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Neoplasia > Cancer Progression, Invasion, Metastasis And Therapy > Flashcards

Cancer Progression, Invasion, Metastasis And Therapy Flashcards

1
Q

Genetic instability

A

Increases mutation rate and aneuploidy

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2
Q

APC

A

Loss or mutation induces adenoma formation as a result of abnormality of:

  • > orderly cell replication (overactive B-catenin)
  • > adhesion
  • > cell migration
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3
Q

Inactivation of APC

A

Induces a change in crypt architecture replicating cells heap up in the mucosa - making secondary hits or mutations are made more likely

Induces adenoma formation

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4
Q

Gliomas

A

Tumours of astrocytes

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5
Q

Driver mutation

A

Key in driving tumour formation along pathway of development to malignant tumour

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6
Q

Passenger mutations

A

Other DNA changes which don’t promote malignant tumours

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7
Q

Grade 1 glioma

A

Only seen in children

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8
Q

Grade III/IV

A

associated with 3-4 driver mutations

Most frequent of which IDH 1/2 and P53 loss

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9
Q

Grade 4 glioma

A

6-8 mutations

IDH 1/2 enzymes
Loss of Rb pathway 
Loss of p53 pathway
Telomerase activation
Amplification of growth factor receptor
Loss of PTEN
1p19q co-deletion
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10
Q

Leukemia

A

No chromosome changes can be identified and sequencing is necessary to identify the mutations

Only 1-3 chromosomal abnormalities - no gross aneuploidy or multiple chromosome rearrangements characteristic of carcinomas

More specific clonal chromosome abnormalities usually translocation, deletions or inversions

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11
Q

Philadelphia chromosome Ph+

A

Translocation of 9 and 22-Signature change of chronic myeloid leukaemia

abl found on chromosome 9 - codes for tyrosine kinase signalling molecule with own controls
bcr found on chromosome 22 -

Changed chromosome 22 - Philadelphia chromosome

bcr and abl fuse and produce protein lose control of production of tyrosine kinases sending growth signal

Initiating mutation in chronic myeloid leukemia

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12
Q

Sequence of changes when cell begins to invade and metastasise

A
  1. Detachment and invasion into surrounding tissue, neo-vascularisation
  2. penetration of body cavities and vessels
  3. Release of tumour cells for transport into vessels
  4. Evasion of host defences, avoiding immune destruction
  5. Adherence and re-invasion or extravasation at the site of arrest
  6. Manipulation of the new environment to promote tumour cell survival, vascularisation and growth in new site
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13
Q

Invasion requires

A

Change and/or loss in cell-cell and cell-matrix adhesion

Focal proteolysis of the matrix

Movement to occupy th space

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14
Q

Cadherins

A

Essential for adhesion - establish cell polarity and cell-cell differentiation

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15
Q

Integrins

A

Cell-matrix adhesion and signalling for cell survival and proliferation

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16
Q

Tumour cells lose

A

the apoptotic response to changes in matrix signals, after changing distribution and stability of integrin receptors

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17
Q

Cancer cells in matrix proteolysis

A

Switch on synthesis and secretion of matrix proteases

Signal to stromal fibroblasts to turn on secretion of matrix proteases (MMPs, collagenases, hyaluronidases)

Down regulate expression of TIMPs

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18
Q

Tumour angiogenesis

A

Allows tumour to increase in size by creating new blood vessels

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19
Q

Without vascularisation

A

Tumours can only grow 1-2nm

Mitosis rates = apoptosis rates

20
Q

When tumours outgrow new blood supply

A

Necrosis occurs

21
Q

Mechanisms of tumour angiogenesis

A

Cancer cells secrete angiogenic factors and permeability factors

Tumour macrophages release angiogenic factors

Breakdown of the matrix by proteolysis releases sequestered growth factors such as fibroblasts growth factor

Tumours elaborate an abnormal matrix leading to abnormal vessel formation

22
Q

Metastatic spread is not random

A

Common sites of metastasis are liver, lung, bone and brain

Depends on anatomy and organ specificity

23
Q

Cancer stem cells

A

Sub-population in leukemias and solid tumours that contain a small sub-population of cells that:

  • > self renew
  • > proliferate indefinitely
  • > can reproduce indefinitely
  • > can reproduce in cancer through serial transplantation in mice
24
Q

Cancer stem cells could arise by

A

Mutations in the stem cell

Mutations in a transit amplifying cell

25
Q

In order to become a stem cell a cancer must either

A

Escape niche control or manipulate the niche

26
Q

Surgery

A

Remove or de-bulk local tumour - to reduce chances of clone resistance from chemotherapy

Will leave small unseeable tumours

27
Q

Radiotherapy

A

Used if primary tumour has not spread - for local and regional disease

28
Q

Chemotherapy

A

Systemic treatment for metastatic disease combinations of drugs each with a different site of action needed for effective treatment

29
Q

Standard cancer therapies work by

A

inducing cancer cells to undergo apoptosis

30
Q

Radiation induced killing and killing by certain drugs such as topoisomerases inhibitors is dependent on

A

Expression of wild type p53

31
Q

Chemotherapies are

A

Toxic to normal and cancer cells but genetically unstable cancer cells can evolve drug resistance

32
Q

Targeted therapy targets

A 
Growth factors
Growth factor receptors
Signalling molecules
Cell cycle proteins 
Pro angiogenesis molecules
Pro apoptic molecules
33
Q

Angiostatic agents

A

Block vessel growth to keep tumour small

Unlikely to acquire resistance

34
Q

Imagining/Glivec

A

SMall molecule inhibitor bcr/abl fusion protein in chronic myeloid leukaemia

35
Q

Herceptin

A

Monoclonal antibody to the HER-2/neu receptor protein - successful treatment in breast cancers expressing HER-2

36
Q

Vemurafenib

A

Small molecule drug inhibitor of the mutant BRAF in melanoma

37
Q

Panitumumab / cetuximab

A

monoclonal antibodies to the EGF receptor in colorectal cancer

38
Q

Immunotherapies

A

Stimulate patient’s immune system to recognise and destroy cancer cells

39
Q

Immune checkpoint inhibitors

A

Boost immune response against melanoma cells and other cancers

40
Q

Ipilimumab

A

Targets CTLA-4

41
Q

Pembrolizumab

A

Targets PD-1/ PD-L1 which are T cells

42
Q

Successful invading and metastasising cells have evolved to evade host defences by

A

Downregulating MHC class 1 on tumour cells
Induction of CTL non-responsiveness to tumour
Induction of immunosuppressive factors from tumour e.g. TGF-Beta

43
Q

Synthetic lethality

A

Using genomic instability for tumour selective drugs

44
Q

BRCA1 and BRCA2 mutations in tumours

A

Homologous recombination (DNA repair method) is non functional, so base excision repair compensates

PARP inhibition disables base excision repair leading to cell death

45
Q

Olaparib

A

A PARP inhibitor used in some breast and ovarian cancers to kill BRCA1/2 cancers

46
Q

How are cancer therapies chosen

A

Tumour profiling - genomic, transcriptomic and proteomics analysis, inform about molecular abnormalities that may respond to tailored therapies

47
Q

Combination of therapies

A

Is most successful - especially when the genetic constitution of the individual cancer allows the oncologist to design the optimal treatment programme for that patient

Neoplasia (4 decks)

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