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Miscellaneous > MCB Lecture 65 Neoplasia II > Flashcards

MCB Lecture 65 Neoplasia II Flashcards

0
Q

Conventional cancer therapies are effective against …

A

The tumour cells, not the cancer stem cells or progenitors

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1
Q

Describe the paradigm of cancer

A 
Normal cell
-hit-
Cancer stem cell
-more hits-
Progenitor cells
Tumour
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2
Q

What is a ‘hit’?

A

This is genetic or epigenetic changes to the Cell

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3
Q

What is the effect on a cell of a ‘hit’?

A

Increased self renewal potential

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4
Q

What are the four genetic events that result in cancer?

A
  1. Activation of a proto oncogene
  2. Deactivation of a tumour suppressor gene
  3. Replication despite DNA damage
  4. Inhibition of apoptosis or senescence
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5
Q

Describe proto-oncogene activation causing cancer

A

Eg. KRAS

When a proto oncogene is activated, the cell undergoes increased proliferation

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6
Q

Why does mutation of KRAS result in cancer?

A

Constitutively active proliferation pathways such as MAPK

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7
Q

Describe mutation in tumour supressor genes resulting in cancer

A

Eg. APC or Rb

When APC is mutated, beta catenin is not marked for breakdown.
Beta catenin stabilises and switches on genes that result in proliferation

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8
Q

Which tumour suppressor genes mutate commonly to form cancer?

A

APC and Retinoblastoma

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9
Q

What does SNPs of APC cause?

A

Adenomatous polyposis

1000s of polyps in the small intestines
One polyp then may undergo malignant transformation, resulting in cancer

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10
Q

What is the function of APC?

A

It is an integral part of the beta catenin destruction complex

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11
Q

Describe replication causing genomic instability

Which gene in commonly involved?

A

p53

If DNA is replicated despite genomic instability, mutations in the cells are perputuated, possible resulting in cancer

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12
Q

Describe the function of p53 in healthy and cancerous cells

A 
Healthy:
When there is DNA damage, three things will occur:
- try to repair the damage
- G1 arrest
- apoptosis

p53 mutation:
When there is DNA damage, p53 isn’t able to effect all these changes that would stop the perpetuation of the mutated DNA and mutation survives in the cell population

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13
Q

Homozygous loss of … is seen in almost every type of cancer

A

p53

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14
Q

Describe how inhibition of apoptosis or senescence results in cancer

Which genes are involved?

A

p53, Fas receptor, bcl-2, bcl-xL

If there is a mutation in any of these genes, apoptosis can not occur

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15
Q

Which epigenetic events result in cancer?

A

DNA methylation

Histone tail modification

16
Q

Where does DNA methylation occur?

A

On the cysteine of CpG islands in the promoter region

17
Q

What is the outcome of DNA methylation?

A

That DNA is bulky and thus is not transcribed: is silenced

18
Q

What patterns of methylation are seen in cancer?

What does this result in ?

A

Genome wide demethylation

CpG island hypermethylation (promoters of tumour suppressor genes)

19
Q

Describe how histone tail modifications result in cancer

A

The histone tails can be acetylated or methylated on lysine residues resulting in either silencing or activation

This results in activation of proto oncogenes or silencing of tumour suppressor genes

20
Q

Epigenetic modifications are …

Thus they are a … for the cell

A

Reversible

Selective advantage

21
Q

Describe the selective pressures that cancer cells face

A

Hypoxia
Low nutrients
Natural barriers to tissues

22
Q

How is diversity generated in cancer cell populations?

A

Consecutive rounds of mitosis, mutation

23
Q

Natural selection of cancer cells results in …

A

More aggressive cells

24
Q

Describe the mechanism of invasion and dissemination of cancer cells

What are the genetic requirements for this to occur?

A

They must break down the tissue in which they are, then migrate in the blood stream, and then adhere to another tissue

Requirements:

  • Lose Adherens junctions
  • Proteolytic enzymes
  • Evasion of immune systems
  • Angiogenesis
  • Colonising the new site: GF etc
25
Q

Describe the ‘vogelgram model’ of tumour progression using the example of adenoma formation

A 
Normal epithelium
- hit -
Hyper-proliferative epithelium, Mucosa at risk
Early adenoma
Intermediate adenoma
Late adenoma
Malignant adenoma/ carcinoma
Metastasis
26
Q

What criticism is there for the vogelgram model?

A

Too simplistic

However, it is ok for colorectal cancer

27
Q

What is the parallel model of tumour progression?

A

There is a population of heterogeneous progenitor cells

From this population, some will go on to form the bulk of the tumour in the tissue
Conventional treatments target these cells.

Further down the track, other cells from the progenitor population, with different mutations, form tumours.

There are now multiple tumours in the tissue, all with different mutations and resistances.

We can’t treat all the tumour with the same treatment

28
Q

What are the conventional cancer treatments?

A

Chemotherapy
Radiotherapy
Surgery

29
Q

Describe conventional treatment with the example of colorectal cancer

A 
Early stage: surgery to remove the adenoma
Late stage (metastasis has occurred) : surgery, chemotherapy and radiotherapy - COMBINATION THERAPY
30
Q

How does colorectal cancer arise?

A

Adenomas in the gut undergo malignant transformation and become metastatic

31
Q

What happens in colorectal cancer metastasis

A

The cancerous cells spread to the liver

32
Q

How does chemotherapy work?

A

It targets rapidly dividing cells will poor selectivity

33
Q

How does radiotherapy work?

A

It kills malignant cells with radiation

34
Q

What is problematic with the conventional cancer treatments?

A

They are coarse and kill healthy cells as well

35
Q

What is required to proceed from hyper-proliferative epithelium to early, intermediate and late adenoma?

A

Accumulation of mutation: such as mutations in APC, beta catenin, KRAS

36
Q

What is required to transform from late adenoma to carcinoma and metastasis?

A

Mutation in p53

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