L29. Neoplasia 2: Carcinogenesis Flashcards
What is lost on a cellular level in cancer?
Cellular homeostasis
Proliferation goes higher and cell death reduces and differentiation becomes more prominent
What is lost on a cellular level in cancer?
Cellular homeostasis
Prolifeation goes higher and cell death reduces and differentiation becomes more prominent
What are some causes of mutations in cancer?
Ageing (accumulation)
Exposure to external environment (eg. smoking, toxins, micobes)
Challenges with inflammation and cell death
Inhereted mutations
Unknown
Genetic changes usually occur in a particular order which dictates the biological outcome and therapeutic response of the cancer. What are these changes?
Germline
Methylation abnormalities
Proto-oncogene mutations
Homozygous loss of cancer suppressors (adenomas)
Additional mutations (gross) and chromosome alterations (carcinoma)
What are the Four classes of normal regulatory genes that are PRINCIPAL targets of genetic damage relevant to carcinogenesis?
Growth promoting = proto-oncogenes
Growth inhibiting = tumour suppressor genes
Regulation of programmed cell death = apoptosis
Genes in DNA repair
In almost all carcinogenesis, all classes are involved
What are the types of cancer gene point mutations? (mutation vs. polymorph)
Mutation: any change in sequence away from normal (rare and abnormal)
Polymorph: Single Nucleotide Polymorphism (SNP) is a DNA sequence variation common in the population. They often occur in introns (non-coding)
What are the consequences of different SNPs?
Depends on the genomic location of the polymorph
outside of genes: no effect
Non-coding SNP region: changes in the AMOUNT of protein produced
Coding region SNP: changes amino acid sequence and can lead to inactivation or activation of the genes
What are the three main types of mutations that occur in cancer?
Point mutations: activating in oncogenes and inactivating in tumour suppressor genes
Amplifications of oncogenes (having multiple copies)
Chromosomal rearrangements
What are the three main types of mutations that occur in cancer?
Point mutations: activating in oncogenes and inactivating in tumour suppressor genes
Amplifications of oncogenes (having multiple copies): where the coding region for a gene is amplified and the formation of DOUBLE MINUTES (independent chromosome fragments)
Chromosomal rearrangements: translocations and gusions of chimaeric molecules: inappropriate fusion of different chromosomal regions- out of promotor and controller gene contexts
What are the major cell proliferation pathways in cancer?
PI3K pathway (Ras or Ras independent) and MAPK pathway (via Ras)
A growth factor binds to a ligand with TYROSINE KINASE activity and downstream signalling often leads to the activation of the PI3K pathway or RAS to the PI3K or MAPK
They both lead to the activation of transcription of MYC proteins which encourages the progression of the cell cycle
Describe the PI3K pathway
PI3K is activated and leads to phosphorylation of Akt which acts transcribe and activate factors that promote cell survival, growth and proliferation.
PTEN is a tumour suppressor that inhibits the pathway
Mutations in PTEN leads to increased activity as well as mutations in P110 (subunit of PI3K) leading to more
Only 1 allele of an oncogene needs to be mutated while both alleles of a tumour suppressor gene needs to be mutated to cause tumour development. Why is this?
Because mutation of an oncogene leads to the increased activity and this is enough to start over proliferation.
Mutation of 1 allele of a tumour suppressor has the other allele to fall back on for normal function. There needs to be a COMPLETE loss of the suppression in order to achieve full loss of function. This is called LOSS OF HETEROZYGOUSITY (LOH)
What are the ways a loss or inactivation of a tumour suppressor gene expression can occur?
Mutation: non-functional suppressor gene Deletion: no expression at all of the gene DNA methylation (epigenetics): promotor regions are hypermethylated and blocking gene transcription leading to no expression of the gene
What are the ways a loss or inactivation of a tumour suppressor gene expression can occur?
Mutation: non-functional suppressor gene Deletion: no expression at all of the gene DNA methylation (epigenetics): promotor regions are hypermethylated and blocking gene transcription leading to no expression of the gene
What are miRNAs and how are they relevant to carcinogenesis?
Small RNA molecules (transcribed but not translated) that form secondary structures to stabilise themselves for survival. They are involved in the regulation of transcription and translation of Normal genes.
Expression at different levels leads to different expression of tumour suppressor genes (reduced) and oncogenes (abundant miRNA).
Describe the tumour suppressor gene p53
It is a transcription factor that regulates the expression of cell cycle factors that regulate:
apoptosis, cell-cell arrest, dna repair, differentiation and senescence
Thus all of these functions are defective with p53 is mutated or deleted
What happens to the cell cycle in cancer?
There is a loss of proliferative control (either direct or indirect cell cycle changes)
CANCER IS A DISEASE OF THE CELL CYCLE
What is the normal role of the cell cycle?
Regulate growth and mitotic phases
Ensure a faithful and segregation of genetic material (has important checkpoints)
The number of cells in a certain organ or tissue is kept at homeostasis by a balance between two factors. What are they?
Cell Division vs. Apoptosis
What are the two pathways of apoptosis? Briefly describe each one
Extrinsic: FasL binds to Fas receptor on the surface of the cell and leads to caspase activity which eventually leads to a controlled degradation of the nucleaus and cell death
The intrinsic pathway is caused by stress, radiation or signal that causes DNA damage. p53 picks up this damage and activates BAX a pro-apoptotic mediator which enables mitochondrial release of cytochome C and other caspase activities leading to cell death.
What are two major controllers of apoptosis?
BCL-2 anti apoptotic
BAX pro apoptotic
What are some mechanisms for evading apoptosis?
Reduced Fas Receptor (CF95) expression Inactivation of signalling complexes Upregulation of BCL-2 of reduced BAX (loss of p53) Loss of other important enzymes Upregulation of apoptosis inhibitors
What is the importance of telomeres to immortality of cells?
Telomeres are repeats at the endpoints of chromosomes (non-coding) that are shortening with each replication (because RNA requires primers so some parts don’t get replicated with each process).
Reduction in telomere length = ageing
Cancer cells are good at maintaining high telomerase activity and thus immortalise themselves leading to faster growth and escape of senescence
What are some mechanisms for evading apoptosis?
Reduced Fas Receptor (CF95) expression Inactivation of signalling complexes Up-regulation of BCL-2 of reduced BAX (loss of p53) Loss of other important enzymes Up-regulation of apoptosis inhibitors
What is the importance of telomeres to immortality of cells?
Telomeres are repeats at the endpoints of chromosomes (non-coding) that are shortening with each replication (because RNA requires primers so some parts don’t get replicated with each process).
Reduction in telomere length = ageing
Cancer cells are good at maintaining high telomerase activity and thus immortalise themselves leading to faster growth and escape of senescence
What are the major steps [4] of metastasis?
- Detachment of tumour cells
- Degradation of ECM
- Attachment to novel ECM components
- Migration of the tumour cells
What is contact inhibition? Why is this important in cancer?
Contact inhibition is cell-cell signalling and communication that prevents cells from stacking up and growing in an unfavourable and unorganised manner.
Tumour cells lose contact inhibition and grow anywhere
What is contact inhibition? Why is this important in cancer?
Contact inhibition is cell-cell signalling and communication that prevents cells from stacking up and growing in an unfavourable and unorganised manner.
Tumour cells lose contact inhibition and grow anywhere
What are three important molecular mechanisms of metastasis?
Mutations in …
- Integrins - receptor like molecules allowing cell-cell interactions
- Catenin - inner membrane associated with cadherins
- Connexins - gap junctions
These are disrupted and allow cells to escape their normal niche
What is important about the tumour microenvironment?
Tumour cells require contact and factors released by endothelial cells, fibroblasts and (especially) macrophages to signal and maintain acceleration of tumour growth
What is important about the tumour microenvironment?
Tumour cells require contact and factors released by endothelial cells, fibroblasts and (especially) macrophages to signal and maintain acceleration of tumour growth
What are two major factors involved (and potentially mutated) in angiogenesis? Why is this important
Vascular Endothelial Growth Factor (VEGF) and their receptors and they enable angiogenesis
What are tumour initiating cells?
Tumour cells with stem cell-like activity that are likely to be able to evade chemo and radiation therapy because they divide much more slowly (because traditional therapies target rapid growing cells)
What are some causes of mutations of the critical control factors in cancer?
Ageing (accumulation)
Exposure to external environment (eg. smoking, toxins, microbes)
Challenges with inflammation and cell death
Inherited mutations
Unknown
What are the three main types of mutations that occur in cancer?
Point mutations: activating in oncogenes and inactivating in tumour suppressor genes
Amplifications of oncogenes (having multiple copies): where the coding region for a gene is amplified and the formation of DOUBLE MINUTES (independent chromosome fragments)
Chromosomal rearrangements: translocations and fusions of chimaeric molecules: inappropriate fusion of different chromosomal regions- out of promotor and controller gene contexts
Only 1 allele of an oncogene needs to be mutated while both alleles of a tumour suppressor gene needs to be mutated to cause tumour development. Why is this?
Because mutation of an oncogene leads to the increased activity and this is enough to start over proliferation.
Mutation of 1 allele of a tumour suppressor has the other allele to fall back on for normal function. There needs to be a COMPLETE loss of the suppression in order to achieve full loss of function. This is called LOSS OF HETEROZYGOSITY (LOH)
What are the two pathways of apoptosis? Briefly describe each one
Extrinsic: FasL binds to Fas receptor on the surface of the cell and leads to caspase activity which eventually leads to a controlled degradation of the nucleus and cell death
The intrinsic pathway is caused by stress, radiation or signal that causes DNA damage. p53 picks up this damage and activates BAX a pro-apoptotic mediator which enables mitochondrial release of cytochrome C and other caspase activities leading to cell death.
