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HC2 cancer biologyMalignant cells:
- unorganized, not differentiated
- unlimited proliferation
- angiogenisis (growth of bloodvessels from existing vessels)
Hallmarks of cancer:
- sustaining proliferative signaling
- evading growth suppressors
- avoiding immune destruction
- enabling replicative immortality
- tumorpromoting inflammation > inabler
- activating invasion and metastasis
- inducing angiogenesis
- genome instability & mutation > inabler
- resisting cell death
- deregulating cellular energetics
inabler: these hallmarks feed the others,
Sustaining proliferative signaling:
- Overexpression of a growth factor that works on the cell itself (autocrine)
- Overexpression of cell surface receptors and/or activating mutations of the receptor
> doesn’t need growth factors anymore
> by targetting tyrosine kinase domain because it activates proteins by phosphorylation
> breast cancer: amplification of HER2
- Overexpression of intracellular signaling molecules or activating mutations of intracellular
signaling molecules
- Overexpression of transcription factors
Genes that can stimulate cancer development are referred to as proto-oncogenes
Overexpression of a ligand is more easily treatable
Evading growth suppressors:
In healthy cells the activity of growth suppressors is high and the activity of growth promoters are
low, in a cancer cell it is the opposite
There are checkpoints in the cell cyclus to prevent the cell from proliferating uncontrollably. The
checkpoint before synthesis (S phase) is controlled by retinoblastoma > when fosforylated by CDK >
RB releases E2F > transcriptional activation
In a normal cell retinoblastoma is not fosforyalted and it keeps E2F which blocks transcription, so
retinoblastoma is a tumorsurpressor gene.
Loss of function mutations of growth inhibitors (TGFbeta, p16)
Gain of function mutations or growth factors (CDK, cyclin D)
TP53 = the major tumor suppressor:
- hyperproliferative signals/DNA damage/telomere shortening etc > cell-cycle arrest/ apoptosis etc
- mutated in >50% of all human tumors
,- TP53-related pathways affected in >90% of all tumors
- Li Fraumeni syndrome = hereditary mutation in TP53, dominant inheritance > develop multiple
primary tumors at young age
Wnt signalling pathways generates cell proliferation by activating TCF in the nucleus.
But in a normal cell, there is no activation of TCF because the intracellular molecul beta-catenin (that
is responsable for activating TCF) gets destroyed by APC.
In a cancer cell, WNT is stimulated which leads to TCF activation and proliferation
> APC is tumor suppressor gene, beta-catenin is oncogene
> in cancer cells APC is targeted by inactivating mutations
or beta-catenin is targeted by activating mutations
Evading immune destruction:
Not producing MHC class I
Enabling replicative immortality:
The end of chromosomes get shorter by time. Cancer cells activate the enzyme (=telomerase/TERT)
that increases telomere length.
(HC3 Cancer genetics)
Activation of invasion and metastasis:
In order to be capable of metastasis the cell has to:
- loosen up tumor cell-tumor cell interaction
- degradation of extracellular matrix
- (epithelial tumors: lose epithelial differentiation)
>only a few cells are able to metastasize
Inducing angiogenesis:
The growth of tissue requires nutrients and oxygen and the ability to waste products. Therefore new
blood vessels and lymphe are necessary.
Tumor size is limited by the capacity of cancer cells to induce angiogenesis.
Resisting cell death:
Anti-apoptotic factors are over expressed, pro-apoptotic factos are targeted or lost in cancer cells.
Deregulating cellular energetics:
,In tumor cells there is a switch from oxidative phosphorylation to glycolysis >= Warburg effect
> results in more production of lactate which stimulates angiogenesis
Tumor-promoting inflammation:
- Release of factors that promote proliferation
- Removal of growth suppressors
- Enhanced resistance cell death
- Inducing angiogenesis
- Activating invasion and metastasis
- Evading immune destruction
>this also happens if you have a wound infection
HC3 Cancer genetics
Cancer is a multi-step process: you don’t need all the hallmarks at the same time, it can take years
Mutation = permanent alteration in a parental DNA sequence (has to be both strengs)
Multi-locus deletion > leads to loss of function of the deleted alleles, and to loss of heterozygosity
(the other chromosome is intact)
You can have a deletion of a exon but no loss of function > because there is no change of the reading
frame (and it is a deletion of a small protein)
Nonsense mutation: nucleotide becomes stopcodon
Silent mutation (often the last codon): the aminoacid stays the same
Mutations in proto-oncogenes can lead to cancer:
- coding mutation > abnormal protein
- regulatory mutation > excessive amount of protein
- translocation > novel protein or increased protein
expression
- gene amplification > excessive amount of protein
Typical mutated (substitution) oncogene > Ras:
A mutation in RAS/KRAS prevent GAP from
hydrolysing the GTP on Ras which would make Ras
inactive. So a mutated KRAS always stays active.
Double minutes = small fragments of DNA outside of
the chromosome that are an amplificated gene
(probably a gene that is an advantage for cancer)
Homogeneously staining regions (HSRs) = same as
double minutes but larger
Chromosomal translocations can lead to overexpression of a protein:
With Burkitt lymphoma: MYC is an oncogene and goes to sit behind the promotor of IGH (=
immunoglobolin expressor of B cell), MYC becomes highly active (in normal cells MYC is inactive)
Activation mutation of proto-oncogene: only need a mutation in 1 allele
Inactivation of tumor suppressor: need a mutation in both alleles >= two hit rule
> In people with a native heterozygosity (at birth there is already a mutation in 1 allele) there only
, needs to be 1 more mutation, so these people often develop cancer at a young age
> exception 2-hit rule: tp53 works as a tetramere. If there is a mutation in 1 allele the complex
doesn’t work, usually a missense mutation because if it was a deletion the protein wouldn’t be
expressed and p53 is still a wild type
>= dominant negative mutation
Methylation leads to condensed DNA > not open for RNA polymerase
- hypermethylated heterochromatin > hypomethylation > oncogene activation
- hypomethylated CpG region (promotor) > hypermethylation > loss of tumor suppressor gene
activity
Mutation patterns:
- oncogenes: accumulation of missense mutations in
particular spots
- tumor suppressor gene: doesn’t matter where the
mutations are, but there are a lot of truncating mutations (=
results in a shorter version of the protein being produced, by
stopcodons or frameshift)
Driver vs passenger genes:
- mutations in driver genes: frequent, functionally relevant (for forming of cancer)
- mutations in passenger genes: random, functionally irrelevant (for cancer cells)
Co-occurence of mutations:
- mutual exclusivity = 2 mutations never occur in the same cell > because it is the same mutation or
the cell can’t survive with both mutations or they occur in different cancer subtypes
> vb. KRAS & BRAS (they are in the same pathway)
- random assortment = independence of effects
- co-occurence = 2 mutations often go together > because together they give some properties to the
cell that are adventages or one mutation promotes the development of the other mutation
> vb. mismatch repair & HLA/MHC class I (mutation in HLA leads to deficiency in mismatch repair)
HC4 etiology of cancer
Cancer is often caused by cell division of stem cells because they proliferate a lot.
The chance of getting prostate cancer is higher at a higher age (and in developed countries because
people can get older)
Tabak contains benzopyrene, you can see the signature of bezopyrene (G > T & C > A) in DNA and
with that predict the type of damage that caused the cancer.
Alcohol contains acetaldehyde (metabolite of alchohol processing) that can damage cells > higher risk
of hepatical cancer
Some hormones can give a higher chance of getting cancer. Oestrogen fuels the growth and division
of breast cancer cells. An exogenous source can be menopausal horomone therapy.
Obesitas is associated with oestrogen production and chronic inflammation.
A bad diet can influence the microbiomes in the intestinal flora which protects us from pathogens
UV light can cause pyramidine dimers which leads to skin cancer.
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