L29. Neoplasia 2: Carcinogenesis

Question 1

What is lost on a cellular level in cancer?

Answer 1

Cellular homeostasis

Proliferation goes higher and cell death reduces and differentiation becomes more prominent

Question 2

What is lost on a cellular level in cancer?

Answer 2

Cellular homeostasis

Prolifeation goes higher and cell death reduces and differentiation becomes more prominent

Question 3

What are some causes of mutations in cancer?

Answer 3

Ageing (accumulation)
Exposure to external environment (eg. smoking, toxins, micobes)
Challenges with inflammation and cell death
Inhereted mutations
Unknown

Question 4

Genetic changes usually occur in a particular order which dictates the biological outcome and therapeutic response of the cancer. What are these changes?

Answer 4

Germline
Methylation abnormalities
Proto-oncogene mutations
Homozygous loss of cancer suppressors (adenomas)
Additional mutations (gross) and chromosome alterations (carcinoma)

Question 5

What are the Four classes of normal regulatory genes that are PRINCIPAL targets of genetic damage relevant to carcinogenesis?

Answer 5

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

Question 6

What are the types of cancer gene point mutations? (mutation vs. polymorph)

Answer 6

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)

Question 7

What are the consequences of different SNPs?

Answer 7

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

Question 8

What are the three main types of mutations that occur in cancer?

Answer 8

Point mutations: activating in oncogenes and inactivating in tumour suppressor genes

Amplifications of oncogenes (having multiple copies)

Chromosomal rearrangements

Question 9

What are the three main types of mutations that occur in cancer?

Answer 9

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

Question 10

What are the major cell proliferation pathways in cancer?

Answer 10

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

Question 11

Describe the PI3K pathway

Answer 11

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

Question 12

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?

Answer 12

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)

Question 13

What are the ways a loss or inactivation of a tumour suppressor gene expression can occur?

Answer 13

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

Question 14

What are the ways a loss or inactivation of a tumour suppressor gene expression can occur?

Answer 14

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

Question 15

What are miRNAs and how are they relevant to carcinogenesis?

Answer 15

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).

Question 16

Describe the tumour suppressor gene p53

Answer 16

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

Question 17

What happens to the cell cycle in cancer?

Answer 17

There is a loss of proliferative control (either direct or indirect cell cycle changes)

CANCER IS A DISEASE OF THE CELL CYCLE

Question 18

What is the normal role of the cell cycle?

Answer 18

Regulate growth and mitotic phases

Ensure a faithful and segregation of genetic material (has important checkpoints)

Question 19

The number of cells in a certain organ or tissue is kept at homeostasis by a balance between two factors. What are they?

Answer 19

Cell Division vs. Apoptosis

Question 20

What are the two pathways of apoptosis? Briefly describe each one

Answer 20

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.

Question 21

What are two major controllers of apoptosis?

Answer 21

BCL-2 anti apoptotic

BAX pro apoptotic

Question 22

What are some mechanisms for evading apoptosis?

Answer 22

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

Question 23

What is the importance of telomeres to immortality of cells?

Answer 23

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

Question 24

What are some mechanisms for evading apoptosis?

Answer 24

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

Question 25

What is the importance of telomeres to immortality of cells?

Answer 25

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

Question 26

What are the major steps [4] of metastasis?

Answer 26

1. Detachment of tumour cells
2. Degradation of ECM
3. Attachment to novel ECM components
4. Migration of the tumour cells

Question 27

What is contact inhibition? Why is this important in cancer?

Answer 27

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

Question 28

What is contact inhibition? Why is this important in cancer?

Answer 28

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

Question 29

What are three important molecular mechanisms of metastasis?

Answer 29

Mutations in …

1. Integrins - receptor like molecules allowing cell-cell interactions
2. Catenin - inner membrane associated with cadherins
3. Connexins - gap junctions

These are disrupted and allow cells to escape their normal niche

Question 30

What is important about the tumour microenvironment?

Answer 30

Tumour cells require contact and factors released by endothelial cells, fibroblasts and (especially) macrophages to signal and maintain acceleration of tumour growth

Question 31

What is important about the tumour microenvironment?

Answer 31

Tumour cells require contact and factors released by endothelial cells, fibroblasts and (especially) macrophages to signal and maintain acceleration of tumour growth

Question 32

What are two major factors involved (and potentially mutated) in angiogenesis? Why is this important

Answer 32

Vascular Endothelial Growth Factor (VEGF) and their receptors and they enable angiogenesis

Question 33

What are tumour initiating cells?

Answer 33

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)

Question 34

What are some causes of mutations of the critical control factors in cancer?

Answer 34

Ageing (accumulation)
Exposure to external environment (eg. smoking, toxins, microbes)
Challenges with inflammation and cell death
Inherited mutations
Unknown

Question 35

What are the three main types of mutations that occur in cancer?

Answer 35

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

Question 36

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?

Answer 36

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)

Question 37

What are the two pathways of apoptosis? Briefly describe each one

Answer 37

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.