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Cancer > The Biology of Cancer > Flashcards

The Biology of Cancer Flashcards

1
Q

What is cancer a term for?

A

Diseases in which abnormal cells divide without control and can invade nearby tissues

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2
Q

Cancer cells can spread to other parts of the body through what?

A

The blood and lymph systems

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3
Q

What is malignancy and mortality of cancer cells present through?

A

Ability of cancer cells to spread through body

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4
Q

Cancer do not always occur in a linear fashion, multiple factors play a role however what are the key stages involved?

A

Initiation (Stage 1): Mutagenic agents-inherited factors, viruses, chemicals or radiation (initiators). Not yet cancerous.

Promotion (Stage 2): Mutagenic agents- viruses, chemicals or radiation (promoters). Thus further attacks on genome leading to processes such as oncogenic activation. Behaviour of cells is changed, cells are beginning to proliferate and change from benign cells.

Progression (Stage 3): Continued progression from stage 2 leads to malignant cell.

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5
Q

What are the causes of cancer?

A

Environmental/lifestyle factors:
Infectious agents- HPV
Environmental carcinogens- smoking
Diet – alcohol

Genetics:
Inherited – BRCA in breast cancer
Somatic- RAS in pancreatic cancer

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6
Q

It is almost with absolute certainty that one isolated change in the genome will not result in a malignant tumour

True or false

A

True

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7
Q

What are the hallmarks of cancer?

Clue: Some, evil, genes, really, eat, ice cream, apples

A 
Sustaining proliferative signalling
Evading growth suppressors
Genome instability and mutation 
Resisting cell death
Enabling replicative immortality
Inducing angiogenesis
Activating invasion and metastasis
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8
Q

What is the cell cycle?

A

The interval between successful mitoses

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9
Q

What is the cell cycle divided into?

A

2 phases, interphase (I) and mitosis (M)

Interphase further divided into G1, S and G2 phases

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10
Q

What are the 3 main control points of the cell cycle?

A

In G1 - decision to enter S phase - Role of RB

End of G2- decision to enter M phase

Progression through M

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11
Q

In cultured mammalian cells how long does the entire cell cycle last?

A

Approximately 20 hours with mitosis lasting approximately 1.5 hours

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12
Q

What is the role of Rb family and E2Fs transcription factors?

A

Epigenetic regulation of cell cycle genes

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13
Q

What is the Cell cycle mainly controlled through?

A

Activity of cyclin dependent kinases (CDKS) and cyclins subunits and there is an extra level of control as CDKs can be inhibited by CDK inhibitors such as cip/kin and Ink4 families

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14
Q

What is the key to early stages of cancer progression?

A

Uncontrollable cell division- Cancer cells are repeatedly entering cell cycle (M Phase) and do not enter G phase

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15
Q

What is a oncogene?

A

A gene whose expression contributes to the development of cancer

Derived from a cellular “proto-oncogene”

Dominant over the normal proto-oncogene

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16
Q

Activation of what is one reason as to why cancer cells continue to enter cell cycle and thereby proliferate uncontrollably?

A

Oncogene

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17
Q

What is the difference between a Proto-oncogene and an oncogene?

A

Proto-oncogene: A gene that, when mutated or over expressed, contributes to the development of cancer i.e. has potential to give rise to an oncogene

Oncogene: A gene that contributes to the development of cancer

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18
Q

When do oncogenes occur?

A

When there is a change in genomic sequence, typically this is a mutation that activates protein, protein typically has lost some regulation and is now an oncogenic protein

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19
Q

What are the four functions of proto-oncogenes?

What can they promote?

A
  1. Signal transduction pathways involved in promoting cell growth
  2. Regulation of apoptosis
  3. Regulation of differentiation
  4. Regulation of cellular life-span

Sufficiency in growth signals and infinite growth

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20
Q
  1. Why do oncogenes cause cancer when proto-oncogenes do not?
  2. What is a classic example of how this can occur?
  3. What are other means?
A
  1. Oncogenes cause enhanced activity of the encoded protein
  2. Classic example of mutant leading to enhanced activity of the encoded protein is RAS oncogene, whereby G12V mutant leads to activated and unregulated version of protein
  3. Elevated expression through promoter exchange e.g. Bcl-2, Enhanced activation through gene fusion e.g. BCR-ABL, Elevated expression through gene amplification e.g. EGFR
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21
Q

Describe the Ras family?

A
  • 3 closely related proto-oncogenes:
    H-RAS, K-RAS (4a/4b), N-RAS
  • Bound to inner surface of the plasma membrane by a c-terminal lipid tail
  • Bind GTP/GDP
  • Have intrinsic GTPase activity
  • Play a central role in signal transduction
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22
Q

How is Ras activated?

A

RAS is not efficient as hydrolysing GTP in cells or exchanging GDP for GTP and therefore proteins GEF promote activation of RAS into GTP state and proteins GAPs aid RAS in hydrolyse GTP back to GDP

Only in on state that RAS can bind to downstream proteins and elicit cellular response

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23
Q

What is an example of the significance of RAS as a driver of sustaining proliferative signalling?

A

Amplification and mutations leading to constitutively active RAS present in 30% of all human cancers (12, 13 and 61 mutants most common)

24
Q

Which pathways does active RAS drive?

A

RAS/RAF/MAPK PI3K

Wnt, Hedgehog, Notch, Hippo

25
Q

What is a tumour suppressor gene?

A

A gene whose loss contributes to the development of cancer

26
Q

What are two characteristics of tumour suppression genes?

What have they been defined as and why?

A
  1. A mutation in a single allele is insufficient to disrupt protein function*
  2. Loss of both alleles is usually required to disrupt tumour suppressor function

Defined as “gatekeepers- generally associated with regulation of cell cycle” and “caretakers- maintaining regulation of genome”.

27
Q

What protein is a major cell cycle regulator?

A

Retinoblastoma gene (Rb)

28
Q

What does the Retinboblastoma gene (RB1) encode?

A

A 105 kd nuclear phospho-protein

29
Q

Retinoblastoma gene is expressed at…

A

High levels (106 molecules/cell) in most, if not all tissues i.e. function not confined to retinoblasts

30
Q

Retinoblastoma gene has a “pocket” that binds to what?

A

Many cellular proteins

31
Q

What is one of the most important targets of Rb protein

A

E2F family of transcription factors (esp. E2F1, E2F2, and E2F3) which regulate the expression of cell cycle genes

32
Q

The hypophosphorylated form of Rb prevents what?

A

Entry into S phase

33
Q

Rb is hypophosphorylated in…

A

G0/G1

34
Q

Rb is hyperphosphorylated in…

A

S phase

35
Q

How does the hypophosphorylated form of Rb prevents entry into S phase?

A

By binding and inhibiting E2F transcription factors

36
Q

What occurs when a cell is triggered to enter cell cycle through growth factor signalling?

A

CyclinD/CDK4 activated, RB inactive and E2F transcribes responsive genes, gene targets of E2F are proteins that will aid cell enter S phase thus overcoming RB block in cell cycle

Therefore hyperphosphorylated form of Rb allows for entry to S phase

37
Q

Apoptosis induced in response to DNA damage or oncogene activated is mediated by what?

A

p53

38
Q

Resistance to apoptosis is achieved by what?

A

Loss of p53

[Upregulation of pro-survival factors, including Bcl2, PI3K pathway]

39
Q

P53 involved in cellular regulation to what?

A

DNA damage, metabolic stress, hypoxia, deregulated grown

40
Q

Changes in p53 expression and covalent modification lead to what cellular outputs?

What remains unclear?

A

Transient cell cycle arrest- may be in context of DNA damage to allow cell to repair this

Senescence- Often case downstream of oncogenic activation, thus cell not necessarily killed off but remains in the tissue but no longer divides

Apoptosis- if cell catastrophic then driven to apoptosis

How cell differentiates between different outputs, believed to be p53 expression and modification systems that helped to fine tune p53 response

41
Q

Why is it that when p53 is expressed in the cell it is targeted for degradation and ubiquitination by Mdm2?

A

So that cell has a very acute and active response to any DNA damage that may occur.

For example, if there is DNA damage p53 is quickly phosphorylated to protect from degradation pathway and p53 translocate into nucleus and can begin to stimulate expression of mitogenic and cell survival signals, cell cycle arrest while cell tries to repair other DNA damage and other stimulation of target genes.

42
Q

P53 is a tetramer and regulated by several pathways

True or false

A

True

43
Q

What is evidence supporting the role of p53 as a tumour suppressor?

A

More than 50% of human tumours contain a mutation or deletion of the p53 gene

Chromosome 17 long arm (TP53 locus = 17p13) deletions are often accompanied by mutations in the remaining TP53 allele (LOH: Knudson’s two-hit hypothesis)

Many tumours lack p53 expression all together

WT p53 actively suppresses oncogene-mediated cellular transformation

44
Q

In tumours that retain a normal p53 gene, what other elements of the p53 pathway are often defective?

A

MDM2 or MDM4 overexpression
(e.g. retinoblastoma – MDM2/4 levels exceed the sequestering capacity of Arf)

Inactivation of DNA-damage kinases
(e.g. germline mutations in Chk2 have been found in some Li Fraumeni-like families rather than p53 mutations)

Defective transcriptional regulation of p53
(e.g. some breast tumours have low levels of p53 due to suppression of HOXA5, a transcription factor involved in p53 expression)

45
Q

Cancer cells typically enable replicative immortality.

What does this mean and lead to?

A

Can repeat cell cycle unlimitedly- important as increase in number of times cell cycle undergone increases risk of introducing mutations into DNA sequence

46
Q

Why should telomere shortening be avoided?

A

Activates a DNA damage response involving p53

47
Q

In a normal somatic cells, what is the role of a telomere sequence?

A

To protect chromosomal DNA as overtime cells divide and replicate DNA, telomere sequence preserve integrity of chromosomal DNA

48
Q

Cancer cells re-express enzyme telomerase which adds telomere repeats back onto chromosomal DNA.

What does this lead to?

A

The cell is able to repeat cell cycle unlimitedly

49
Q

Telomerase expression/activity is gained in approximately what percentage of human carcinomas?

A

85%

50
Q

What is the greatest risk factor for breast and ovarian cancer?

A

Susceptibility genes, BRCA1 or BRCA2.

51
Q

What is Metastasis?

A

The spread of cancer cells to new areas of the body, often by way of the lymph system or bloodstream

52
Q

Describe the metastatic cascade?

A

Primary malignant neoplasm

New vessel formation

Invasion

Embolism

Enter heart, lungs

Adherence to vessel wall

Extravasation

Establishment of microenvironment

Proliferation/angiogenesis

Metastasis

53
Q

What does tumour progression, invasion and spread involve?

A

Angiogenic switch

Altered cell adhesion to cells and matrix

Local invasion

Increased motility

Intravasation, survival in circulation, arrest, extravasation

Tumour microenvironment
- cancer associated fibroblasts, inflammatory cells, macrophages

54
Q

Why is there a theory that cancer cells are undergoing epithelial to mesenchymal transition?

A

Cells generally epithelial in origin which do not move inside tissue

Thus mechanism must exist which cause epithelial cells to be able to move in cell

School of thought that cells are undergoing epithelial to mesenchymal transition (EMT) and that this is replicative of a normal developmental process thus EMT exists in developmental biology e.g. neural crest cells, therefore thinking is that cancer cells are hijacking a EMT programme that exists in the cellular genome in order to leave primary tumour and spread around body

In cancer setting changes in expression of epithelial markers are seen, cells are less attached and express mesenchymal markers and that such changes are driven through activation of transcription factors such as snail, slug that upregulate expression of some epithelial like genes and downregulation expression of E cadherin – this is a hypothesis

55
Q

What are the patterns of cancer spread?

A

Anatomical factors
e.g. GI tract drains to liver, and GI tract tumours metastasize to liver.

But the first capillary bed encountered is not the only determinant. e.g. muscle and kidney are both well-vascularized, but are infrequently involved in metastasis.

Tissue-specific interactions between particular endothelial cells and particular tumour cell types may play a part.

Some environments present favourable niches for dissemination eg. Bone

Seed and Soil Hypothesis: states that metastatic tumor cells will metastasize to a site where the local microenvironment is favourable, just like a seed will only grow if it lands on fertile soil

56
Q

Non cancer cells/ host cells are important in driving tumour progression

True or false

What is an example?

A

True

Several factors drive primary tumours that are not from the tumour cells themselves e.g. Cancer associated fibroblasts that secrete factors that support tumour cell growth

57
Q

A mutation in a single allele can result in deregulation of signalling

What does this refer to?

A

Oncogene

Cancer (20 decks)

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