................................................................24
Ionizing radiation.................................................................................................. 24
Ultraviolet radiation...............................................................................................25
Chemical carcinogens.......................................................................................... 27
Infectious pathogens as carcinogens......................................................................... 28
Endogenous carcinogenic reactions.......................................................................... 28
§2.4 DNA repair and predispositions to cancer................................................................28
§2.5 conventional therapies: chemotherapy and radiation therapy..................................30
Chemotherapy............................................................................................................ 30
Alkylating agents and platinum-based drugs........................................................30
Antimetabolieten...................................................................................................31
Organische middelen............................................................................................31
Radiation therapy....................................................................................................... 31
Heterogeneous cell sensitivity and drug resistance................................................... 32
§2.6 strategies that target DNA repair pathways..............................................................32
Synthetic lethal strategies.......................................................................................... 32
Hoofdstuk 12 (owg 3)........................................................................................................... 33
§12.1 lymphocytes: B cells and T cells............................................................................ 33
§12.2 tumor suppresive roles of the immune system.......................................................34
The cancer immunity cycle......................................................................................... 34
§12.3 immune checkpoints...............................................................................................34
§12.4 cancer immunoediting and tumor promotion.......................................................... 35
§12.5 mechanisms of avoiding immune destruction........................................................ 35
§12.6 therapeutic antibodies............................................................................................ 36
§12.7 cancer vaccines......................................................................................................36
, Therapeutic vaccins................................................................................................... 36
Whole-cell vaccines..............................................................................................37
Peptide-based vaccines....................................................................................... 37
Dendritic cell vaccines.......................................................................................... 37
Vaccines for cancer prevention.................................................................................. 37
Hurdles to jump.......................................................................................................... 37
§12.8 immune checkpoint blockades............................................................................... 37
§12.9 adoptive T-cell transfer, modified T-cel receptors and chimeric antigen receptors.38
§12.10 oncolytic viruses and virotherapy......................................................................... 38
Hoofdstuk 5 (owg 4)............................................................................................................. 39
§5.1 cyclins and cyclin-dependent kinases (cdks)........................................................... 39
§5.2 mechanisms of cdk regulation..................................................................................40
§5.3 progression through the G1 checkpoint................................................................... 40
Structure of the RB protein......................................................................................... 40
Molecular mechanisms of the effects of RB............................................................... 41
§5.4 the G2 checkpoint.................................................................................................... 41
§5.5 the mitotic checkpoint...............................................................................................42
Aurora kinases........................................................................................................... 42
§5.6 the cell cycle and cancer.......................................................................................... 43
§5.7 cyclin-dependent kinase inhibitors........................................................................... 43
§5.8 other cell cycle kinase targets.................................................................................. 43
§5.9 inhibitors of the mitotic spindle................................................................................. 43
Hoofdstuk 7 (owg 4)............................................................................................................. 44
§7.1 molecular mechanisms of apoptosis........................................................................ 44
The extrinsic pathway: mediated by membrane death receptors...............................44
The intrinsic pathway: mediated by the mitochondria................................................ 45
Cross-talk between extrinsic and intrinsic pathways.................................................. 46
P53 and apoptosis......................................................................................................46
§7.2 apoptosis and cancer............................................................................................... 46
TRAIL receptors......................................................................................................... 47
Mutations that affect the extrinsic pathway.................................................................47
Mutations that affect regulators of the intrinsic pathway.............................................47
Alternative death pathways........................................................................................ 47
§7.3 Apoptosis and chemotherapy...................................................................................47
§7.4 apoptotic drugs.........................................................................................................48
Targeting TRAIL and its receptor................................................................................48
Regulation of the Bcl-2 family of proteins...................................................................48
Direct and indirect activation of caspases.................................................................. 48
Hoofdstuk 9 (hoorcollege)...................................................................................................48
9.1 How do tumors spread?............................................................................................. 49
9.2 The process of metastasis......................................................................................... 49
9.3 Invasion and epithelial-mesecnhymal transition.........................................................49
Induction of EMT........................................................................................................ 49
Tools of invasion......................................................................................................... 50
, Cell adhesion molecules.......................................................................................50
Integrins................................................................................................................50
Proteases............................................................................................................. 50
9.4 Intravasation...............................................................................................................50
9.5 Transport.................................................................................................................... 50
9.6 Extravasation..............................................................................................................51
9.7 Metastatic colonization............................................................................................... 51
The pre-metastatic niche............................................................................................ 51
Exosomes...................................................................................................................51
Metastatic suppressor genes..................................................................................... 51
9.8 metalloproteinase inhibitors (MPIs)............................................................................ 51
9.9 Strategies for restoring metastasis suppressors........................................................ 52
Hoofdstuk 10 (hoorcollege).................................................................................................52
10.1 the angiogenic switch............................................................................................... 52
Angiogenic inducers................................................................................................... 52
Angiogenic inhibitors.................................................................................................. 52
10.2 cell behavior during angiogenic sprouting................................................................ 53
10.3 other means of tumor neovascularization................................................................ 53
10.4 anti-angiogenische therapy...................................................................................... 53
Belangrijke termen:................................................................................................................ 54
