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ATU 3 > Molecular Oncology > Flashcards

Molecular Oncology Flashcards

1
Q

Describe cancer?

A

A large class of very different diseases, which all grow uncontrollably and have the ability to spread (metastasise) throughout the body.

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2
Q

What cell types are involved in cancer?

A

Not one type of cell, many which have important roles in the tumour microenvironment.

Endothelial cells: form vasculature and lymphatic vessels.

Pericytes: wrap the blood vessels to prevent damage from high pressure.

Immune inflammatory cells: Tumour antagonising and promoting leukocytes. They secrete proteolytic enzymes, cytokines and chemokines which enhance tumour growth, stimulate angiogenesis, induce fibroblast migration.

Cancer associated fibroblasts: often main cell population in tumour, 2 types:

  1. Cells with similarities to fibroblasts which create structural foundation for tumour
  2. Myofibroblasts – secrete a variety of extracellular matrix components to enhance proliferation.

Stem and progenitor cells of the tumour stroma: key source of these cells is the bone marrow.

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3
Q

Describe the current cancer trends?

A
  • Lung and bronchus is the most common to die from
  • Colon and rectum have few deaths, lower incidence and higher survival rates due to earlier diagnosis
  • Breast cancer incidence is increasing due to a greater diagnosis, but number of deaths is reducing (the same for prostate too)
  • Pancreas is aggressive and difficult to diagnose early and it has a high death rate and no reduced incidence
  • Skin cancer is increasing
  • Liver is incidence is increasing and so is death, alcohol is an issue.
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4
Q

What are the six hallmarks of cancer? (just the names)

A
  1. Sustaining a proliferative signal
  2. Evading growth suppressors
  3. Resisting cell death
  4. Enabling replicative immortality
  5. Inducing angiogenesis
  6. Activating invasion and metastasis.
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5
Q

Describe the two emerging hallmarks or cancer?

A

Controlling energy metabolism:

  • cancer cells reprogram cells to favour the anaerobic glycolysis
  • although this provides less ATP per cycle, in comparison to the darwinian and evolutionary favoured aerobic respiration, it allows for the cancer to proliferate free of the constraints or concern of oxygen limitation.

Immune evasion:
- tumour cells secrete immunosuppressive factors to “paralyse” infiltrating CTLs and NK cells.

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6
Q

How does cancer overcome the ATP production problem, due to its control on energy metabolism and use of anaerobic glycolysis?

A

Constitutive c-Myc mutants found in many cancers.
MYC up-regulates GLUT1 expression:
- Glucose is transported across the plasma membrane by the glucose transporter GLUT1
- Myc also activates hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1), resulting in enhanced conversion of glucose to lactic acid.

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7
Q

Describe the cancer hallmark of sustaining a proliferative signal?

A

A fundamental trait of cancer is its ability to proliferate. Growth promoting signals which bind to cel surface receptors and activate cascades (still poorly understood). An example of a pathway used is the Ras- Raf- MEK- ERK.

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8
Q

Describe the cancer hallmark of evading growth suppressors?

A

Tumour surppressor genes work to suppress the formation an growth of tumours, cancer has to work to inactivate these genes.

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9
Q

Describe the cancer hallmark of resisting cell death?

A

Apoptosis is triggered in cancer due to signalling imbalances due to oncogene signalling (eg myc overexpression) and an increase in DNA damage to hyper proliferation. Therefore, cancer has to bock this pathway to survive. It does this by mutating and overexposing the anti-apoptotic regulators (Bcl-2 and Bcl-xl).

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10
Q

Describe the cancer hallmark of enabling replicative immortality?

A

Cancer has learnt to manipulate telomerase activity.
In early stages cancer reduces its activity to allow for mutations and DNA damage to occur.
In later stages: telomerase activity is increased to ensure survival.

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11
Q

Describe the cancer hallmark of inducing angiogenesis?

A

In order for tumours to metastasise and grow, cancer promote angiogenesis by creating an imbalance between VEGF-A and TSP-1.

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12
Q

Describe the cancer hallmark of activating invasion and metastasis?

A

In order to spread and progress as a disease cancer activates invasion and metastasis by promoting, mutating and over expressing certain genes.

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13
Q

What are the basic steps of metastasis?

A
  1. Local invasion
  2. Intravasation
  3. Survival in circulation
  4. Extravasation
  5. Adaptation
  6. Colonisation and outgrowth.
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14
Q

What can cause metastatic dormancy?

A

Lack of vigorous growth hallmark, nutrient starvation, anti-growth signals and tumour suppression action.

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15
Q

What are the two models of cancer acquiring metastatic properties and which is favoured by evidence?

A
  1. Linear Model:
    - Primary tumour cells undergo successive rounds of mutation and selection
    - Gives rise to a heterogenous population – subset of cells have accumulated sufficient alterations necessary for metastasis
    - Tumour cells may then further evolve at the secondary site

Support for this idea : Reduction in metastatic risk upon primary tumour removal. Direct correlation between size of primary tumour and metastatic events.

  1. Parallel Model
    - Small primary tumour
    - Tumour cells may disseminate very early in malignant progression
    - Colonise multiple secondary sites at different times and accumulate mutations independently of primary tumour

Support for this idea: Studies have compared growth rates of primary tumours and secondary lesions – metastasis were to big to be initiated at advanced stage of primary tumour. Animal breast cancer models have observed early dissemination of tumour cells from primary source.

Linear model is favoured by evidence.

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16
Q

What is additionally required for metastasis?

A

Initiation genes, progression genes, virulence genes, the surrounding stroma, a ‘tumour propagating’ or ‘cancer stem-cell’ phenotype to overcome colonisation issues.

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17
Q

Describe initiation genes?

A

Genes required for metastasis which promote epithelial-mesenchymal transition (EMT), angiogenesis, cell motility and extracellular mart degeneration.

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18
Q

Describe EMT in terms of metastasis?

A

EMT allows for epithelial cells to lose their characteristics and become mesenchymal cells which is vital for morphology and organ formation.

Primary tumour cells have a regular epithelial structure, EMT causes shift to mesenchymal marker which break up the adhesion junctions allowing them to become extremely motile and aggressive.

  • allows invasion
  • resistance to apoptosis
  • allows dissemination.

Over-expression of master regulators SNAI1, Twist and SANI2 (SLUG) leads to down regulation of E-cadherin which promotes the EMT change.

19
Q

Describe the metastasis progression genes?

A

Role is to break down endothelial adherents to allow for metastasis.

Epiregulin (EREG) and prostaglandin G/H synthase 2 (PTGS2): increase the ability of cancer cells to pass through endothelial barriers, a function that increases cancer cell extravasation.

Angiopoietin-like 4 (ANGPTL4): dissociates vascular endothelial cell–cell junctions, increases the infiltration of ANGPTL4-secreting cancer cells into the parenchyma.

LOX: acts on extracellular matrix proteins to establish a permissive niche for infiltrating cancer cells.

20
Q

Describe metastasis virulence genes?

A

Allow for upregulation of inhibitor of differentiation (ID1 and ID3) leads to metastatic growth.
Mechanisms still poorly understood.

21
Q

Describe the therapeutic targets for metastasis?

A

Disseminated cells have completed several steps of the metastatic cascade, such that invasion- and intravasation-preventing therapies would be too late.
Therefore, targeting dormant metastatic cells and preventing their outgrowth could be a promising approach to interfere with metastasis.
Perhaps more preferable to interfere with the tumor microenvironment or CSC niche permissive for outgrowth of metastases.

At present, many therapeutic approaches for advanced cancers target both the primary tumour and metastases simultaneously, by blocking tumour cell proliferation and survival or tumour vascularisation, which are required in both settings.

22
Q

Describe novel therapeutics for bone therapeutics?

A
  1. Tumor cells secrete factors that stimulate osteoblast production of RANK-L
  2. RANK-L binds to its receptor on osteoclasts, leads to osteoclast differentiation and activation, creating osteolytic lesions.
  3. Bone resorption releases factors such as BMPs TGF-β, that in turn stimulate production of PTHrP from tumor cells.
  4. Increased Src activity leads to activation of osteoclasts and bone resorption

Agents such as denosumab, bisphosphonates, and dasatinib are being developed which can interrupt each stage of this cycle and reduce osteoclast activity.

23
Q

What is an oncogene?

A

A gene with potential to cause malignant neoplastic growth (cancer). They are altered forms of cellular genes.

24
Q

What is a proto-oncogene?

A

An un-altered form of an oncogene. Usually involved in division, proliferation, differentiation or apoptosis.

25
Q

Describe the discovery of RSV?

A

1911, Peyton Rous found it caused sarcomas in chickens and that transmission is possible.

26
Q

Define v-Src?

A
  • An oncogene
  • c-Src lacking c-terminal tail
  • protein tyrosine kinase
  • lack of c-temrinal tail causes it to be constitutively active
  • cell proliferation results.
27
Q

Describe transfection?

A
  1. Treat donor cells with chemical carcinogen
  2. Isolate DNA
  3. Transfect with donor DNA
  4. A focus of morphologically transformed cells form
  5. Inject into mouse host
  6. Tumour formation.
28
Q

How do proto-oncogenes become oncogenes?

A

Mutational activation, gene amplification, gene fusion/translocation.

29
Q

Give an example of an oncogene activated by mutations?

A

H-Ras:

  • a small GTPase
  • found in human bladder cancers
  • mutation on the 12th codon G to a T resulting in a glycine to valine exchange
  • this blocks the binding of GAP which causes Ras to be trapped on in GTP-bound state.
30
Q

Give an example of an oncogene activated by gene amplification?

A

EGFR/ErbB2:

  • amplified in some breast cancers
  • both are receptor tyrosine kinases
  • over expression causes ligand-independent signalling this causes an increase in unwanted signalling.
31
Q

Give an example of an oncogene activated by gene fusion/ translocation?

A

c-myc

  • a nuclear transcription factor
  • chromosomal translocation between 8 and 24 give Myc Igh enhancer control = high level expression.

c-myc can also become oncogenic via viral infection and amplification.

32
Q

How can RTKs proto-oncogenes become oncogenes?

A

Through mutation, amplification or truncation.

33
Q

Discuss Bcr-Abl?

A

Chronic myelogenous leukaemia (CML) patients have a short chromosome 22, named the Philadelphia chromosome. Chromosome 9 is concomitantly longer.
The Philadelphia chromosome causes fusion of c-Abl tyrosine kinase domain and breakpoint cluster (Bcr) this causes up regulation of Abl signalling.

34
Q

Discuss co-operation in oncogenes?

A

Generally speaking, a single oncogene rarely results in transformation and malignancy (some exceptions: CML). Typically, oncogenic changes in ~5 key cellular ‘circuits’ are needed to yield a transformed phenotype.

Often ‘collaboration’ between classical oncogenes (e.g. Ras) and inactivating mutations in tumour suppressor gene(s) (e.g. p53). Cancer cells usually have multiple genetic lesions – some ‘drivers’, others ‘passengers’.

35
Q

When was Rb discovered?

A

1980s: a deletion of a locus on chromosome 13 in a tumour of a child found and was identified as Rb1.

36
Q

What are the two tumour suppressor genes discussed in this topic?

A

Rb and P53.

37
Q

What does loss of Rb result in?

A

Increased risk of osteosarcoma, retinoblastoma, cell lung carcinoma and HPV-related cervical and head/neck cancer. Mainly through metastasis.

38
Q

What is the classical role of Rb?

A

RB represses transcription of genes required for the G1-S transition, by causing G1 arrest. RB binds E2F transcription factors and recruits them away from their target genes.

Rb also has roles in:

  • Control of cellular differentiation during embryogenesis and in adult tissues Regulation of apoptotic cell death
  • Maintenance of permanent cell cycle arrest
  • Preservation of chromosomal stability.
39
Q

What is Rb classed as (other than a tumour suppressor)?

A

A transcriptional co-factor and an adaptor protein.

40
Q

How is Rb related to COX-2?

A

Changes in Rb expression has been found to increase levels of COX-2. High levels of COX-2 have been found in various epithelial cancers and has a role in motility and invasion of cancer cells.

41
Q

What function of Rb is surprising?

A

Rb has a pro-survival function, it can inhibit cell death.
Loss of Rb may also lead to apoptosis this is obviously not beneficial to tumour growth.
Probably over-ridden by other genetic mutations.

42
Q

When was p53 discovered?

A

1979

43
Q

Give three facts about p53?

A

Originally thought to be an oncogene, ~43.7 kDa not 53, it is not the most prominent cancer protein.

ATU 3 (3 decks)

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