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BIOM 4150 Cancer Biology > Unit 2- Growth Factors, Receptors, and Cancer > Flashcards

Unit 2- Growth Factors, Receptors, and Cancer Flashcards

1
Q

What are growth factors?

A
  • signaling proteins that stimulate cell growth/ differentiation/ survival
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2
Q

Why do we need growth factors?

A
  • cell communication
  • to maintain proper tissue architecture
  • many cell types > control proliferation, so have the right # of cells
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3
Q

Why do we need growth factor receptors?

A
  • plasma membrane is impermeable to most signaling molecules (h20 soluble)
  • proteins/ genes that regulate cell function are located within cell
  • receptors transmit extracellular signals > intracellular proteins
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4
Q

How can growth factors contribute to cancer?

A
  • GF/ GFR signaling is tightly controlled
  • tumor cells can alter GF production/ GFR signaling
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5
Q

What gene provided the initial clues about cell signaling via growth factors?

A

Src (v-src = viral src)
- first discovered oncoprotein
- gene from rous sarcoma virus > induced sarcomas in chickens

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6
Q

What happened when cells transformed with v-src?

A
  • ↑ cell proliferation
  • altered glucose uptake/ cell shape
  • resulted in anchorage-independent growth > tumor formation
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7
Q

What kind of a protein is Src/ how was this determined?

A

Tyrosine Kinase
- anti-Src antibody phosphorylated

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8
Q

Why is Src unlike other kinases?

A
  • phosphotyrosine rare compared to phosphothreonine/ phosphoserine
  • many substrates (>50) can explain pleiotropic effects
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9
Q

What is the common structure of tyrosine kinase receptors?

A
  • at least 1 tyrosine kinase domain in intracellular space
  • ligands bind extracellular
  • most receptors are monomers/ dimerize when bind ligand
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10
Q

What are gene mutations?

A
  • permanent alteration in DNA sequence that makes up a gene, so sequence differs from what is found in most people
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11
Q

How can mutations impact the function of a protein?

A
  • affect whether full-length/ truncated protein is produced (↑/↓ function)
  • influence intracellular localization
  • impact whether protein expressed in particular cell
  • alter ability of signals to turn on/off protein
  • alter protein ability to interact with other cell components
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12
Q

How can mutations lead to deregulation of receptor signaling?

A

normal receptor > ligand binds > ligand-dependent firing
mutations > ligand-independent firing

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13
Q

What are 3 mechanisms of deregulation of receptor signaling in tumors?

A

mutation > ligand-independent firing
autocrine signaling
receptor amplification > ↑ # of receptors to ↑ activation

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14
Q

How are tyrosine kinase receptors activated?

A

Transphosphorylation
> monomers dimerize

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15
Q

What are the Src homology domains? (protein interaction domains)

A

SH2- allows protein to bind phosphorylated tyrosine residue
SH3- allows protein-protein interactions

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16
Q

What provides protein binding sites?

A
  • receptor phosphorylation
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17
Q

What provides negative feedback of tyrosine kinase signaling?

A

Phosphatases- remove phosphate from tyrosine
(Kinase-add phosphate/ activate)

18
Q

What factors promote Ras activation/ inactivation?

A

GDP-Ras = inactive/ GTP-Ras = active
GEF = Guanine Exchange Factors > promote Ras activation ex) Sos
- Shc/ Grb2 proteins recruit Sos
GAP = GTPase Activating Protein > GTP hydrolysis/ Ras inactivation

19
Q

How does Ras signaling work?

A

Ras- tethered/ stuck on plasma membrane
Ras = GTPase (GDP-Ras = inactive/ GTP-Ras = active)
- SOS (a GEF) recruited to Ras > facilitates GDP > GTP exchange > Ras activation

20
Q

How can a mutation impact Ras signaling?

A
  • oncogenic mutation causes GAP (GTPase activating protein) blockage
    > GAP can not inactivate Ras (GTP-Ras overactivated)
21
Q

What are the major Ras signaling cascades?

A

MAPK > ↑ transcription factors
Ral > metastasis
AKT/PKB > promotes cell proliferation/ survival/ growth

22
Q

How does Ras > AKT/PKB signaling work?

A

PIP2 = phospholipid inactive/ PIP3 = active
- Ras activates PI3K enzyme > PIP2 to PIP3 > AKT/PKB localization to plasma membrane > activation
- PTEN inactivates PIP3 to PIP2 (opposite of PI3K)

23
Q

What is the result of a loss of PTEN in AKT/ PKB signaling?

A
  • AKT hyperactivation
  • PTEN normally inactivates PIP3 > PIP2/ controls AKT/ PKB activation
24
Q

What does AKT/PKB signaling do?

A
  • stimulates proliferation
  • stimulates angiogenesis
  • inhibits apoptosis
25
Q

What are 3 key tyrosine kinase receptors in human cancer?

A

EGFR2/ HER2 = Epidermal Growth Factor Receptor 2
IGF-IR- Type I Insulin-like Growth Factor Receptor
EGFR1/ EGFR = Epidermal Growth Factor Receptor 1

26
Q

How was EGFR2/ HER2/ p185neu identified as an oncogene?

A
  • DNA from tumor cells > transform normal rodent cells
    HER2 overexpressed in 25-30% of breast cancers > worse prognosis
27
Q

What is next after establishing a protein is an oncogene?

A
  1. General Cell lines/ Cell Culture Systems
  2. Create Animal Model
28
Q

What are the pros/ cons of cell line/ cell culture studies?

A
  • isolate tumor cells/ can overexpress gene
  • useful to study mechanisms, but environment is artificial (isolated)
29
Q

What are the pros of animal models?

A
  • inject tumor cells into mice
  • use transgenic mouse to overexpress a gene of interest
  • use tumor suppressors to knock out gene of interest
  • more physiologically relevant environment
  • can study tumor growth/ metastasis
30
Q

How was a transgenic HER2/ neu mice model developed?

A
  • superovulate mouse/ isolate fertilized eggs
  • insert expression construct/ inject DNA into pronuclei
    MMTV promoter > upstream of gene, so transcription of gene only in specific tissue of interest (mammary gland)
31
Q

What was the result of trangenic overexpression of neu in mice?

A
  • induces mammary tumors in mice
32
Q

What drug was developed for HER2/ EGF2 as a therapeutic target?

A

Herceptin (Traztuzamab) = muMAb4D5 (mouse monoclonal antibody)
- enhanced effects of chemotherapy/ ↑ survival in patients with HER2 overexpression

33
Q

What is a problem with targeted therapies?

A

Drug Resistance > tumors non-responsive to Herceptin
- mutation in target (HER2)/ stop expressing HER2
- upregulation of other pathways

34
Q

What is the IGF family/ IGF-IR?

A

IGF-IR= type I Insulin-like GFR = Mitogenic/ Anti-Apoptotic
- 6 binding proteins (IGFBP) prevent GF degradation

35
Q

What pathways does IGF-IR signaling activate?

A

MAPK/ PI3K AKT/ STATS

36
Q

How do IGFs/ IGF-IR contribute to breast cancer?

A

in vitro- IGFs stimulate breast cancer cell proliferation/ inhibit apoptosis
- targeting IGF-IR ↓ breast cancer cell survival

in vivo- ↑ circulating IGF-I associated with ↑ breast cancer risk
- IGF-IR overexpressed in high % of human breast tumors

  • although present, the exact role of IGF-IR in tumor initiation/ progression/ metastasis is unclear
37
Q

What is interesting about IGF-IR signaling-dependent tumors?
How was this studied?

A
  • generation of double transgenic mouse > Dox inducible IGF-IR
  • IGF-IR overexpression > induces mammary tumor formation
  • high IGF-IR expression in mammary tumors
  • remove DOX/ suppress IGF-IR signaling > tumors regress
  • tumors induced by IGF-IR rremain dependent on IGF-IR signaling
38
Q

What are drugs targeting EGFR/ HER1?

A

Iressa (Gefitinib)/ Tarceva (Erlotinib)
- small molecule EGFR inhibitors

39
Q

What is interesting about mutations to EGFR/HER1 tumors?

A
  • mutations make receptor more sensitive to drugs (gefitinib/ erlotinib)
  • ↑ survival if you have mutation
40
Q

What is the first-line therapy in patients with EGFR mutation-positive NCSLC?

A

Erlotinib (Tarceva)
- unfortunately, patients often become resistant

41
Q

What are integrin receptors?

A
  • transmembrane proteins
  • cell-cell adhesions/ receptor binding in ECM (extracellular)
  • short cytoplasmic tail/ protein binding cytoskeleton/actin (cytoplasm)

BIOM 4150 Cancer Biology (6 decks)

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