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BIOL3043 - Cellular and molecular pathology > Lectures 1&2 - Molecular basis of cancer > Flashcards

Lectures 1&2 - Molecular basis of cancer Flashcards

1
Q

Define Cancer

A

A group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body

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2
Q

What are three ways to classify cancer?

A

tissue of origin, level of malignancy, genetically

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3
Q

How do the different tissues of origin define the type of cancer?

A

Epithelial tissues = carcinomas > 80%

Mesenchymal tissues (bone, muscle, fat) = Sarcomas, around 1%

Hematopoietic tissues = lymphoma/leukemia, around 10%

Neuroectoderm tissues = Blastoma/melanoma/neuroblastoma, around 5% (related to ectoderm)

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4
Q

Describe the different levels of malignancy of cancers

A

Mild hypoerplasia

Advanced hyperplasia

Carcinoma In situ - still confined however much bigger mass

Invasive carcinoma – invading into other tissues in the organ or other organs

Metastatic carcinoma

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5
Q

What is TNM staging in cancer?

A

T describes the size of the tumor and any spread of cancer into nearby tissue; N describes spread of cancer to nearby lymph nodes; and M describes metastasis (spread of cancer to other parts of the body)

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6
Q

Whats the difference between staging and grading of cancer

A

Staging, characteristics of a tumour

Grading, characteristics of tumour cells

High grade = the cells are further away from what they’re meant to look like

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7
Q

What are the three ways cancer is defined genetically?

A

Sporadic : no family history

Familial: mutation is unknown - similar to hereditary but skips generations

Hereditary: mutation is known

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8
Q

What would a microscope image of a mildly hyperplasic milk duct look like?

A

more cells than usual lining the lumen (normally would be a thin layer but is thicker than normal)

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9
Q

What would a more hyperplasic milk duct look like in a microscope image?

A

Lumen still visible but very small due to a thick layer of cells around the duct

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10
Q

Describe what you would see in a microscope image of a ductal carcinoma in situ

A

Lumen no longer present due to ballon expansion, some narcotic cells present, basement membrane still intact

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11
Q

Describe what you would see in a microscope image of an invasive ductal carcinoma

A

Lumen no longer present, basement membrane broken and invading neighbouring membrane and fat tissue

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12
Q

What are the 6 hallmarks of cancer?

A

Self-sufficiency in growth signals

Evading apoptosis

Insensitivity to anti-growth signals

Sustained angiogenesis

Limitless replicative potential

Tissue invasion and metastasis

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13
Q

What is considered the one main hallmark of cancer? who considered this true? (what paper was it said in)

A

tissue invasion and metastasis (Yuri Lazebnik, Nature Reviews Cancer, Volume 10, 2010, pp 232-233)

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14
Q

Describe simply the multistep process to carcinogenesis

A

Normal —> initiated —> pre-cancer —> cancer

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15
Q

Describe how cancer develops through clonal selection

A
  1. initiating mutation
  2. First colonel expansion
  3. Second mutation
  4. Second clonal expansion
  5. Third mutation
  6. Third clonal expansion
  7. Fourth mutation
  8. Fourth clonal expansion
  9. etc. 15-500 mutations needed to get cancer (dependent on tissue)
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16
Q

Explain the development of colon cancer by multiple cancer inclined molecular/genetic changes

A

Normal epithelium –> loss of APC (a gene that suppresses tumor growth) leading to hyperplasic epithelium –> DNA hypomethylation leading to early adenomas –> activation of K-ras leading to intermediate adenomas –> loss of 18q TSG leading to late adenomas –> loss of p53 leading to carcinoma –> invasion and metastasis

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17
Q

Define an oncogene

A

Oncogene - a gene that has the potential to cause cancer, must have mutated

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18
Q

How do oncogenes get activated? give some examples of oncogenes

A

1- Activating mutations (e.g. Ras, CDK4) - gene mutates and cell divides

2- Gene amplifications (e.g. myc, mdm2, Her2, Cyclin D1) - gene itself is amplified - normally have 2 (one from mother and one from father) but now have e.g. 1000

3- Translocations (myc/IgH, bcr/abl) - takes gene to a different part of genome where it is expressed more readily

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19
Q

Give an example of an experiment that can be done to test for an oncogene

A

Isolate DNA from chemically transformed mouse fibroblasts

Transfection using calcium phosphate co-protection procedure

Insert into normal mouse fibroblasts

Due to insertion of chemically transformed DNA, Cells divide at a faster rate and create a 3D cell plate (only happens in cancer)

These cells are extracted and inserted into mouse host

Tumor grows

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20
Q

What is Ras?

A

RAS is a bottleneck in survival of cells

Lots of different factors lead to the activation of Ras

Ras then activates the main pathway - ERK pathway (which leads to oncogenic transcription)

Also activates other pathways e.g. PI3K pathway which leads to oncogenic transcription, cell survival and cell growth and metabolism

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21
Q

Describe the active and inactive state of Ras

A

ACTIVE:
GEF triggers GTP to bind and Ras to become activated
Oncogenic mutations cause Ras to stay in active state

INACTIVE:
GTP hydrolysis (creating GDP) and Ras inactivation induced by GAP
Ras becomes inactive with GDP bound

22
Q

Describe how Ras mutations lead to cancers in humans

A

Glycine 12 to Valine 12 point mutation (and other particular point mutations, mean that GTP cannot unbind from Ras and so Ras becomes permanently active, leading to oncogenic transcription, cell survival and cell growth and metabolism, all of which promote carcinogenesis

23
Q

What are the three different Ras genes and what happens when they are mutated, give examples of where you find these different genes

A

Ras K, Ras H and Ras N, when they are mutated they become oncogenes:
pancreas K
Thyroid all 3
Colorectal K
Liver N
Kidney H

24
Q

Whats another name for the HER2 gene

A

EGRF2

25
Q

How does the Her2 gene work in a normal cell vs a cancer cell

A

2 ligands (both with intracellular tyrosine kinase domains) are far apart floating on plasma membrane

when growth factor comes it brings 2 together (ligand binding)

This leads to cross phosphorylation

In cancer cells, there are many more ligands, so they come together without the need for growth factors and so this leads to ligand- independent firing

26
Q

What happens to the her2 gene in breast cancer

A

it is amplified/over-expressed leading to ligand-independent firing, theres NO mutation

27
Q

Give two examples of a gene which is translocated to cause cancer, and the fusion genes these create

A

myc and bcr, create myc-IgH, bcr-abl fusion genes

28
Q

When it comes to the myc gene causing cancer, why does it only cause cancer in B cells?

A

Due to the IgHb gene which its translocated onto only being expressed in B cells

29
Q

Define a tumor supressor gene

A

also known as an anti-oncogene, a gene that regulates a cell during cell division and replication, when mutated or deleted it positively contributes to carcinogenesis

30
Q

What are the two classes of tumour suppressor genes?

A

1- Gatekeeper genes encode a system of checks and balances that monitor cell division and death (Rb, p53, APC, p16)

2- Caretakers are responsible for genomic integrity - related to DNA repair (MLH1, MSH2, BRCA1, BRCA2)

31
Q

What is the R-point in the cell cycle?

A

near end of G1 phase (cell is getting ready to divide): its the checkpoint to see if the cell is ready to replicate its DNA and divide

32
Q

What is the Rb gene?

A

Retinoblastoma gene, A tumour suppressor gene

33
Q

Whats the most common type of mutation in the Rb gene?

A

Nonsense/stop mutations

34
Q

What is the Knudson hypothesis?

A

(two-hit hypothesis) most tumour suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change

35
Q

whats the difference between familial and sporadic retinoblastoma?

A

Familial retinoblastoma : Children born with one already mutated allele and then other gene mutates

Sporadic retinoblastoma : Both alleles need to mutate for cancer to occur

36
Q

What gene is known as “the master guardian of the genome” what type of tumour suppressor gene is it?

A

p53 (TP53), gatekeeper

37
Q

How does p53 usually function?

A

Senses stresses in cell e.g. lack on nucleotides or DNA damage leading to lots of things: cell cycle arrest, DNA repair, block of angiogenesis, apoptosis

38
Q

Describe how different TP53 mutations have different phenotypes

A

Remove p53 completely, cancer grows, p53 mutant - more cancer than when p53 not present at all

39
Q

What two things lead to p53 inactivity?

A

mutations in the gene and viruses

40
Q

what are the 6 steps in the invasion-metastasis cascade?

A

1- Breaking down basal membrane

2- EMT and Intravasation

3- Anoikis resistance

4- Extravasation

5- Colonisation and MET

6- Dormancy-Proliferation

41
Q

Explain the first step in the invasion-metastasis cascade: breaking down basal membrane

A

The basal membrane is broken down using Matrix metalloproteinases (MMPs), they cleave furin, produce invadopodia which posseses ECM degrading activity and can undergo extracellular cleavage

42
Q

Explain the second step in the invasion-metastasis cascade: EMT and intravasation

A

cells turn from epithelial to mesenchymal (this is EMT) and Reciprocal interactions between tumour associated macrophages (TAMS) and tumour cells lead to intravasation

43
Q

what is EMT?

A

Epithelial-mesenchymal transition is a reversible genetic trans-differentiation program when epithelial cells lose E-Cadherin and other epithelial markers and acquire expression of mesenchymal markers resulting in enhanced cell motility and invasiveness

44
Q

Explain the features of EMT

A

Committed migratory cells do not divide
Migratory cells should be resistant to apoptotic stimuli
Committed migratory cells should retain the ability to give rise to more than one type of cell (stem cell properties)
Anoikis resistance

45
Q

What pathways are there to EMT?

A

Cadherin switch

Mucin downregulation

Loss of epithelial cell polarity

Increased matrix metallo-protease expression

Increased mesenchymal markers (such as vimentin)

46
Q

Explain the third step in the invasion-metastasis cascade: Circulation and Anoik’s resistance

A

tumour cells in circulation) are present as individual cells or a slow clusters. They interact with the immune cells.

47
Q

What are the cancer stem cell markers

A

low CD24 and high CD44

48
Q

Describe features of non-stem cells compared to cancer stem cells

A

Non-stem cells:
Low tumourigenicity
Drug sensitive
Low metastatic

Cancer stem cells:
High tumourigenicity
Drug resistant
Highly metastatic
Self-renewal
Anoikis resistance

49
Q

Explain the fourth step in the invasion-metastasis cascade: Extravasation

A

First rolling and arrest must happen, VCAM1 protein is an endothelial ligand for integrin α4β1, ICAM1 is a ligand for integrin αXβ2. VCAM1 and ICAM1 both help arrest the cell before extravasation happens

50
Q

whats thought to be an alternative extravasation theory, that most likely happens in the liver

A

Trapping
Microclot with platelets
Contact with BM
Dissolving of the clot
Proliferation within the vessel
Invasion

51
Q

Explain the fifth step in the invasion-metastasis cascade: Mesenchymal-epithelial transition (MET)

A

cancer cells are no longer in the primary tissue anymore, once extravasation occurs, mesenchymal cancer cells either remain dormant or form secondary tumours

BIOL3043 - Cellular and molecular pathology (11 decks)

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