Cell Signalling and Oncogenes Flashcards
(81 cards)
1
Q
What do cells respond to?
A
Specific chemicals that signal them to divide
2
Q
What do the pathways for cell signalling utilised by cells have in common?
A
They all display the same fundamental characteristics
3
Q
What do all signalling pathways involve?
A
- Chemical messenger
- Receptor
- Cellular response
4
Q
What is signal transduction?
A
Essentially, the transmission of a signal from the outside of a cell to the nucleus
5
Q
What can the signal transduced from the outside of the cell to the inside result in?
A
Alterations in cell metabolism, gene transcription, and/or cell shape
6
Q
What does alteration in gene transcription lead to?
A
Changes in protein expression
7
Q
What are proto-oncogenes?
A
Genes coding for proteins that help regulate cell growth and differentiation
8
Q
In what physiological process are proto-oncogenes fundamental?
A
Homeostasis
9
Q
What happens to proto-oncogenes in malignancy?
A
They become activated to an oncogene due to mutations, or increased expression
10
Q
Where is oncogene activation an important mechanism?
A
In human cancers
11
Q
What are the types of mutations that can cause cancer?
A
- Deletion
- Insertion
- Substitution
- Amplification
- Translocation
12
Q
What can be deleted in mutations?
A
- Base pair(s)
- Genes
- Chromosomes
13
Q
What can be inserted in mutations?
A
- Repeats of base pair(s)
- Novel insertions
- Viruses
14
Q
What can be substituted in mutations?
A
Base pairs .
15
Q
What can be amplified in mutations?
A
- Genes
- Regions
- Chromosomes
16
Q
What can be translocated in mutations?
A
Chromosomes
17
Q
What kind of proteins are encoded for by oncogenes?
A
- Growth factors
- Growth factor receptors
- Protein kinases/proteins that activate protein kinases
- Proteins that control the cell cycle
- Proteins that affect apoptosis
- Transcription factors
18
Q
What do growth factors do?
A
Stimulate cells to divide
19
Q
Give an example of a growth factor
A
PDGF
20
Q
What do growth factor receptors do?
A
Transduce signals from the outside of the cell to the inside
21
Q
Give an example of a growth factor receptor
A
EGF receptor (erbB)
22
Q
Give two examples of protein kinases
A
- Src
- Ras
23
Q
Give an example of a protein that activates protein kinases
A
Raf
24
Q
Give an example of a protein that controls the cell cycle
A
Cyclin D
25
Give an example of a protein that affects apoptosis
Bcl-2
26
Give an example of a transcription factor
Myc
27
What is the significance of Myc in malignancy?
It is one of the most commonly altered oncogenes
28
What are the mechanisms of oncogene activation?
* Insertional mutagenesis
* Chromosomal translocation
* Chromosomal amplification
* Point mutation
* Ras signalling
29
What happens in insertional mutagenesis?
DNA viruses incorporate a viral oncogene, which is inserted into the host DNA
30
Give two examples of viruses capable of insertional mutagenesis
* Human papillomavirus 16/18
* Hepatitis B
31
What is human papillomavirus 16/18 associated with?
Cervical cancer
32
What advancement has been made with HPV and cervical cancer?
There is now an immunisation, so hopefully it will get eradicated over time
33
What is hepatitis B associated with?
Hepatocellular cancer
34
Give two examples of cancers caused by chromosomal translocations?
* Chronic myeloid leukaemia
* Burkitt's lymphoma
35
What is the chromosomal translocation in chronic myeloid leukaemia?
9;22 - c-abl (9) is truncated onto bcr (22)
36
What is the result of the chromosomal translocation in chronic myeloid leukaemia?
Fusion protein has abnormal tyrosine kinase activity
37
What is chromosomal translocation in Burkitt's lymphoma?
8;14 - c-myc (8) is translocated onto igh (14)
38
What is the result of the chromosomal translocation in Burkitt's lymphoma?
It produces a strong promoter leading to constitutive MYC expression
39
What happens in chromosomal amplification?
Tumour genomic instability leads to amplification, and may lead to over-production of normal protein, as multiple copies of the same gene are being expressed
40
What can activate Ras?
Different activating mutations at codons 12, 13, and 61
41
What is the most commonly activated Ras oncogene?
Ki-ras
42
How is Ras activated?
By receptor tyrosine kinases that sit on the inside of the membrane
43
What kind of protein is Ras?
A GTP-binding monomeric switch protein
44
When is Ras active?
When it is bound to GTP, *and therefore inactive after GTP hydrolysis*
45
What is the action of Ras?
Activates the MAP kinase pathway
46
What does the type of Ras mutation determine in colorectal cancer?
The prognosis
47
What is the 2 year survival in colorectal cancer patients with mutant Ras compared to wild type Ras?
It is 49% in mutant ras, compared to 69% in wt ras
48
What mutations were significantly associated with a high risk of recurrence of colorectal cancer?
12 TGT and 13 GAC
49
What did the RASCAL study find that the presence of KRAS mutation was associated with?
An increased risk of recurrence and death
50
How did the RASCAL II study results compare with RASCAL?
It confimed the findings, but only in Dukes C (stage 3) tumours
51
What are the activating mutations in the RAS-MAPK, PI(3)K signalling network?
* KRAS
* PI3KCA
* BRAF
52
What do activating mutations in the RAS-MAPK, PI(3)K signalling network correlate with?
Poor survival in colon cancers
53
What must the role of KRAS be interpreted in the context of?
Other molecular and signalling abnormalities
54
What is any mutation in KRAS, BRAF, or PI3KCA associated with?
A shorter 3 year survival
55
Where can a KRAS mutation status identify an increased risk of recurrence?
In lymph nodes of stage 2 patients
56
Why is it difficult for pharmaceutical companies to block Ras?
Ras is involved in widespread functions in the human body, but only 1 amino acid is changed in the mutant form, and so its hard to target.
57
Give an example of a physiological role of Ras
It is an important pathway for synaptic remodelling in the human brain
58
What % of metastatic melanomas have a mutation in BRAF?
50%
59
What are the BRAF mutations found in metastatic melanoma?
Around 80% are V600E, 16% are V600K, and 3% are V600R
60
Are BRAF mutations found in benign nevi?
Yes
61
What is vemurafenib?
A BRAF inhibitor developed by Plexicon and Genentech
62
What were the results of clinical trials involving vemurafenib?
1. In Phase I, 16 patients with stage 4 cancers were enrolled into the programme, and it increased median survival from 9 to 15 months
2. In Phase II, 132 patients with stage 4 cancers were enrolled into the programme, and 53% of patients responded.
3. In phase III, 375 patients with stage III or IV cancers were enrolled in the programme, which compared vemurafenib to decarbazine. The trial was stopped early, and decarbazine patients were moved to vemurafenib
63
What is the problem with vemurafenib?
It improves the patient for a window, but then the patient relapses with resistant disease
64
What gene is associated with human breast cancers?
Her-2 (human epidermal growth factor receptor 2)
65
In what % of human breast cancers is her-2 amplified and over-expressed?
10-30%
66
What is HER-2 amplification in breast cancer linked to?
Poor prognosis - marker of aggressive cancer
67
How is HER-2 amplification in human breast cancers detected?
By FISH and immunohistochemistry
68
How is HER-2 positive breast cancer treated?
With drugs that bind to the receptor and prevent growth
69
What drugs are used in the targeted therapy of HER-2 positive breast cancer?
* Trastuzumab (Herceptin)
* Pertuzumab (Perjeta)
* Ado-trastuzumab emtansine (Kadcyla)
* Lapatinib (Tykerb)
70
What kind of drug is herceptin?
Monoclonal antibodies
71
What is herceptin often used with?
Chemotherapy, *but it can be used by itself*
72
What is herceptin used to treat?
Early- and late-stage breast cancer
73
How long would a patient typically take herceptin for after surgery?
12 months
74
What kind of drug is perjeta?
Monoclonal antibody
75
What can perjeta be given with?
Trastuzumab and chemo
76
When is perjeta given?
Either before surgery to treat early-stage breast cancer, or to treat advanced trastuzumab in chemo
77
What kind of drug is Kadcycla?
A monoclonal antibody attached to a chemotherapy drug
78
What is kadcycla used to treat?
Advanced breast cancer in women who have already been treated with trastuzumab and chemo
79
What kind of drug is Tykerb?
A kinase inhibitor
80
What is tykerb used to treat?
Advanced breast cancer, most often when trastuzumab is no longer working
81
What is tykerb typically used with?
Certain chemotherapy or hormone therapy drugs
