Hoorcolleges Oncogenesis P1
HC 1: Course outline; explanation literature study/lecture discussion
All information will be posted on Canvas and will stay there during the course. Afterwards it will be
deleted.
Administration and logistics: Sandra Biemans ()
Coordinator master Oncology: Miriam van Strien ()
The course consist of 3 parts:
1. Morning sessions;
2. Discussion of basic lectures per group on 21th, 22nd, and 23th September;
3. Literature (self-)study on a specific familial cancer syndrome followed by a presentation on
Monday 26th September.
Goal is to understand and reproduce the topics of Oncogenesis (cancer genes and cancer pathways
(1), cancer genomics and epigenetics (2), mechanisms models and methods (3), viruses causing
cancer (4), clinical aspects (5) and DNA repair, clinical genetics and predisposition syndromes (6)).
Handouts of the presentation will be posted on Canvas. Lecture content is the main exam
knowledge. Exam is 70% of the final mark. The exam consist of 24 open questions.
Lecture discussion (10%) contains a well-structured interactive presentation of 15 minutes on an
important topic of which a lecture was given and 15 minutes discussion. Presentation and discussion
may be separate but also integrated. Aim: repetition with discussion of a complex and important
topics.
The aim of this literature study (20%) is to prepare a comprehensive presentation on a form of
familial cancer. You have time to prepare the presentation during the afternoons of the course and
the presentations will be given in the last week.
Lectures need to contain:
- Inheritance of the disease;
- Clinical features;
- Discovery of the affected genes;
- Animal models;
- Molecular pathway in which the gene product is involved;
- Remarkable observations of any kind.
HC 2: Cell signalling and cancer genes
1. Signal transduction (mechanism to translate extracellular signals into a cellular response)
2. Oncogenes and tumor suppressor genes (defect in these genes causes cancer)
Cancer is caused by a genetic defect in regulation of:
- Proliferation
- Apoptosis
- Cell adhesions
Understand how proliferation, survival and adhesion is controlled in a normal cell → better
understanding of tumorigenesis → better prevention, diagnosis, and treatment.
,Kinase phosphorylates substrates and causes conformational changes where it can bind to other
proteins. Signalling by phosphorylation.
GTPase is active in the GTP state and inactive GDP state. When it is active it can bind to other
proteins. Signalling by GTP-binding protein.
G-protein-coupled receptors: receptor gets activated →activated alpha subunit of G-protein →
activation of adenylate cyclase → activate PKA by ATP → transported into the nucleus where it
activates and phosphorylates CREB → activated CREB can bind and thereby activate an target gene
which enables transcription.
- Phospholipase C hydrolyse is a phospholipid which produces diaglycerol and IP3. DG
activates PKC and IP3 binds to the receptor of the ER resulting in opening Ca2+ canals.
- Proteins kinase C activated can activated MAPK which can activate transcription factors.
Receptor tyrosine kinase (growth factor receptors) which are activated by dimerization. Hereby
cross-phosphorylation will occur, making a recruitment of other adaptor proteins containing a SH2-
and SH3 domains possible.
- RAS is an important protein regulated by G-proteins.
GAP speed up the inactivation of RAS and GEF speed
up the activation of RAS by removing the GDP proteins
so GTP can bind again. Activate RAS can bind and
activate Raf, Raf (MAPKKK) phosphorylate and thereby
activate MEK, MEK (MAPKK) can phosphorylate and
thereby activate MAPK.
- PKC can also activate Raf.
- DG can also interact with RAS-GEF
- PI3K can phosphorylate lipid molecules. PI3 activate →
PH-domains are produced → activation of PKB ad
PDK1 → activation + dissociation of PKB → BAD is
phosphorylated and thereby inactivated and Bcl2 is
released from BAD and can now inhibit apoptosis.
Foci-formation assay demonstrates the information that gene damage causes cancer! Rous Sarcoma
Virus is the first known oncovirus. In “normal” retrovirus the SCR-gene is not present. The gene is
highly similar to a human gene encoding a tyrosine kinase. Apparently it is high-jacked by the
retrovirus from the host DNA. The gene that cause cancer in human cancer cells turned out to be
mutant alleles of the same genes as previously identified in the retroviruses.
Proto-oncogene = normal, oncogene (is a gain of function mutation
(dominant) and only 1 allele can be mutated) upon:
- Mutation = activation. Point-mutation in RAS or Neu-receptor
cause constitutively active cells
- Amplification = overexpression. Myc can be activated by
amplification by double minutes and homogeneously staining
region (found in neuroblastomas).
- Chromosomal translocation = overexpression or activation.
, - Viral insertion inducing
overexpression.
Tumor suppressor genes are a
counterpart of oncogenes.
Normally it suppresses tumor
formation so you need a loss of
function mutation (recessive) and
both alleles need to be mutated
(Knudson two-hit model). These
mutations are often found in
sporadic and hereditary. In hereditary cancer almost exclusively TSG mutations are found.
- Retinoblastoma: Rb controls the cell cycle. When this gene is absent or inactive E2F is overly
activated. In hereditary RB you are born with 1 allele and only need 1 hit to develop
Retinoblastoma. In non-hereditary RB you are born with to healthy alleles and need 2 hits to
develop Retinoblastoma.
- Wnt signalling defects causes colorectal cancer. Mutations in APC are often found in
hereditary tumors and mutations in beta-catenin in sporadic tumors.
- P53 is involved in blocking DNA synthesis and/or initiates apoptosis and is thereby the
guardian of the genome. Puts the cell in senescence.
Epigenetic changes can also cause cancer; gene silencing by hypermethylation of the promotor of
tumor suppressor genes, including mismatch repair genes.
Cancer is caused by a combination of various mutations! Major targets for precision
medicine/targeted therapy: small-molecule inhibitor and antibody therapy.
Receptor tyrosine G1S cell cycle
kinase pathway checkpoint
Oncogenes RTKs (like HER2/Neu), NF-1 (= RasGAP), PTEN
PI3K, Ras, Raf, Akt/PKB, (= PIP3 phosphatase)
Bcl2
Tumor suppressor genes HER2/Neu, Ras, cyclin D, P53, p14ARF, p16INK4a,
Cdk4 p27, Rb1
, HC 3: Deregulated cellular processes in cancer – Hallmarks of cancer
Characteristics in every type of cancers and its underlying principles. The hallmarks can help as a
framework in understanding cancer.
Hallmarks (14 in total):
1. Self-sufficiency in growth signals.
a. Quiescent/normal cell contain cadherins for cell-cell adhesion and integrins for cell-
matric adhesion. When a growth factor binds to a growth receptor a cell can
proliferate. Cancer cells have an overexpression of growth receptors of oncogenic
mutations in signal transducers causes independent proliferation.
2. Insensitivity to anti-growth signals.
a. Normal cell react to contact inhibition. Cancer cells have a loss of these sensors or
cadherins to ignore contact inhibition. Oncogenic signalling, low glucose
concentration, DNA damage, reactive oxygen species, and nucleotides are sensors in
a cell causing the cell in cell cycle arrest, apoptosis and oncogene-induced
senescence. Notice that many sensors signal through TP53.
3. Evading apoptosis
a. In the intrinsic pathway anti- and pro-apoptotic signals are balanced. DNA damage or
cellular stress causing the balance more pro-apoptotic inducing apoptosis. Extrinsic
proteins binding to death receptors trigger apoptosis by the extracellular pathway.
Cancer cells have a loss in pro-apoptotic signals and increased
survival signals.
4. Limitless replicative potential – telomeres
a. Telomeres are the end of chromosomes protecting the DNA during
replication. DNA-polymerase only goes for 5’ to 3’ so a little end of
the telomeres will by chopped off. Telomere extension by
telomerase with and RNA template making the DNA a bit longer.
Cancer cells expresses telomerase to avoid a senescence crisis by
inactivation of p53, p16 and pRb.
5. Sustained angiogenesis
a. Making new blood vessels to the tumor to provide it with oxygen
and nutrients. This can be stimulated by VEGF and thrombospondin.
6. Invasion/metastasis
a. Benign (no invasive growth,
often encapsulated, well-
differentiated, slow and
limited growth, not
metastasize) and malignant
(invasive growth, not
encapsulated, abnormal
differentiation, fast and
unlimited growth, potentially
metastasized). During
invasion the integrin and
cathenin expression is altered
disconnecting them from neighbouring cells and its basement membrane.
b. Metastasis = dissociation → invasion → intravasation → circulation → extravasation
→ colonization.
HC 1: Course outline; explanation literature study/lecture discussion
All information will be posted on Canvas and will stay there during the course. Afterwards it will be
deleted.
Administration and logistics: Sandra Biemans ()
Coordinator master Oncology: Miriam van Strien ()
The course consist of 3 parts:
1. Morning sessions;
2. Discussion of basic lectures per group on 21th, 22nd, and 23th September;
3. Literature (self-)study on a specific familial cancer syndrome followed by a presentation on
Monday 26th September.
Goal is to understand and reproduce the topics of Oncogenesis (cancer genes and cancer pathways
(1), cancer genomics and epigenetics (2), mechanisms models and methods (3), viruses causing
cancer (4), clinical aspects (5) and DNA repair, clinical genetics and predisposition syndromes (6)).
Handouts of the presentation will be posted on Canvas. Lecture content is the main exam
knowledge. Exam is 70% of the final mark. The exam consist of 24 open questions.
Lecture discussion (10%) contains a well-structured interactive presentation of 15 minutes on an
important topic of which a lecture was given and 15 minutes discussion. Presentation and discussion
may be separate but also integrated. Aim: repetition with discussion of a complex and important
topics.
The aim of this literature study (20%) is to prepare a comprehensive presentation on a form of
familial cancer. You have time to prepare the presentation during the afternoons of the course and
the presentations will be given in the last week.
Lectures need to contain:
- Inheritance of the disease;
- Clinical features;
- Discovery of the affected genes;
- Animal models;
- Molecular pathway in which the gene product is involved;
- Remarkable observations of any kind.
HC 2: Cell signalling and cancer genes
1. Signal transduction (mechanism to translate extracellular signals into a cellular response)
2. Oncogenes and tumor suppressor genes (defect in these genes causes cancer)
Cancer is caused by a genetic defect in regulation of:
- Proliferation
- Apoptosis
- Cell adhesions
Understand how proliferation, survival and adhesion is controlled in a normal cell → better
understanding of tumorigenesis → better prevention, diagnosis, and treatment.
,Kinase phosphorylates substrates and causes conformational changes where it can bind to other
proteins. Signalling by phosphorylation.
GTPase is active in the GTP state and inactive GDP state. When it is active it can bind to other
proteins. Signalling by GTP-binding protein.
G-protein-coupled receptors: receptor gets activated →activated alpha subunit of G-protein →
activation of adenylate cyclase → activate PKA by ATP → transported into the nucleus where it
activates and phosphorylates CREB → activated CREB can bind and thereby activate an target gene
which enables transcription.
- Phospholipase C hydrolyse is a phospholipid which produces diaglycerol and IP3. DG
activates PKC and IP3 binds to the receptor of the ER resulting in opening Ca2+ canals.
- Proteins kinase C activated can activated MAPK which can activate transcription factors.
Receptor tyrosine kinase (growth factor receptors) which are activated by dimerization. Hereby
cross-phosphorylation will occur, making a recruitment of other adaptor proteins containing a SH2-
and SH3 domains possible.
- RAS is an important protein regulated by G-proteins.
GAP speed up the inactivation of RAS and GEF speed
up the activation of RAS by removing the GDP proteins
so GTP can bind again. Activate RAS can bind and
activate Raf, Raf (MAPKKK) phosphorylate and thereby
activate MEK, MEK (MAPKK) can phosphorylate and
thereby activate MAPK.
- PKC can also activate Raf.
- DG can also interact with RAS-GEF
- PI3K can phosphorylate lipid molecules. PI3 activate →
PH-domains are produced → activation of PKB ad
PDK1 → activation + dissociation of PKB → BAD is
phosphorylated and thereby inactivated and Bcl2 is
released from BAD and can now inhibit apoptosis.
Foci-formation assay demonstrates the information that gene damage causes cancer! Rous Sarcoma
Virus is the first known oncovirus. In “normal” retrovirus the SCR-gene is not present. The gene is
highly similar to a human gene encoding a tyrosine kinase. Apparently it is high-jacked by the
retrovirus from the host DNA. The gene that cause cancer in human cancer cells turned out to be
mutant alleles of the same genes as previously identified in the retroviruses.
Proto-oncogene = normal, oncogene (is a gain of function mutation
(dominant) and only 1 allele can be mutated) upon:
- Mutation = activation. Point-mutation in RAS or Neu-receptor
cause constitutively active cells
- Amplification = overexpression. Myc can be activated by
amplification by double minutes and homogeneously staining
region (found in neuroblastomas).
- Chromosomal translocation = overexpression or activation.
, - Viral insertion inducing
overexpression.
Tumor suppressor genes are a
counterpart of oncogenes.
Normally it suppresses tumor
formation so you need a loss of
function mutation (recessive) and
both alleles need to be mutated
(Knudson two-hit model). These
mutations are often found in
sporadic and hereditary. In hereditary cancer almost exclusively TSG mutations are found.
- Retinoblastoma: Rb controls the cell cycle. When this gene is absent or inactive E2F is overly
activated. In hereditary RB you are born with 1 allele and only need 1 hit to develop
Retinoblastoma. In non-hereditary RB you are born with to healthy alleles and need 2 hits to
develop Retinoblastoma.
- Wnt signalling defects causes colorectal cancer. Mutations in APC are often found in
hereditary tumors and mutations in beta-catenin in sporadic tumors.
- P53 is involved in blocking DNA synthesis and/or initiates apoptosis and is thereby the
guardian of the genome. Puts the cell in senescence.
Epigenetic changes can also cause cancer; gene silencing by hypermethylation of the promotor of
tumor suppressor genes, including mismatch repair genes.
Cancer is caused by a combination of various mutations! Major targets for precision
medicine/targeted therapy: small-molecule inhibitor and antibody therapy.
Receptor tyrosine G1S cell cycle
kinase pathway checkpoint
Oncogenes RTKs (like HER2/Neu), NF-1 (= RasGAP), PTEN
PI3K, Ras, Raf, Akt/PKB, (= PIP3 phosphatase)
Bcl2
Tumor suppressor genes HER2/Neu, Ras, cyclin D, P53, p14ARF, p16INK4a,
Cdk4 p27, Rb1
, HC 3: Deregulated cellular processes in cancer – Hallmarks of cancer
Characteristics in every type of cancers and its underlying principles. The hallmarks can help as a
framework in understanding cancer.
Hallmarks (14 in total):
1. Self-sufficiency in growth signals.
a. Quiescent/normal cell contain cadherins for cell-cell adhesion and integrins for cell-
matric adhesion. When a growth factor binds to a growth receptor a cell can
proliferate. Cancer cells have an overexpression of growth receptors of oncogenic
mutations in signal transducers causes independent proliferation.
2. Insensitivity to anti-growth signals.
a. Normal cell react to contact inhibition. Cancer cells have a loss of these sensors or
cadherins to ignore contact inhibition. Oncogenic signalling, low glucose
concentration, DNA damage, reactive oxygen species, and nucleotides are sensors in
a cell causing the cell in cell cycle arrest, apoptosis and oncogene-induced
senescence. Notice that many sensors signal through TP53.
3. Evading apoptosis
a. In the intrinsic pathway anti- and pro-apoptotic signals are balanced. DNA damage or
cellular stress causing the balance more pro-apoptotic inducing apoptosis. Extrinsic
proteins binding to death receptors trigger apoptosis by the extracellular pathway.
Cancer cells have a loss in pro-apoptotic signals and increased
survival signals.
4. Limitless replicative potential – telomeres
a. Telomeres are the end of chromosomes protecting the DNA during
replication. DNA-polymerase only goes for 5’ to 3’ so a little end of
the telomeres will by chopped off. Telomere extension by
telomerase with and RNA template making the DNA a bit longer.
Cancer cells expresses telomerase to avoid a senescence crisis by
inactivation of p53, p16 and pRb.
5. Sustained angiogenesis
a. Making new blood vessels to the tumor to provide it with oxygen
and nutrients. This can be stimulated by VEGF and thrombospondin.
6. Invasion/metastasis
a. Benign (no invasive growth,
often encapsulated, well-
differentiated, slow and
limited growth, not
metastasize) and malignant
(invasive growth, not
encapsulated, abnormal
differentiation, fast and
unlimited growth, potentially
metastasized). During
invasion the integrin and
cathenin expression is altered
disconnecting them from neighbouring cells and its basement membrane.
b. Metastasis = dissociation → invasion → intravasation → circulation → extravasation
→ colonization.
