Cancer 10 Flashcards
what are the first 6 hallmarks of cancer?
- Disregard of signals to stop proliferating
- Disregard of signals to differentiate
- Capacity for sustained proliferation
- Evasion of apoptosis
- Ability to invade
- Ability to promote angiogenesis
what 4 hallmarks of cancer were added?
- degregulating cellular energetics
- genome instability and mutation
- avoiding immune destruction
- tumor-promoting inflammation
what occurs briefly at each stage of the cell cycle?
- G0 = the cell is in a quiescent phase = it is not replicating
- G1 = the cell makes sure that it has enough nutrients, nucleotides etc. to replicate
- At the end of G1, the cell has a checkpoint where you get growth arrest to ensure the genetic fidelity of the cell
- Specific proteins accumulate/are destroyed during the cycle eg. cyclins
- Permanent activation of a cyclin can drive a cell through a checkpoint
what is a proto-oncogene?
- proto-oncogene is normal
- it codes for essential proteins involved in maintenance of cell
growth, division and differentiation
what is an oncogene?
- Mutation can convert a proto-oncogene into an oncogene, whose protein product no longer responds to control influences
- oncogenes might be aberrantly expressed, over=expressed or aberrantly active
how might an proto-oncogene be converted into an oncogene?
- A proto-oncogene can be converted to an oncogene by a single mutation
show the stages of oncogene activation?
- normal proto-oncogene
- mutation in the coding sequence
- gene amplification
- gene amplification is the production of multiple gene copies
- it can occur due to problems with a polymerase protein
- having multiple copies will lead to overproduction of the product
- chromosomal translocation
this produces chimeric genes, these are genes formed by combinations of portions of coding sequences to produce new genes
eg. if one of the pieces of translocated DNA is a promoter it will lead to the upregulation of the other gene portion eg. Burkitt’s lymphoma
* insertional mutagenesis
can also be a problem if the fusion gene formed produces an abnormal protein (e.g. Philadelphia chromosomes in CML)
explain the example of chromosomal translocation in cancer :
eg. Philadelphia chromosome
- philidelphia chromosome is formed by the translocation of chromosome segments from chromosomes 9 + 22
- chromosome 9 = ABL
- chromosome 22- BCR
- the BCR - ABL fusion gene leads to development of cancer
show the signal transduction pathway:
- blue spots are the proto-oncogenes
- Activation of proto-oncogenes to oncogenes can disrupt normal activity
- the oncogenes have the ability to
explain the activity of mutant RAS?
- normally upon binding to GTP, RAS becomes active and activates the kinase cascade leading to the production of gene regulatory proteins
- dephosphorylation of the GTP to GDP switches RAS off
- Mutant Ras will fail to dephosphorylate GTP so it remains active
what more complicated pathway is Ras part of?
The Ras pathway is part of a much more complex signaling cascade called the mitogen-activated protein kinase cascade (MAPK)
what does Ras code for?
Ras codes for a family of proteins such as Ki-Ras and Ha-Ras, which are membrane-bound GTPases that are important in the stimulation of cell proliferation
what cancers are the following oncogenes associated with?
SRC
MYC
JUN
Ha - RAS
Ki- RAS
SRC = breast , colon lung
MYC = burkitts lymphoma
JUN = lung
Ha - RAS = bladder
Ki- RAS = colon lung
what is the function of tumor suppressor genes?
- Typically proteins whose function is to regulate cellular proliferation and maintain cell integrity
how can cancer occur from mutation of tumour suppressor genes?
- Each cell has two copies of each tumor suppressor gene
- mutation or deletion of just one copy is not enough to promote the cancer
- Mutation or loss of both copies means loss of control
- (knudsons two hit hypothesis)
what are the features of inherited cancer susceptibility?
- Family history of related cancers
- Unusually early onset
- Bilateral tumors in paired organs
- Synchronous or successive tumors
- Tumors in different organ systems in the same individual
- Mutation inherited through the germline
explain an example of inherited cancer - retinoblastoma?
what tumor suppressor gene does it mutate?
- It is a malignant cancer of developing retinal cells
- Sporadic disease usually involves one eye
- Hereditary causes can be unilateral or bilateral and multifocal
- It is caused by mutation of the RB1 tumour suppressor gene on the chromosome 13q1
- RB1 encodes a nuclear protein that is involved in regulation of the cell cycle
what are the functional classes of tumor suppressor genes?
- Regulate cell proliferation
Maintain cellular integrity
Regulate cell growth
Regulate the cell cycle
Nuclear transcription factors
DNA repair proteins
Cell adhesion molecules
Cell death regulators
- overall they suppress they stop cancer developing
what are the common human tumor suppressor genes?
what are their functions?
what cancers are they associated with?
what are some of the examples of the purposes of P53?
- they have many different functions (very broad)
- some include
- metabolic homeostasis
- antioxidant defense
- DNA repair
- growth arrest
- senescence
- apoptosis
when is P53 active and inactive?
- When p53 is bound to MDM2 it is inactive
- when p53 is NOT bound to MDM2 it is active
how can P53 get mutated to cause cancer?
- mutants of p53 act in a DOMINANT manner and mutation of a single copy is sufficient to get dysregulation of activity
- Phosphorylation of p53 destabilises it so that it isn’t degraded so quickly and can exert its effects
- Phosphorylation is triggered by cellular stress
what is the function of APC?
- APC participates in the WNT signalling pathway
- APC protein is a negative regulator of B catenin therefore preventing uncontrolled cell division
- mutation of APC can result in colon cancer
how does mutation of APC cause colon cancer?
- deletion in 5q21 results in loss of the APC gene
- sufferers develop thousands of multiple benign polyps
- there is a 90% chance of developing a colorectal carcinoma
