Neoplasia II: Oncogenesis & Pre-malignancy Flashcards
What are some hallmarks of cancer?
-Limitless replication potential
-Sustained angiogenesis
-Evasion of apoptosis
-Self-sufficiency in growth signals
-Tissue invasion & metastasis
-Insensitivity to growth inhibition
How do cells accumulate these hallmarks of cancer?
By one of two mechanisms:
Activation of oncogenes
Inactivation of tumour suppression genes
What is oncogenesis?
Development of cancer
What is a proto-oncogene?
A normal gene whose product promotes cell growth.
What is an oncogene?
A dysregulated proto-oncogene causing cell to grow autonomously
What is an oncoprotein?
The product of an oncogene
How do proto-oncogenes become oncogenes?
Through mutations, chromosomal rearrangements, & gene amplifications.
How are oncogenes classified?
They’re classified according to where they are in the signalling pathway, so they may act as either:
-Growth factors
-Growth factor receptors
-Signal transducing proteins
-Nuclear proteins
How do oncogenes maintain the self-sufficiency of growth signals?
They over-express growth factors so that its receptors are constantly stimulated (autocrine activation).
Or
They can also be self-sufficient through inappropriate activation of the receptor, either through ligand-dependent activation or ligand-independent activation
Give some examples of self-sufficiency of growth signals and which cancer was caused.
slide 23
What is an example of a signal transduction protein in oncogenesis?
Ras
What is Ras bound to in its inactive form?
GDP
What happens when Ras is activated through upstream signalling?
It phosphorylates to become bound to GTP and it then induces further donwstream signalling to progress the cell through its cell cycle
Ras is then returned to its inactive state
What happens when there are mutations in Ras?
If it fails to return to its inactive state, it renders this protein to be continuously stimulating downstream proteins, therefore progressing the cell inappropriately through the cell cycle.
What are some examples of gene translocations in neoplasia?
Gene translocation as a mechanism of oncogene activation is relatively common in tumours of the haematopoietic system.
Give an example of gene amplification in oncogenesis.
Amplification of N-myc gene seen in neuroblastomas
Over-expression of oncoprotein may result from the duplication of DNA Sequences.
What is the normal function of tumour suppressor genes?
To regulate cellular proliferation
How are tumour suppressor genes classified?
Gatekeeper genes- inhibit proliferation/induce apoptosis of cells with damaged DNA
Caretaker genes- maintain integrity of genome
How are tumour suppressor genes inactivated?
-Mutation
-Deletion
-Transcriptional silencing
What is the most widely dysregulated tumour suppressor gene in cancer?
p53 known as the guardian of the genome
What is retinoblastoma?
Rare, intra-ocular tumour that affects 1 in 20,000 infants
60% of cases are sporadic (occurs occasionally)
40% of cases are familial (runs in the family, less likely due to chance)
Knudson’s two hit hypothesis - in tumour suppressor genes, both alleles need to be inactivated before it has a significant impact on tumour progression.
What is the role of p53?
A transcription factor that regulates cell-cycle and DNA repair genes.
It is activated in a response to a number of cell/DNA damaging stimuli
Once P53 is activated, what are the 2 possible pathways that could occur?
1 - if the stimuli wasn’t damaging enough, there is G1 arrest and repair is initiated.
2 - If the stimuli was damaging, repair fails and cell undergoes apoptosis
What are some examples of other tumour suppressor genes that are commonly dysregulated in cancer?
look at slide 45
What happens when there is abnormal p53?
The protein cannot direct the cell following damage to G1 arrest or apoptosis.
Any damage that is not lethal will accumulate in the cell.
Why are APC mutations significant?
Beta-catenin needs to translocated to the nucleus as a transcription factor to exert its effects.
Because APC usually binds beta-catenin (cell cycle/Tumour promoter).
This is to stop it translocating to the nucleus to exert its effects but when there is mutations in APC, it can’t do that so beta-catenin is active in inappropriate circumstances
What is BRCA?
-breast cancer (gene) which is usually mutated in 50% of women with breast cancer.
-Forms a complex with RAD51.
-Any mutations in BRCA can cause mutant DNA
What is another important caretaker tumour suppressor gene?
Xeroderma pigmentosum (XP)
Important in nucleotide excision pathway of DNA repair.
Any hereditary XP mutations can cause cancers at young ages
What are 2 additions to the updated hallmarks of cancer?
Immune evasion: Cancers develop antigens which are recognised by the immune system, particularly cytotoxic T cells. Cancers have developed ways to avoid detection from the immune system.
altered metabolism: Cancers adapt to a more glyc
What does the regulation of apoptosis depend on?
Ratio of death antagonists (e.g. bcl-2) to agonists (e.g. bax) determines the cellular response to an apoptotic stimulus.
What is initiation in oncogenesis?
The event that induces the genetic alteration that gives the transformed cell its neoplastic potential.
Is cancer a multistep process?
yes
What is promotion in oncogenesis?
Event that stimulates clonal proliferation of initiated cell.
Do all carcinomas have an adenoma precursor?
No
But carcinoma have pre-malignant phases, dysplastic
Histology
look at slides
