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BIOC2003 > Oncogenes, cell growth and cancer > Flashcards

Oncogenes, cell growth and cancer Flashcards

1
Q

How big is the human genome ?

A

46 chromosomes
3 billion bp
~30,000 (20,000 annotated)
Transcriptome : 40-1000,000 mRNAs
Proteome : 100-400,000 proteins
Protein interactions : > 1e6 interactions
Protein modifications : > 1e8 post-translational modifications

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2
Q

How does gene expression govern cellular function ?

A

Nutrients, hormones, growth, pathogens and stress can alter cellular function, leading to :

  • proliferation
  • apoptosis
  • growth
  • differentiation
  • transformation
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3
Q

Is cancer a genetic disease ?

Why ?

A

The mutational targets of oncogenic transformation are genes, which effect cell growth, proliferation and death :

  • Oncogenes
  • Tumor-suppressors
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4
Q

What external factors can trigger oncogenic transformation (transforming a normal cell into a cancer cell) ?

A
  • Chemical carcinogens
  • Harmful irradiation
  • Tumorigenic viruses
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5
Q

How is DNA repair linked to oncogenic transformation ?

A

If extensive alterations occur in an oncogene or a tumor suppressor gene, the DNA repair system can start making mistakes, thus introducing mutations and leading to oncogenic transformation.

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6
Q

What are examples of oncogenes ? - tumor suppressors ?

A

Oncogenes ==> gain of function :
- c-erbB2, Ras, PI3-K, Myc
Tumor suppressors ==> loss of function :
- p53, Rb, APC

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7
Q

What is the difference between oncogenes and tumor suppressors ?

A

Oncogenes result from the activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they are inactivated (turned off).

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8
Q

How is cancer initiated ?

How does it progress ?

A
  • Only proliferating cells can undergo oncogenic subversion
  • Tumors initiate as a result of a single mutation in a single cell
  • Subsequent mutations in the offspring of the mutated cell are necessary for the progression of malignant phenotype
  • Clonal selection and expansion of cells with growth advantage cause tumour’s heterogeneity
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9
Q

Is cancer a spontaneous process ?

What kinds of functions are affected in cancer ?

A

Cancer is a stepwise accumulation of mutations that affect growth, differentiation and cell survival.

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10
Q

Give an example of progressive transformation of normal human cells into highly malignant descendants.

A
  1. Normal cell
  2. Mutation in Ras/PI3K
  3. Mutation in telomerase
  4. Mutation in p53/Rb
  5. Mutation in E-Cadherin/RhoC
  6. Malignant cell
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11
Q

What as the usual stages of tumorigenesis ?

A
  1. Mutation inactivates suppressor gene
  2. Cells proliferate
  3. Mutations incativate DNA repair genes
  4. Proto-oncogenes mutate to oncogenes
  5. More mutations, more genetic instability, metastatic disease
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12
Q

What is the difference between a benign tumor and a malignant tumor ?

A

Benign tumor cells grow only locally and cannot spread by invasion or matastasis.
Malignant cell invade neighboring tissues, enter blood vessels, and metastasize to different sites

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13
Q

What is the different between an oncogene and a proto-oncogene ?

A
  • Oncogene is a gene that can induce cancer formation when it is activated by mutations or overexpression
  • A proto-oncogene is a normal gene, before it was mutated. Proto-oncogenes are highly conserved in sequence throughout the evolution between different species
  • Sequence comparison between oncogenes and proto-oncogenes revealed the location of mutational changes that have the potential to induce oncogenic subversion.
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14
Q

Where were oncogenes originally discovered ?

Which were the first oncogenes discovered ?

A
  • Oncogenes were originally discovered in cancer-causing viruses (oncogenic viruses prompted their host cells to rapidly divide, gaining the advantage)
  • It was concluded that oncogenic viruses possess genetic material that causes malignant transformation of infected cells
  • These genes were isolated and sequenced, such as v-Src (Rous sarcoma virus)
  • c-Src is present in mammalian cells in the form of proto-oncogene
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15
Q

What are the main classes of oncogenes ?

A
  • Growth receptors : PDGFR, erbBR (EGFR)
  • G-proteins : K-ras
  • Membrane/cytoskeletal proteins : src
  • Cytoplasmic specific tyrosine-specific protein kinases : N-ras
  • Cytoplasmic serine/threonine-specific protein kinases : raf
  • Cytoplasmic steroid-type growth factor receptors : RET
  • Nuclear proteins : myc, bcI, MDM
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16
Q

Do cancer cells originate from :

  • a stem-cell niche ?
  • progenitor cells ?
  • differentiated cells ?
A

Any of the proposed !

Environmental factors can affect cells at any stage of development

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17
Q

What characteristics are shared between tissue stem cells and cancer stem cells ?
What are the differences ?

A

Shared :
- Self-renewal (division w/o differentiation)
- Proliferative quiescence (infrequent replication)
- Multipotency (differentiation into multiple cell types)
- Persistence (long-term survival)
- Drug-resistance (persistence after treatment)
- Infrequent (<1%)
Differences (properties only possessed by cancer cells) :
- Tumorigenicity (ability to initiate new tumors in vivo)
- Proliferative capacity (capacity for rapid expansion of population size)

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18
Q

What is the phenotypical switch between a benign and a malignant tumor ?

A

Benign –> unrestrained growth

Malignant –> unrestrained growth –> invasiveness –> metastatic potential

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19
Q

Which level of cellular instability can lead to tumor growth ?
What is this process called ?

A

Normal cells –> low level of instability –> no tumor growth
Cell w/ too much instability –> apoptotic pathway is activated –> no tumor growth
Tumor progenitor cells –> increased level of instability –> tumor growth
This process is called clonal expansion and tumor progression.

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20
Q

What is the analogy between mutation and natural selection during bacterial diseases and cancer development ?

A

At each stage of antibiotic treatment/chemotherapy, a fraction of the most resistance bacteria/cells survive, which is sufficient to re-initiate bacterial growth/re-grow the tumor, with degrees of resistance increased with the stages of treatment (unless all the infected cells are killed).

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21
Q

What are the steps of oncogenic transformation and dissemination of cancer ?

A
  1. Transformation
  2. Angiogenesis
  3. Motility + invasion –> capillaries, venules, lymphatics)
  4. Embolism + circulation –> multi-cell aggregates (lymphocytes, platelets) –> lead to transport
  5. Arrest in capillary beds
  6. Adherence
  7. Extravasation onto organ parenchyma
  8. Response to environment
  9. Tumor cell proliferation and angiogenesis
  10. Metastases
  11. Metastasis of metastases
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22
Q

What signal cascade can lead to changes in DNA and protein synthesis ?

A
  1. Growth factors
  2. Membrane receptors
  3. Signal transducers (2nd messengers)
  4. TFs
  5. Induction of DNA and protein synthesis
  6. Cellular response.
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23
Q

Which ligands can activate signalling pathways leading to growth, proliferation, differentiation and apoptosis ?

A

Hormones
Growth factors
Cytokines

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24
Q

What are the four main ways by which oncogenic transformation can occur ?

A
  • Translocation of transposition (in front of a new promoter): normal growth stimulating protein in excess
  • Gene amplification : normal growth stimulating protein in excess
  • Point mutation w/in a control element : normal growth stimulating protein in excess
  • Point mutation w/in the gene : hyperactive or degradation-resistant protein
25
Q

What is the product of the sis oncogene of the simian sarcoma virus (SSV) ?
What are steps of this process ?

A

The product of the sis oncogene of the Simian sarcoma virus is PDGF-like growth factor (Platelet-Derived Growth factor)
1. Infection by SSV
2. Integration of viral DNA into cell’s genome
3. Expression and secretion of sis oncogene
4. Autocrine stimulation of cell proliferation
Viral infection leads to constitutive secretion of sis (PDGF-like), activation of PDGF-R, induction of growth and proliferation

26
Q

What is the product of the erbB oncogene of the Avian Erythroblastosis virus ?
How does this process occur ?

A

the product of the erbB oncogene of the Avian Erythroblastosis virus is a truncated form of EGF-R :

  1. Loss of the ligand-binding domain and of 22 aa at the C-terminus produces an activated form of this receptor tyrosine kinase
  2. Constitutive mitogenic signal to the nucleus in the absence of the ligand (EGF)
  3. Continuous stimulation of proliferation
27
Q

What is the product of the neu oncogene of the rat ?

How does this process occur ?

A

It was identified as an activated oncogene in chemically-induced neuroblastomas (rat model).
In comparison with normal neu gene, oncogenic counterpart contains only 1aa difference in transmembrane domain of EGF-R :
Normal TFIIATVVGVLLFLILVVVVGILI
Oncogenic neu TFIIATVEGVLLFLILVVVVGILI
This mutation results in ligand-independent receptor dimerisation and tyrosine kinase activation. The oncogenic neu resembles a ligand- stimulated receptor (conformationally).

28
Q

How is the neu oncogene related to the c-erbB oncogene in humans ?

A

c-erbB (human) or neu (rat) oncogene c-erbB are closely related to EGF-R.

29
Q

Growth factors can become oncogenes when over-expressed.
How can EGF-R over-expression occur ? Where are these found ?
What about c-erbB2 (or neu) ?

A 
EGF-R over-expression occurs through:
a) gene amplification or
b) increased expression
Found in: 
* squamous carcinomas 
* invasive bladder tumors
* glioblastomas
Over-expression of c-erbB2 (or neu) :
- found in approximately 30% of breast cancer
- correlates with tumor progression and poor prognosis
30
Q

How does EGFR expression rate vary in different cancers ?

A 
Breast : 14-91% 
Colon : 25-77%
Lung cancer (non small cell) : 40-80%
Head and neck : 80-95%
Ovarian : 35-70%
Pancreatic : 30-50%
31
Q

What kinds of cellular function can regulated via EGFR ?

By which pathways ?

A
  1. Growth factor binding to EGFR (EGF, TGF-alpha, etc.)
  2. EGFR phosphorylation (cytosolic domain)
  3. Downstream signalling :
    - JAK/SRC –> STAT => survival, proliferation, oncogenesis
    - PI3K (inhibited by PTEN) –> Akt => angiogenesis, tumorigenesis, inhibition of apoptosis
    - Ras, RAf, MEK –> ERK (inhibited by MKP1) => gene expression, cell-cycle progression
    - PLCgamma, DAG –> PKC => transformation, differentiation, apoptosis
32
Q

What family of receptors does EGFR belong to ?

A

EGFR belongs to the HER family of receptors.

33
Q

What are the 4 members of the HER family of receptors ?

A 
HER1 (erb-b1) (e.g. EGFR)  : 
- ligands : EGF, TGFalpha, amphiregulin, betacellulin, HB-EGF, epiregulin
- TK domain
HER2 (erb-b2) (e.g neu) : 
- no known ligands
- TK domain
HER3 (erb-b3) : 
- ligands : heregulins
- no TK domain
HER4 (erb-b4) : 
- ligands : NRG2, NRG3, heregulins, betacellulin
- TK domain
34
Q

Name an example oncogene transformation by DNA re-arrangements ?

A
  • HGF-R (Hepatocyte Growth Factor Receptor) or c-Met HGF-R is a heterodimer, which is localised on cellular membranes
  • This re-arrangement results in aberrant localisation and activation of Met tyrosine kinase activity
  • Tpr-Met was identified in osteomic sarcomas
35
Q

What is the consequence of deregulated HGF signalling ?

A

Deregulated signaling via HGF receptor is implicated in invasive growth.

36
Q

What kinds of cellular processes does HGF-signalling mediate ?
By which pathways ?

A
  1. HGF binds to MET receptor
  2. Cross phosphorylation of cytoplasmic domains
    3.Then :
    PI3K recruited –> survival
    STAT+BRG2, attached to SOS+RAS –> proliferation
    Also, STAT –> branching morphogenesis
    GRB2, attached to GAB1, itself attached to PLCgamma and SHIP2 –> branching morphogenesis
    GAB1 also attached to PI3K –> motility
37
Q

What is the prototypic oncogene ?

A

The prototypic TK oncogene is bcr/abl. The bcr/abl fusion oncogenei is formed when the c-abl TK gene on chromosome 9 is translocated to chromosome 22 and fused with part of the bcr gene on that chromosome. The resulting hybrid chromosome, the Philadelphia chromosome, encodes a new protein called Bcr/Abl. The new protein has increased kinase activity and drives proliferation causing transformation. Charatceristic of CML (Chronic Myelogenous Leukemia) and some forms of ALL (Acute Lymphblastic Leukemia).

38
Q

What is the role of small GTPase at different stage of tumor progression (e.g. cell junctions, cell polarity, etc) ?

A

Stage a) (normal cells) Cell polarity : RHOA, RAC1, CDC42, RAR6
Cell junctions : RHOA, RAC1
b) Loss of polarity : RAC1, RHOA
Multi-layering : RHOE/RND3
c) Loss of cell junctions : RAC1, RHO, ROCK
Motility : RHOA, ROCK, RAC1, CDC42
d) (tumor cells) : Intravasation : RHO, ROCK
Vascularization : RHOC

39
Q

What is the role of small GTPase in cell function ?

A

Regulation of the cytoskeleton and cell motility.

40
Q

What are the diverse roles of MMP (Matrix Metalloproteinases) in metastatic growth ?

A
  • Degradation of matrix barriers
  • Degredation to reveal cryptic sites (laminin and angiotensin 5)
  • Disruption of cell-cell adhesions (E-cadherin)
  • Disruption of cell-matrix adhesion (CD44)
  • Release of Growth Factors
41
Q

What are the two forms of MMPs ?

A

Soluble and membrane MMPs.

42
Q

What are the different groups of metalloproteinases ?

A
  • Matrilysins
  • Collagenases
  • Stromelysins
  • Metalloelastases
  • Gelatinases
  • Membrane-type MMPs
43
Q

What is the role of angiogeness ?

A

Angiogenesis allows the switch from limited growth to fast growth of the tumor.

44
Q 
What kinds of molecules stimulates angiogenesis ?
Give examples for each class you name.
A
  • Growth factors: VEGF, FGF, EGF, PDGF, TGFα
  • Cytokines: IL8, TNFα
  • Small second messangers: adenosine, prostoglandins, nicotinamide
45
Q

Which factors lead to apoptosis ?

How does this change in cancer cells ?

A

Numerous extracellular factors can lead to the induction of apoptosis (programmed cell death).
In most cases, cancer cells have lower rates of apoptosis.

46
Q

Which factors can lead to the activation of the caspase cascade ?

A 
DNA damage
Stress
Starvation 
Oncogene activation 
Inactivation of tumor suppressors
47
Q

What are the role of PI3K, PKB/Akt, and Bcl2 in cancer ?

A
  • Bcl-2 is a proto-oncogene, which inhibits the protease cascade that leads to cell death
  • PI3-K/Akt signalling regulates cell survival pathway
  • Overexpression or activating mutations in Bcl2, PI3K, PKB/Akt are found in many types of human cancer
48
Q

How is the glucose metabolism of cancer cells altered ?

A
  • Increased glucose uptake
  • Increased glycolysis
  • Increased glycolytic intermediates to biosynthetic pathways
49
Q

What is the effect of oncogenes on cellular biosynthesis ?

A
  • GF and hormones activates PI3K —> PIP3 –> mTOR + TSC2/TSC1 (inhibits mTOR)
    mTOR –> S6K –> 4E-BP1 –> protein synthesis –> growth
    PIP3 inhibied by PTEN
    mTOR activates PKB (+ve feedback)
    TSC2/TSC1 inhibited by 14-3-3
    AMP –> AMPK –> TSC2/TSC1
    –> = activates/stimulates
  • Nutrients also directly activate the mTOR pathway
50
Q

How is the G1/S checkpont controlled in healthy cells ?

How do oncogenes affect the cell cycle ?

A

G1/S checkpoint is controlled by phosphorylation of Rb by cyclin-dependend kinases (CDK4/6)
In cancer –> deregulation of G1/S checkpoint, such as cyclin D1 over-expression or inactivation of CDK inhibitors
Consequence : increased transcription of genes that lead to entry in S-phase

51
Q

What are the properties of transformed cells ?

A
  1. Reduced requirement for growth supplements (serum, growth factors, hormones)
  2. Loss of the capacity to go into a quiescent state (growth arrest)
  3. Altered morphology (look different from the precursors)
  4. Loss of contact inhibition (tumor cells grow on top of each other)
  5. Loss of anchorage dependence (tumor cells grow in soft agar)
  6. Form tumors in “nude” mice–> many cancer cell lines, derived from naturally occurring tumors, have these properties in culture
52
Q

What are the acquired capabilities of cancer ?

A 
- Self-sufficiency in growth signals 
Example: Activation of H-Ras (Oncogene)
- Insensitivity to anti-growth signals
Example: Loss of Rb (Tumor suppressor)
- Evading apoptosis
Example: Expression of surviving factors (IGF-1)
- Limitless replicative potential
Example: Turn on Telomerase
- Sustained angiogenesis 
Example: Expression of VEGF
- Tissue invasion and metastasis
Example: Inactivate E-Cadherin
53
Q

How many types of cancer exist ?

How many cancer drugs do we have ?

A

• There are approximately 100 distinct types of cancer
• More then 50 anti-cancer drugs are available for treatment, but only one third of them are commonly used
All anti-cancer drugs:
* mainly cytotoxic
* non-selective for cancer cells * very strong side-effect

54
Q

WHat are the 4 main types of cancer therapies proposed to this day ?

A
  • Surgical removal of the tumor * Chemotherapy
  • Radiotherapy
  • Immunotherapy
55
Q

What is the difference between tumors arising from stem cells and those arising from late progenitor cells ?

A 
Tumors from stem cells : 
- heterogeneous cancer
- increased metastatic potential (+ self renewing cancer SCs can regenerate the tumor more easily) 
Tumors for late progenitor cells : 
- homogeneous cancer
- less metastatic potential
56
Q

What are the strategies for inhibiting EGFR signalling in cancer?

A
  • EGFR TK inhibitors
  • Anti-EGFR mAbs (monoclonal Antibodies)
  • Anti-EGF mAbs
57
Q

What are the futur prospect for the treatment of cancer treatment ?

A

Current target is to cure main forms of cancer within 25-30 years
The ways to achieve this target:
- Better diagnostic
- New cancer specific markers and targets for drug development will emerge, based on human genome project and proteomics
- New technologies for research on cancer will produce more drugs and shorten the time of their development
- New types of treatment, including gene and immunotherapy, are in clinical trials

58
Q

Which MMPs are present in malignant tumors ?

A 
MMP-2 = Gelatinase-A
MMP-9 = Gelatinase-B

BIOC2003 (15 decks)

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