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Carcinogensis + Anticancer drugs > Growth factors > Flashcards

Growth factors Flashcards

1
Q

why are growth factors necessary and how do they work

A
  • Normal cells growing in culture will not divide unless stimulated by growth factors in the culture medium
  • Extracellular growth factor molecules bind to specific receptor proteins embedded in the plasma membrane
  • Triggers a cascade of signaling events inside the cell
  • Involves protein kinases, that attach phosphate groups to the Tyr, Ser or Thr groups of other proteins
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2
Q

Oncogenes activation deregulates normal growth signal control pathway by =

A

○ Phosphorylation cascade transfers signal to the nucleus, regulating cell cycle control proteins and transcription factors
○ Some of the genes turned on by activated transcription factors encode cyclins and other cell cycle control proteins that regulate cell cycle progression
○ Genes that participate in any one of the growth signal transduction steps can become oncogenes if: [mutated so their product becomes constitutively active (i.e., active all the time even in the absence of a positive growth signal), Overexpressed (e.g. by gene amplification, or promoter alteration)]

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3
Q

How do platelet derived growth factor (PDGF) and v-sis interact

A
  • The simian sarcoma virus oncogene (v-sis) was found to encode a 28kd protein (p28sis) with strong homology to PDGF
  • PDGF is a potent growth factor released from blood platelets as part of the normal wound healing response
  • In virally transformed cells, p28sis acts as an autocrine growth stimulatory factor for the infected cells and has a local paracrine effect on neighbouring stromal tissue
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4
Q

The PDGFB gene has found to be overexspressed where

A

The PDGFB gene (c-sis) has been found overexpressed in a range of human cancers

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5
Q

Which oncogenes which related to fibroblast growth family (FGF)

A

□ Hst = Derived from a human stomach cancer & also a Kaposi’s sarcoma, using the NIH3T3 transfection assay. Encodes a 205 amino acid protein member of the fibroblast growth factor family (FGF4)
□ int2 = Identified from the cloning of host genes at the integration site of the murine mammary tumour virus (MMTV).Encodes a 245 amino acid protein also homologous to FGF family (FGF3)
□ FGF3, FGF4 & FGF19 = Amplified in breast (15-17%), Head & neck (11-12%), bladder (8-9%) cancers

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6
Q

Which oncogenes have products which related to growth factor receptor

A

erbB or EGF-receptor family
Comprises 4 members = ErbB1-4, also known as HER1-4
- erbB1 = A human homologue of the v-erbB receptor derived from the avian erythroblastosis virus. Encodes the Epidermal Growth Factor Receptor (EGFR)
- erbB2(neu) = Encodes a receptor related to EGFR, but is not directly stimulated by EGF

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7
Q

erbB family are part of which larger superfamily of what

A

Cell surface tyrosine kinase receptors
Span the plasma membrane, with an extracellular ligand binding domain and an intracellular tyrosine kinase domain linked by a hydrophobic transmembrane region that anchors the receptors in the plasma membrane.

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8
Q

the first human member of the erbB family to be discover with

A

EGF-receptor, EGF (epidermal growth factor) is the normal ligand for this receptor
- Intracellular tyrosine kinase domain activity stimulated by EGF binding

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9
Q

what is an alternative ligand for the EGF- receptor

A

Transforming growth factor-α (TGF-α) is an alternative ligand believed to act as an autocrine growth stimulator in some tumours

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10
Q

what is EGF-receptor and the relationship to v-erbB oncogenes

A
  • The EGF-receptor was purified from A431 human vulval carcinoma cells
  • The EGFR amino acid sequence showed a high degree of similarity to the predicted product of the v-erbB gene of the avian erythroblastosis virus.
  • v-erbB encodes a truncated form of EGFR, missing most of the extracellular domain, but retaining the intracellular tyrosine kinase domain and transmembrane anchoring region
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11
Q

what is the signalling related to EGF

A
  • EGF ligand binding induces receptors to dimerize and activates intracellular kinase activity
  • Receptor tyrosine kinases cross phosphorylate their homodimer or heterodimer partner, on multiple tyrosine residues
  • Phosphorylated tyrosine residues are docking sites for intracellular signalling proteins
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12
Q

What is the significance of EGF receptors in human cancer

A
  • Frequent over-expression: Several types of human tumour, particularly squamous cell carcinomas and gliomas, show abnormally high EGFR expression, often associated with gene amplification
  • EGFR expression in breast cancer: Inverse correlation with oestrogen receptor expression, Indicator of poor prognosis
  • EGFR expression in bladder cancer: Increased expression in late stage invasive tumours, For patients with superficial tumours, indicator of likely recurrence, invasive progression and poor survival
  • EGFR as therapeutic target: Specific inhibitors of the EGFR tyrosine kinase developed and have activity against a number of cancers (e.g. Iressa (Gefitinib), AstraZeneca & Cetuximab (Erbitux)
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13
Q

how was the erbB2 oncogene discovered

A
  • Identified as a novel transforming oncogene from a chemically (ENU) induced rat neuroblastoma
  • Also independently isolated in cDNA library screens by cross-hybridisation with EGFR cDNA and designated erbB2
  • Sequence and overall structure similarity suggested encoding of a growth factor receptor closely related to EGFR
  • Only binds ligands as part of a heterodimer with other receptors
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14
Q

what is the link between C-erbB2 (HER2) in breast cancer

A

Frequent amplification and over-expression of erbB2
Associated with higher incidence of early relapse and poor survival

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15
Q

what is erbB2 causal role in transformation and growth

A

Overexpression of transfected c-erbB2 transforms NIH3T3 cells
Antibodies to erbB2 protein shown to inhibit the growth of breast tumour cells in vitro and in vivo
Humanised anti-erbB2 antibody, trastuzumab (Herceptin) used both as a single agent and combined with chemotherapy, for metastatic breast cancer

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16
Q

What is Herceptin and how does it link to breast cancer

A
  • Humanised monoclonal antibodies which bind to the extracellular segment of the HER2 receptor
  • Herceptin has multiple modes of actions = Blocks dimerization and cleavage of the receptor, and also targets the receptors for antibody-dependent cell-mediated tumour lysis by immune cells and promotes degradation of the receptor by endocytosis.
17
Q

What is the interrelationship/co-operation between the erbB family of receptor

A

The tyrosine kinase domain is the most conserved (erbB1, erbB2 and erbB4 are the most closely related members)
Multiple ligands, but none directly for erbB2
- erbB2 is the preferred heterodimer for other family members and enhances proliferation signals from all the other receptors
- Co-expression of erbB2 with other erbB family members associated with poor prognosis in a range of tumour types

18
Q

What is an oncogene protein family which encodes protein involved in intracellular growth signals transduction

A

The RAS G-protein family

19
Q

What are the two rat sarcoma retrovirus genes and what mutated homologues are detected by the NIH3T3 transfection assay

A

V-H-ras Harvey + V-Ki-ras Kirsten
C-H-ras, C-Ki-ras

20
Q

what member of the RAS-G protein family was isoloated form a human neuroblastoma cell line

A

N-ras

21
Q

what percentage of human tumours contain mutated ras genes

A

20-30%

22
Q

what is the mechanism of activation for ras gene

A

Single missense gain of function point mutations
Always found at the same specific points: codons 12 or 13, and codons 59,61 or 63.

23
Q

what are the properties of the RAS gene products

A

21kD phosphoprotein
- Inner plasma membrane attachment required for transforming activity
- Localisation to inner membrane requires post-translational modification by a farnesyl transferase
- A number of pharmaceutical companies have developed and tested farnesyl transferase inhibitors

24
Q

What is the occurence of RAS mutation and what is the effect

A

Frequency of mutations depends on tumour type and method of detection, ranging from little or no evidence in neuroblastoma, to >80% in pancreatic adenocarcinoma
RAS mutations have a strong causal link with cancer, establishing mutant RAS as a therapeutic target

25
Q

what was the use of Farnesyl transferase inhibitors

A

Reversal of RAS-mediated transformation of human cell lines
Inhibition of the growth of human tumour xenografts
Regression of some tumours in transgenic mice
However - but failed to impress for KRAS and NRAS mutant cancers in clinical trials
However, tipifarnib recently (2021) granted Breakthrough Therapy Designation by the FDA because of positive results for HRAS-mutant HNSCC and thyroid cancer

26
Q

why would someone target the KRAS-G12C mutation

A

Recent breakthrough progress has been made with specific targeting of the KRAS-G12C mutant form
- The mutant cysteine renders the protein susceptible to specific irreversible binding with cysteine reactive small molecules
- Allosteric binding to the Switch-II domain locks KRAS in the inactive GDP-bound form
- Currently 7 KRAS-G12C inhibitors are in clinical trials
- Sotorasib granted accelerated FDA approval for second line KRAS-G12C +ve NSCLC and colorectal cancer (2019)

27
Q

What are the connection between cell surface receptor and RAS signalling

A
  • Src homology regions, SH2 and SH3 are non-catalytic conserved regions found on many cytoplasmic signalling proteins
  • SH2 domains bind tyrosine phosphorylated proteins
  • SH3 domains link to adaptor proteins that couple tyrosine kinase receptors to specific target proteins, e.g. EGF-receptor and RAS.
28
Q

what is Grb2

A

(growth factor receptor binding) protein binds to tyrosine phosphorylated regions of activated receptors via its SH2 domain and to a second coupling protein, Sos (Son of sevenless)

29
Q

What is Sos (Son of sevenless)

A

guanine nucleotide release factor and interacts with RAS to displace the GDP nucleotide and replace it by GTP to activate RAS

30
Q

RAS, RAF, MEK and ERK are collectively referred to as

A

the mitogen activated protein kinase (MAPkinase) pathways

31
Q

what can be used to target aberrant growth signalling pathways

A

mTor inhibitors
Herceptin/Cetuximab = target EGFr,TGF-a,EGF
TK-inhibitors (gefitinib,lapatinib)
Sotorasib
Vemurafenib
trametinib
CDK inhibitors (palbociclib

32
Q

what are some examples of nuclear oncogenes which encodes transcription factors

A

Jun and fos = AP1 transcription factor complex
MYC = Transcription factor family

33
Q

explain the regulation of nuclear oncogenes which encodes transcription factors

A
  • Normal expression is high regulated.
    (Expressed at low levels in quiescent cells but rapidly switched on in response to growth signals)
  • Function at the nuclear end of growth signal transduction pathways, converting primary stimuli to long-term responses.
  • Because regulation of their expression is central to their function, oncogenic activation generally involves upregulation of expression.
    e.g. Activation of myc by the avian leukosis virus, Amplification of the MYCN oncogene in neuroblastoma
34
Q

what proteins do nuclear oncogenes which encode cell cycle control protein produce

A

Cyclins
Cyclin-dependent kinases

35
Q

What do cyclins and cyclin-dependent kinases control

A

positive regulation of cell cycle progression

36
Q

what do CDKs do

A

induce other proteins to perform their function by phosphorylating key amino acid residues, and cyclins bind to Cdk’s to control their kinase function

37
Q

what is an example of deregulated expression of cyclins/CDKs seen in cancer which can be considered to act as oncogenes

A

Cyclin D1(also known as PRAD-1/CCND1 is an example of a cell cycle protein that behaves as an oncogene and is found amplified and over-expressed in a range of cancers

Carcinogensis + Anticancer drugs (16 decks)

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