Theme IA – Cancer biology and genetics
HC2 – Cancer biology
From healthy to malignant
Healthy cells/tissues are highly organized (in number and function).
(a) and (b) show normal tissue.
(d) – (g) show cancer. You see:
- outgrowth.
- invasion of adjacent tissues.
- loss of functional organization (loss of sense of space).
Hallmarks of cancer
(1) Sustaining proliferative signaling.
(2) Evading growth suppressors.
(3) Avoiding immune destruction.
(4) Enabling replicative immortality.
(5) Tumor-promoting inflammation.
(6) Activating invasion & metastasis.
(7) Inducing angiogenesis.
(8) Genome instability & mutation.
(9) Resisting cell death.
(10) Deregulating cellular energetics.
Green shade = enablers (not only typical of cancer, but it also supports malignant
transformation).
(1) Sustaining proliferative signaling
Normal signaling cascade: Growth factors binds receptor (is often a
tyrosine kinase) → they phosphorylate substrates → cascade of
phosphorylation → leads to activation of a transcription factor → starts
to bind genes (stimulating cell proliferation and differentiation) →
activates transcription.
Deregulation of this system can be via:
• Overexpression of growth factors (EGF, VEGF).
o Epidermal growth factor, vascular epidermal growth
factor.
• Overexpression of cell surface receptors and/or activating
mutations (EGFR, HER2).
, • Overexpression of intracellular signaling molecules or activating mutations (KRAS,
BRAF).
• Overexpression of transcription factors (MYC, beta-catenin).
• Inactivation of inhibitory factors of the cascade (PTEN).
Genes that can stimulate cancer development are referred to as proto-oncogenes.
Genes that suppress cell proliferation, that, if removed, stimulate cancer development, are
called tumor suppressor genes.
Overexpression/activation of cell surface receptors
• Activating mutations or amplification of EGFR are common in lung cancer. Activating
mutations are all in the same domain (tyrosine kinase), because it needs the
functional consequence (it needs to auto phosphorylate, otherwise it will not lead to
cancer). The same goes for tumor suppressor genes: the mutations must be in the
same domain because it has to have functional consequences.
• Amplification of HER2 is common in breast cancer. Normal cell has limited amount of
HER2 receptors. A breast-cancer cell has a huge increase of the HER2 receptors.
Activation of intracellular signaling molecules
Mutations can happen everywhere.
Objective = a cancer cell wants to become independent of extracellular signals.
(2) Evading growth suppressors
In a healthy cell, growth suppressors dominate. In a healthy cell, all the transitions in the cell
cycle are checked before it proceeds. All this is controlled by growth suppressors and tumor
suppressor genes.
In tumors, this is lost. They can replicate even with mistakes in the DNA.
Start checkpoint
TGF-beta is an important growth inhibitor. It activates inhibitors, that control the
phosphorylation status (important). They in turn control retinoblastoma protein (RB).
It lies around E2F (transcription factor), inhibiting it.
Only if there is activation of growth factors, RB becomes activated to release E2F,
leading to transcription.
In a cancer cell, there may be:
- Loss of inhibition by mutations of growth inhibitors (by e.g., mutate the receptor
for TGF-beta or mutate RB to activate it).
- Gain of function by mutations of growth factors (leading to activation of RB).
TP53 – the most important tumor suppressor
Controls everything!
, • Mutated in >50% of all human tumors (guardian of the genome).
• P53-related pathways affected in >90% of all tumors.
Loss of p53 → loss of cell cycle checkpoints and proliferation of cells with DNA
damage.
• Hereditary (heterozygous) mutation in TP53 gene leads to Li Fraumeni syndrome,
where you develop multiple primary tumors of various kinds (because p53 involved in
many aspects of the cell and all tissues) at young age. Dominant autosomal
inheritance.
Wnt signaling
Wnt signaling starts with binding of Wnt-ligand to Wnt-receptor → APC (= tumor
suppressor gene) releases from beta-catenin → cell activated to go into transcription.
In cancer, no binding (of Wnt-ligand) is necessary anymore for the cell to proliferate.
APC is a main tumor suppressor in colorectal cancer.
Beta-catenin = oncogene.
Also, a part of the cytoskeleton (E-cadherin) holds beta-catenin. Mutations in E-
cadherin makes cells to become detached from each other, and it increases the
amount of beta-catenin that is free in the cytoplasm and can therefore increase
proliferation.
E-cadherin = tumor-suppressor gene (TSG).
(3) Evading immune destruction (mainly another lecture)
Cancer cells evade immune system via:
- getting rid of MHCI molecules on the surface. Tumor cells do not need to present
peptides to T-cells anymore.
- recruiting immune cells that suppress inflammation.
(4) Enabling replicative immortality
They are not immortal, but cancer cells can divide a lot compared to a healthy cell.
Normally, somatic cells divide, and their telomere length shortens. Telomeres are repetitive
stretches at the terminal ends of the chromosome. When the telomere is short enough, the
chromosome is not stable anymore (= senescence), and they cannot replicate anymore.
Adult stem cells have to divide more during the life span so these have longer telomeres.
Embryonic stem cells have even longer telomeres because they have to divide indefinitely.
, - Normal cells have limited proliferative capacity.
- They enter a state of senescence where they cannot re-enter the cell cycle.
- Number of doublings is dependent on species, tissue, and age of organism.
Human telomeres:
- Contain 5-15 kb of TTAGGG repeats.
- Telomerase increases the size of the telomeres.
- Telomerase (encoded by TERT-gene) required for their replication.
- Somatic cells do not express telomerase.
Activation of the TERT (telomerase) is a mechanism by which cancer stabilizes telomeres.
They can keep dividing.
(5) Activation of invasion and metastasis (one of most serious features of cancer)
Invasion:
• Loosening up of tumor cell to tumor cell interactions (via inactivation of E-cadherin).
• Degradation of extracellular matrix (via expression of proteolytic enzymes).
• Epithelial tumors → lose epithelial differentiation.
Metastasis is an inefficient process: millions of tumor cells might be released from a primary
tumor per day, only few are able to metastasize. The cancer cells got used to the
environment they originated in.
(6) Inducing angiogenesis
Like normal tissues, tumors require nutrients and oxygen as well as an ability to evacuate
waste products.
Tumor size is limited by the capacity of cancer cells to induce angiogenesis. More
angiogenesis promoters and less angiogenesis inhibitors lead
to tumor metastasis.
(7) Resisting cell death
There is downregulation of pro-apoptotic factors and
blockage of apoptotic peptidase activating factor 1.
There is upregulation of anti-apoptotic factors and inhibitors
of apoptosis.
(8) Deregulating cellular energetics
Oxidative phosphorylation leads to ATP production.
Glycolysis leads to the production of building blocks.
Tumor cells will not make many mediators anymore to go
into oxidative phosphorylation, but they will use the building blocks from glycolysis to use for
HC2 – Cancer biology
From healthy to malignant
Healthy cells/tissues are highly organized (in number and function).
(a) and (b) show normal tissue.
(d) – (g) show cancer. You see:
- outgrowth.
- invasion of adjacent tissues.
- loss of functional organization (loss of sense of space).
Hallmarks of cancer
(1) Sustaining proliferative signaling.
(2) Evading growth suppressors.
(3) Avoiding immune destruction.
(4) Enabling replicative immortality.
(5) Tumor-promoting inflammation.
(6) Activating invasion & metastasis.
(7) Inducing angiogenesis.
(8) Genome instability & mutation.
(9) Resisting cell death.
(10) Deregulating cellular energetics.
Green shade = enablers (not only typical of cancer, but it also supports malignant
transformation).
(1) Sustaining proliferative signaling
Normal signaling cascade: Growth factors binds receptor (is often a
tyrosine kinase) → they phosphorylate substrates → cascade of
phosphorylation → leads to activation of a transcription factor → starts
to bind genes (stimulating cell proliferation and differentiation) →
activates transcription.
Deregulation of this system can be via:
• Overexpression of growth factors (EGF, VEGF).
o Epidermal growth factor, vascular epidermal growth
factor.
• Overexpression of cell surface receptors and/or activating
mutations (EGFR, HER2).
, • Overexpression of intracellular signaling molecules or activating mutations (KRAS,
BRAF).
• Overexpression of transcription factors (MYC, beta-catenin).
• Inactivation of inhibitory factors of the cascade (PTEN).
Genes that can stimulate cancer development are referred to as proto-oncogenes.
Genes that suppress cell proliferation, that, if removed, stimulate cancer development, are
called tumor suppressor genes.
Overexpression/activation of cell surface receptors
• Activating mutations or amplification of EGFR are common in lung cancer. Activating
mutations are all in the same domain (tyrosine kinase), because it needs the
functional consequence (it needs to auto phosphorylate, otherwise it will not lead to
cancer). The same goes for tumor suppressor genes: the mutations must be in the
same domain because it has to have functional consequences.
• Amplification of HER2 is common in breast cancer. Normal cell has limited amount of
HER2 receptors. A breast-cancer cell has a huge increase of the HER2 receptors.
Activation of intracellular signaling molecules
Mutations can happen everywhere.
Objective = a cancer cell wants to become independent of extracellular signals.
(2) Evading growth suppressors
In a healthy cell, growth suppressors dominate. In a healthy cell, all the transitions in the cell
cycle are checked before it proceeds. All this is controlled by growth suppressors and tumor
suppressor genes.
In tumors, this is lost. They can replicate even with mistakes in the DNA.
Start checkpoint
TGF-beta is an important growth inhibitor. It activates inhibitors, that control the
phosphorylation status (important). They in turn control retinoblastoma protein (RB).
It lies around E2F (transcription factor), inhibiting it.
Only if there is activation of growth factors, RB becomes activated to release E2F,
leading to transcription.
In a cancer cell, there may be:
- Loss of inhibition by mutations of growth inhibitors (by e.g., mutate the receptor
for TGF-beta or mutate RB to activate it).
- Gain of function by mutations of growth factors (leading to activation of RB).
TP53 – the most important tumor suppressor
Controls everything!
, • Mutated in >50% of all human tumors (guardian of the genome).
• P53-related pathways affected in >90% of all tumors.
Loss of p53 → loss of cell cycle checkpoints and proliferation of cells with DNA
damage.
• Hereditary (heterozygous) mutation in TP53 gene leads to Li Fraumeni syndrome,
where you develop multiple primary tumors of various kinds (because p53 involved in
many aspects of the cell and all tissues) at young age. Dominant autosomal
inheritance.
Wnt signaling
Wnt signaling starts with binding of Wnt-ligand to Wnt-receptor → APC (= tumor
suppressor gene) releases from beta-catenin → cell activated to go into transcription.
In cancer, no binding (of Wnt-ligand) is necessary anymore for the cell to proliferate.
APC is a main tumor suppressor in colorectal cancer.
Beta-catenin = oncogene.
Also, a part of the cytoskeleton (E-cadherin) holds beta-catenin. Mutations in E-
cadherin makes cells to become detached from each other, and it increases the
amount of beta-catenin that is free in the cytoplasm and can therefore increase
proliferation.
E-cadherin = tumor-suppressor gene (TSG).
(3) Evading immune destruction (mainly another lecture)
Cancer cells evade immune system via:
- getting rid of MHCI molecules on the surface. Tumor cells do not need to present
peptides to T-cells anymore.
- recruiting immune cells that suppress inflammation.
(4) Enabling replicative immortality
They are not immortal, but cancer cells can divide a lot compared to a healthy cell.
Normally, somatic cells divide, and their telomere length shortens. Telomeres are repetitive
stretches at the terminal ends of the chromosome. When the telomere is short enough, the
chromosome is not stable anymore (= senescence), and they cannot replicate anymore.
Adult stem cells have to divide more during the life span so these have longer telomeres.
Embryonic stem cells have even longer telomeres because they have to divide indefinitely.
, - Normal cells have limited proliferative capacity.
- They enter a state of senescence where they cannot re-enter the cell cycle.
- Number of doublings is dependent on species, tissue, and age of organism.
Human telomeres:
- Contain 5-15 kb of TTAGGG repeats.
- Telomerase increases the size of the telomeres.
- Telomerase (encoded by TERT-gene) required for their replication.
- Somatic cells do not express telomerase.
Activation of the TERT (telomerase) is a mechanism by which cancer stabilizes telomeres.
They can keep dividing.
(5) Activation of invasion and metastasis (one of most serious features of cancer)
Invasion:
• Loosening up of tumor cell to tumor cell interactions (via inactivation of E-cadherin).
• Degradation of extracellular matrix (via expression of proteolytic enzymes).
• Epithelial tumors → lose epithelial differentiation.
Metastasis is an inefficient process: millions of tumor cells might be released from a primary
tumor per day, only few are able to metastasize. The cancer cells got used to the
environment they originated in.
(6) Inducing angiogenesis
Like normal tissues, tumors require nutrients and oxygen as well as an ability to evacuate
waste products.
Tumor size is limited by the capacity of cancer cells to induce angiogenesis. More
angiogenesis promoters and less angiogenesis inhibitors lead
to tumor metastasis.
(7) Resisting cell death
There is downregulation of pro-apoptotic factors and
blockage of apoptotic peptidase activating factor 1.
There is upregulation of anti-apoptotic factors and inhibitors
of apoptosis.
(8) Deregulating cellular energetics
Oxidative phosphorylation leads to ATP production.
Glycolysis leads to the production of building blocks.
Tumor cells will not make many mediators anymore to go
into oxidative phosphorylation, but they will use the building blocks from glycolysis to use for
