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Y2 MECHANISMS OF DISEASE > Carcinogenesis - Molecular Hallmarks of Cancer Cells > Flashcards

Carcinogenesis - Molecular Hallmarks of Cancer Cells Flashcards

1
Q

What are the 6 main hallmarks of cancer cells?

A
  1. evading apoptosis
  2. self-sufficiency in growth signals
  3. insensitivity to anti-growth signals
  4. sustained angiogenesis
  5. limitless replicative potential
  6. tissue invasion and metastasis
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2
Q

What are the 10 hallmarks of cancer cells?

A
  1. sustaining proliferative signalling
  2. evading growth suppressors
  3. avoiding immune destruction
  4. enabling replicative immortality
  5. tumour-promoting inflammation
  6. activating invasion and metastasis
  7. inducing angiogenesis
  8. genome instability and mutation
  9. resisting cell death
  10. deregulating cellular energetics
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3
Q

What is meant by the “hallmarks of cancer”?

A

when cells progress towards a neoplastic state, they acquire distinctive capabilities

cancer cells acquire the hallmarks through mutations, which allow them to progress and spread

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4
Q

What is meant by cancer cells sustaining proliferative signalling?

A

this involves signals by growth factors that bind to cell-surface receptors, typically containing intracellular tyrosine kinase domains

intracellular signalling pathways regulate progression through the cell cycle, as well as cell growth

these signals influence other cell properties, such as survival and energy metabolism

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5
Q

Why is sustaining proliferative signalling perhaps the most fundamental trait of cancer cells?

A

it allows for self-sufficiency in positive growth signalling

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6
Q

What is the role of Rb protein?

How does it interact with growth factors?

A

Rb protein is a key regulator of the cell cycle as it prevents progression from G1 to S phase

negative Gfs inhibit progression of the cell cycle by activating Rb protein

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7
Q

How can cancer cells act to evade growth suppressors?

A

inactivation of Rb gene is a common event in tumours

this results in resistance to negative growth regulation

the gatekeeper between G1 and S phase is lost

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8
Q

How do cancer cells avoid immune destruction?

A

The tumour cell expresses PD1, which binds to PD-L1 receptor on T cells

When they bind, the T cell becomes silenced and is no longer destructive

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9
Q

How can cancer be treated, using the fact that it can evade the immune system?

A

Blocking PD-1 and PD-L1 prevents the interaction between the tumour cell and the T cell

this allows the T cell to resume killing the tumour cell

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10
Q

How can cancer cells have replicative immortality?

A

In normal cell division, the telomere becomes shorter with each division until it cannot divide anymore

cancer cells have telomerases which elongate and maintain the length of the telomeres

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11
Q

What is meant by ‘tumour-promoting inflammation’?

A

inflammation associated with the tumour helps to accelerate progression of cancer

knowing how the tumour behaves to inflammation can be used to determine if a patient would benefit from immune therapy

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12
Q

What is meant by activating invasion and metastasis of cancer cells?

A
  1. cancer usually becomes dysplastic and progresses from low-grade to high-grade dysplasia
  2. the cells break through the basal lamina
  3. the cells enter the bloodstream
  4. the cells adhere to the blood vessel and penetrate the capillary wall
  5. the cells then divide to form a tumour
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13
Q

What is meant by cancer cells inducing angiogenesis?

A

small tumour is growing and releases angiogenic factors

this stimulates capillaries to sprout and supply oxygen and nutrients to the tumour

this also allows for metastatic spread

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14
Q
A
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15
Q

Why do cancer cells want to have genome instability and mutations?

A

it is beneficial for cancer cells to have an unstable genome with lots of mutations present

this allows cancer to progress from a pre-malignant to an invasive form

it allows cancer cells to react quicker to changes and adapt

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16
Q

How do cancer cells resist cell death?

A

Bcl2 is not activated normally, allowing apoptosis to occur

If Bcl2 is upregulated, there is no apoptosis meaning that the cell does not die

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17
Q

What is meant by cancer cells deregualting cellular energetics?

A

cancer cells have a deregulated metabolism

this is anaerobic as tumour cells cannot be reliant upon limited oxygen supplies

they use up glucose and produce lactate

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18
Q

What are proto-oncogenes?

A

normal genes that promote cell proliferation, survival and angiogenesis

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19
Q

What are oncogenes?

A

mutated versions of proto-oncogenes that cause increased/uncontrolled activity of expressed proteins

20
Q

What is meant by oncogenes being dominant gain-of-function genes?

A

1 mutant copy of the gene acts dominantly to the remaining normal parental gene

21
Q

What are the 4 mechanisms of oncogene activation?

A
  1. translocation
  2. point mutation
  3. amplification
  4. insertion
22
Q

What is meant by translocation as a mechanism of oncogene activation?

A

it involves translocation of an oncogene from a low to an active transcriptional site

this leads to aberrant expression of the oncogene

23
Q

What is meant by point mutation as a mechanism of oncogene activation?

A

substitution of a single base within the amino acid sequence which produces a hyperactive oncoprotein

24
Q

What is meant by amplification as a mechanism of oncogene activation?

A

insertion of multiple copies of an oncogene

this leads to increased expression

25
Q

What is meant by insertion as a mechanism of oncogene activation?

A

insertion of a promoter or enhancing gene (by retroviruses) near an oncogene leads to increased expression

26
Q

What are examples of oncogenes?

A
  1. RAS
  2. myc
  3. RAF
  4. HER2
  5. EGFR
27
Q

What are the 3 genes in the RAS family of proteins?

A

KRAS

NRAS

HRAS

28
Q

What types of molecules to oncogenes code for?

A

tyrosine kinase family

they are involved in growth and stimulation of cell division

over-expression leads to tumour growth and proliferation

29
Q
A
30
Q

What are the 2 categories of tumour suppressor genes and their functions?

A

gatekeepers:

  • antioncogenes
  • negative regulators of the cell cycle and proliferation
  • positive regulators of apoptosis

caretakers:

  • maintain genetic stability
31
Q

What happens if there is a mutation in a tumour suppressor gene?

A

this results in loss of their function

32
Q

How do carcinogens interact with tumour suppressor genes?

A

they induce molecular abnormalities in TSGs that cause reduced/lack of protein expression/function

33
Q

What are the 4 mechanisms of TSG loss?

A
  1. inactivating point mutations
  2. deletions
  3. translocations
  4. epigenetic silencing

shutdown of gene expression via methylation of CpG sequences in promoter regions

34
Q

What are the 5 tumour suppressor genes?

A
  1. APC
  2. p53
  3. RB
  4. BRCA1 and BRCA2
  5. hMLH1, hMSH2
35
Q

What genes and tumours are implicated in the following cancer syndromes?

A
36
Q

What is involved in a familial cancer syndrome?

A

inheritance of a mutant copy of a TSG or caretaker gene

caretakers maintain genetic stability

germline mutations cause genetic instability which predisposes individuals to developing cancer

37
Q

What is the carrier risk associated with familial cancer syndromes?

A

carriers suffer from a risk of developing cancer

this is 70-90% depending on the syndrome

38
Q

What is meant by the adenoma carcinoma sequence?

A
  1. oncogene activation and tumour suppressor gene inactivation occurs in a normal cell
  2. this develops into neoplasia (abnormal growth)
  3. this leads to malignant neoplasia, which leads to invasion and metastasis
39
Q

What is the sequence of steps involved in carcinogenesis?

A
  1. telomerase expression allows for immortality and replication
  2. inactivation of TSGs removes growth inhibition
  3. oncogene activation leads to neoplastic transformation and excessive cell division
40
Q

Which genes are involved in the following process?

What are the stages of this process?

A
41
Q

What are the 4 clinical applications of tumour markers?

A

diagnosis:

  • identification of type and sub-type

prognosis:

  • certain mutations confer worse survival

therapy:

  • predictive markers for therapeutic response
  • development of targeted drugs or gene therapies

monitoring:

  • response to treatment
  • detecting relapse
42
Q

What are the downsides of using serum markers in diagnosis and monitoring?

A

none have sufficient sensitivity or specificity to be used for general screening

43
Q

What serum markers are used as an adjunct for diagnosis?

Which ones are used just for monitoring?

A

adjunct for diagnosis:

  • AFP
  • CA125
  • hCG
  • PSA

monitoring:

  • CEA
  • thyroglobulin
44
Q

How can HER2 be used as a predictive and prognostic marker?

A

HER2 is overexpressed in 30% of breast cancers

only patients with HER2 overexpression have Herceptin treatment as patients without overactive HER2 receptors will have no beneficial effect

45
Q

What are the predictive and prognostic markers in colorectal cancer?

A

50% of colorectal cancers have KRAS mutation

This binds to EGFR receptor

Cetumixab and Panitumumab block EGFR

Y2 MECHANISMS OF DISEASE (36 decks)

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