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BIOC2003 > Oncogenes, Cell Growth and Cancer > Flashcards

Oncogenes, Cell Growth and Cancer Flashcards

1
Q

What is a proteome?

A

The entire set of proteins transcribed by a genome/cell/tissue at a specific time under defined conditions

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2
Q

Which two types of genes are the main mutational targets of oncogenic transformation?

A

Oncogenes

Tumor-suppressors

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3
Q

Which two types of genes are the main mutational targets of oncogenic transformation?

A

Oncogenes

Tumour-suppressors

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4
Q

What three factors can cause a normal cell to become a cancer cell?

A

Chemical carcinogens

Harmful irradiation

Tumourigenic viruses

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5
Q

What are the two possible repair mechanisms related to oncogenic transformation?

A

Alteration occurs in oncogene or tumour-suppressor gene.

No repair ==> CANCER

Repair ==> NO CANCER

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6
Q

How do oncogenes and tumour-suppressor genes lead to oncogenic transformation?

A

ONCOGENES
gain of function: c-erbB2, Ras, PI3-K, Myc

TUMOUR-SUPPRESSORS
loss of function: p53, Rb, APC

Each of these independently results in oncogenic transformation.

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7
Q

Discuss the initiation and progression of cancer.

A

Only proliferating cells can undergo oncogenic subversion.

Tumour 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 the malignant phenotype.

Clonal selection and expansion of cells with growth advantage cause tumour’s heterogeneity.

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8
Q

State the difference between BENIGN and MALIGNANT tumour cells.

A

BENIGN
Grow only locally and cannot spread by invasion or metastasis

MALIGNANT
invade neighbouring tissues, enter blood vessels, and metastasise to different sites

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9
Q

Outline the mulitstage model of tumourigenesis.

A

As time progresses:

  1. Mutation inactivates suppressor gene
  2. Cells proliferate
  3. Mutations inactivate DNA repair gene
  4. Proto-oncogenes mutate to oncogenes
  5. This ultimately results in more mutations, more genetic instability, metastatic disease
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10
Q

Define ONCOGENES and PROTO-ONCOGENES.

A

ONCOGENE
A gene that can induce cancer formation when it is activated by mutations or overexpression

PROTO-ONCOGENE
A normal gene that has not yet been mutated; proto-oncogenes are highly conserved in sequence throughout the evolution between different species

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11
Q

How were oncogenes discovered?

A

Originally discovered in cancer-causing viruses which were found to 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, as present in mammalian cells as
proto-oncogenes

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12
Q

List the main classes of oncogenes.

A

Growth factors

Receptor tyrosine kinases (RTKs)

Cytoplasmic tyrosine kinases (CTKs)

Cytoplasmic Seronine/Threonine kinases

Regulatory GTPases

Transcription factors (nuclear)

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13
Q

Outline the function of oncogenic growth factors and provide an example.

A

GROWTH FACTORS
induce cell proliferation

e.g. c-Sis

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14
Q

Outline the function of oncogenic receptor tyrosine kinases and provide an example.

A

RECEPTOR TYROSINE KINASES
transduce signals for cell growth and differentiation

e.g. EGFR, PDGFR, VEGFR

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15
Q

Outline the function of oncogenic cytoplasmic tyrosine kinases and provide an example.

A

CYTOPLASMIC TYROSINE KINASES
mediate the response to, and the activation receptors of cell proliferation, migration, differentiation, survival

e.g. involved in the immune system

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16
Q

Outline the function of oncogenic cytoplasmic serine/threonine kinases and provide an example.

A

CYTOPLASMIC SERINE/THREONINE KINASES
involved in organism development, cell cycle regulation, cell proliferation, differentiation, cell survival, apoptosis

e.g. cyclin-dependent kinases

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17
Q

Outline the function of oncogenic regulatory GTPases and provide an example.

A

REGULATORY GTPases
involved in signalling a major pathway leading to cell proliferation

e.g. Ras protein

18
Q

Outline the function of oncogenic transcription factors (nuclear) and provide an example.

A 
TRANSCRIPTION FACTORS (NUCLEAR)
regulate transcription of genes that induce cell proliferation

e.g. myc gene

19
Q

What is meant by ‘oncogenic transformation’?

A

The change of a gene from proto-oncogenic to oncogenic via mutation.

20
Q

What characteristics do TISSUE STEM CELLS and CANCER STEM CELLS have in common?

A

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%) - in some cancers, tumourigenic population is expanded

21
Q

What characteristics are found in CANCER STEM CELLS that are NOT found in TISSUE STEM CELLS?

A

TUMOURIGENICITY - ability to start new tumours in vivo

PROLIFERATIVE CAPACITY - capacity for rapid expansion of population size

22
Q

Outline the three possible mechanisms of clonal selection and tumour progression.

A

Normal cells w/ low level of instability:
NO TUMOUR GROWTH

Tumour progenitor cells w/ increased levels of instability:
TUMOUR GROWTH

Cells with too much instability, apoptotic pathway activated: (usually) STOPS TUMOUR GROWTH

23
Q

Outline the major steps starting from oncogenic transformation until the metastasis of metastases.

A

Transformation ==> angiogenesis
==> motility and invasion ==> embolism and circulation
==> arrest in capillary beds ==> adherence
==> extravasation into organ parenchyma
==> response to microenviroment
==> tumour cell proliferation and angiogenesis
==> metastasis ==> metastasis of metastases

24
Q

Which type of cells are the only cells that can become malignant?

A

Only PROLIFERATING cells can be come malignant;

redifferentiation can occur

25
Q

The overexpression of what enzyme can stop cell death?

A

TELOMERASE overexpression can stop cell death.

Normally, telomere shortens with each division and isgnal stop after 40-50 divisions; however, telomerase reduces telomere shortening.

26
Q

Explain one mechanism which demonstrates that proto-oncogenes are key to signal transduction

A

Growth factors ==> Membrane receptors
==> Signal transducers (second messengers)
==> Transcription factors
==> Induction of DNA and protein synthesis
==> CELLULAR RESPONSE

27
Q

Explain another mechanism which demonstrates that proto-oncogenes are key to signal transduction

A

Hormones + Growth factors and Cytokines
==> Activation of signalling pathways ==> NUCLEUS
==> Growth, Proliferation, Differentiation, Apoptosis

28
Q

At which stage of the growth factor response are there proto-oncogenes present?

A

At EACH stage

29
Q

What are the three main mechanisms of oncogenic transformation? What is the result of each of them?

A
  1. TRANSLOCATION / TRANSPOSITION
    ==> Normal growth-stimulating protein in excess
  2. GENE AMPLIFICATION
    ==> Normal growth-stimulating protein in excess
  3. POINT MUTATION WITHIN CONTROL ELEMENT
    ==> Normal growth-stimulating protein in excess
    POINT MUTATION WITHIN GENE
    ==> Hyperactive or degradation-resistant protein
30
Q

Provide a detailed example of growth factors acting as oncogenes, including the mechanism involved.

A

Example: the product of the “sis” oncogene on the Simian sarcoma virus, is PDGF-like growth factor.

Infection by SSV
==> Integration of viral DNA into cell’s genome
==> Expression and secretion of sis oncogene
==> Autocrine stimulation of cell proliferation

Viral infection leads to constitutive secretion of
sis (PDGF-like), activation of PDGF-R,
and induction of growth and proliferation

31
Q

Provide an example of growth factor receptors acting as oncogenes (transformation by DELETION) and outline the mechanism.

A

Example: the product of the “erbB” oncogene of the Avian Erythroblastosis virus is a form of EGF-R with a bit cut off.

Loss of the ligand-binding domain / autoinhibitory domain (and 22aa of C-terminus), so not regulated.

This causes activated form of RTK
==> constitutive mitogenic signal to nucleus w/o EGF
==> continuous stimulation of proliferation

32
Q

Provide an example of growth factor receptors acting as oncogenes (transformation by POINT MUTATIONS) and outline the mechanism.

A

Example: c-erbB (human) or “neu” (rat) oncogene
(c-erbB is closely related to EGF-R)

This mutation results in ligand-independent receptor dimerisation and tyrosine kinase activation. The conformation of the oncogenic “neu” resembles a ligand-stimulated receptor.

In comparison with normal “neu” gene, oncogenic counterpart contains only 1aa difference in trasnsmembrane domain (V –> E)

This transformation involves a point mutation in the transmembrane domain of c-erbB.

This was identified as an activated oncogene in chemically-induced neuroblastomas (rat model)

33
Q

Example 1 of growth factor receptors acting as oncogenes (transformation by OVEREXPRESSION) and outline the mechanism.

A

Example 1: EGF-R

Overexpression occurs through:

 a) Gene amplification, or
 b) Increased expression

Found in:

 - Squamous carcinomas
 - Invasive bladder tumours
 - Glioblastomas
34
Q

Example 2 of growth factor receptors acting as oncogenes (transformation by OVEREXPRESSION) and outline the mechanism.

A

Example 2: c-erbB2 (or neu)

Overexpression of c-erbB2 is found in approximately 30% of breast cancer, and is treated with “herceptin”, which binds amplified receptors and blocks the signal so that it’s not overexpressed

This overexpression correlates with tumour progression and poor prognosis.

35
Q

Identify the range of EGFR Expression Rates for a variety of cancers.

A

Breast - 15% - 90%

Colon - 25% - 75%

Lung - 40% - 80%

Head & Neck - 80% - 95%

Ovarian - 35% - 70%

Pancreatic - 30% - 50%

36
Q

List some process that are regulated by

EGFR phosphorylation.

A

JAK, SRC ==> STAT
(survival, proliferation, oncogenesis)

PI3-K inhibited by PTEN ==> Akt
(angiogenesis, tumourigenesis, inhibition of apoptosis)

Ras, Raf, MEK (inhibited by MKP1) ==> ERK
(gene expression, cell cycle progression)

PLC gamma, DAG ==> PKC
(transformation, differentiation, apoptosis)

37
Q

Which receptor family does EGFR belong to?

A

the HER receptor family

EGFR is HER1 (erb-B1)
neu is HER2 (erb-B2

38
Q

Provide an example of growth factor receptors acting as oncogenes (transformation by DNA re-arrangements) and outline the mechanism.

A

Examples: Hepatocyte GFR (HGFR) a.k.a. c-Met

HGF-R is a heterodimer which is localised on cellular membranes joined by disulfide, 2 ligand binding subunits, and ultimately scatters proteins.

This rearrangement results in aberrant localisation and activation of Met tyrosine kinase activity.

Tpr-Met was identified in osteomic sarcomas (bone cancer)

39
Q

What is the result of deregulated signalling by HGF-R?

A

==> Invasive growth

Cells grow on top of each other and are autosufficient, meaning they produce their own growth factor. They only move where the basal membrane is.

HGF mediated signalling regulates survival, proliferation, motility, and branching morphogenesis

40
Q

What is the chemotaxis of cancer cells?

A

Cancer has a constant chemotaxis towards blood vessels for oxygen and nutrients.

The branching morphogenesis is towards the blood.

41
Q

Discuss the Philadelphia chromosome translocation.

A

Prototypic TK oncogene is the
Philadelphia chromosome translocation 9, 22
==> fusion oncogene.

The Tk oncogene is bcr/abl formed when c-abI TK from 9 translocated to 22 bcr gene ==> encodes Bcr/abI with increased kinase activity, and drives proliferation thereby causing transformation.

42
Q

Do GTPases play a role in cancer?

A

Small GTPases have many roles in cancer, and are often dysregulated

BIOC2003 (8 decks)

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