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Biology Flashcards

1
Q

What is a cancer?

A

Cancer is an uncontrolled growth of abnormal cells in the body. Cancerous cells are also called malignant cells. The balance shifts towards proliferation and survival - accumulation of abnormal cells - increase in division and decrease in cell death

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2
Q

What are the types of gene mutation?

A

Change in genetic information by either addition, removal, or swapping of nucleotides

Can be harmful, beneficial or neutral

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3
Q

Function of proto-oncogenes?

A
  • Increase cell division

- Decrease cell death

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4
Q

Function of tumour suppressor genes?

A
  • Reduce cell division

- Induce cell death

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5
Q

What happens when a mutation occurs in a proto-oncogene?

A

May cause it to become an oncogene
Oncogene: a gene that is mutated (changed) form of a gene involved in normal cell growth. Oncogenes may cause the growth of cancer cells

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6
Q

What happens when a tumour suppressor gene is mutated?

A 
Mutation = lose protective abilities 
Mutations in this gene that allows control of growth may lead to uncontrolled cell growth = cancer 
A third class of important genes (often included in tumour suppressor genes) - encode proteins that maintain DNA stability by repairing DNA and protecting against accumulation of mutations
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7
Q

Name two tumour supressors

A

p53 (TP53, tumour protein 53)

RB1 (retinoblastoma 1)

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8
Q

Tell me about p53

A
  • blocks cell cycle in response to cellular damage
  • induces apoptosis if DNA damage is irreparable
  • transcription factor
  • most commonly mutated gene in cancers
  • activators of p53: low oxygen conc, DNA damage, chemotherapeutic agents, other stress
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9
Q

Tell me about RB1

A
  • blocks cell cycle by binding (and inhibiting) E2F transcription factors - cell cycle can’t proceed past G1/S
  • inhibits transcription of genes needed for cell cycle progression
  • is inhibited by phosphorylation (e.g. by cyclin D-CDK4)
  • leads to changes in gene expression
  • can be inactivated by phosphorylation
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10
Q

How is p53 structured?

A

Homotramer

  • four identical subunits interact at their C-terminal complexing domains
  • central part of each subunit can bind DNA at specific regulatory sequences
  • N terminal transactivation domain switches the gene on by recruiting RNA polymerase
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11
Q

What are the two main proto-oncogenes?

A

MYC

RAS

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12
Q

Lets talk about about MYC!

A
  • transcription factor (partners with MAX)
  • promotes cell growth
  • leads to changes in gene expression
  • produced in response to oncogenic signals
  • MYC protein will then regulate numerous pathways, positively and negatively
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13
Q

Tell me about RAS

A
  • G protein - binds to GDP (inactive) or GTP (active)
  • activated by growth factors
  • activates downstream signaling pathways
  • leads to changes in gene expression
  • single subunit small GTPase
  • not to be confused with GPCRs
  • GTP bound = on; GDP bound = off
  • mutated in ~ 25% of all cancers
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14
Q

Two ways cells can die?

A

necrosis or apoptosis

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15
Q

Explain necrosis

A

Spillage of cell contents due to inflammation
Caused by damage, infection, ischaemia, cancer
Can release pro-inflammatory signals - immune cells recruited whih can promote angiogenesis
Growth factors released which promote proliferation
Necrosis can promote cancer - cell death not always good

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16
Q

Explain apoptosis

A

Programmed cell death
Cellular components are degraded and removed
Two pathways - intrinsic and extrinsic apoptosis pathway

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17
Q

How are cancer cells resistant to apoptosis?

A
  • fine balance between pro- and anti- apoptotic signals
  • often found on mitochondrial membrane
  • upreguation of survival signals (anti-apoptotic) e.g. Bcl2
  • downregulation of pro-apoptotic signals e.g. Bax
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18
Q

What happens to a cell’s telomeres every time it divides?

A

Get shorter

  • unless telomerase is active to restore them
  • ~90% of malignant cells express telomerase
  • telomerase only normally expressed in germ cells and stem cells
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19
Q

Purpose of telomeres?

A

RNA primers tell DNA polymerase where to start and are degraded in the process

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20
Q

What is the alternative to telomere lengthening?

A
  • recombination or fusion between the ends of different chromosomes
  • cells that survive telomere shortening have chromosome rearrangements (e.g. fused chromosomes; deletions; amplifications) -> oncogenic changes
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21
Q

What does EGFR stand for?

A

Epidermal Growth Factor Receptor

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22
Q

Purpose of EGFR?

A

Senses growth signals

Lead to increase in proteins needed for cell division

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23
Q

What is the phosphorylation cascade induced by EGFR binding?

A

Must be a conformational change cause by dimerisation
Activated by phosphorylation

EGFR phosphorylation (due to EGF binding) -> RAS ->. RAF -> MEK -> switch on ~100 genes for cell division -> ERK

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24
Q

Alternative route following EGFR activation?

A

PI3K -> AKT -> protein synthesis, apoptosis, TP53 (provides instruction to code for p53) - allow cell cycle to continue

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25
Q

What happens when EGFR mutates?

A

EGFR permanently activated - behaves as if bound to EGF

- causes the cell to divide

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26
Q

How do drugs target AGFR?

A
  • stop EGF binding to EGFR: cetuximab, an antibody that blocks the receptor
  • stop EGFR activation: erlotinib & gefitinib, looks like ATP (which is required for activation), don’t behave like ATP (block activation)
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27
Q

What are steroid hormone receptors?

A

Steroid hormones are derived from colesterol (a membrane component)
They can diffuse into cells - no need for cell surface receptors
Steroid hormone receptors are part of the nuclear receptor superfamily
They are transription factors which become activated by steroid hormones e.g. estrogen receptor, androgen receptor, progesterone receptor, retinoic acid receptor

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28
Q

Tell me about ER (estrogen receptor)

A
  • an example of a type 1 steroid hormone receptor (activated in the cytoplasm)
  • ligand (estradiol) diffuses into cell
  • binds to the receptor, displacing associated chaperone proteins e.g. HSP90
  • ER dimerises and migrates to the nucleus
  • ER dimer associates with co-activators or co-repressors to modify transcriptions of target genes
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29
Q

Explain the mode of action of tamoxifen

A
  • a prodrug
  • metabolised to active metabolites by CYP2D6
  • binds to ER with much higher affinity that estrogen
  • estrogen antagonist, but with some agonism
  • mostly anti-estrogenic effect (but estrogenic in uterus & bone)
  • selective ER modifier (SERM)
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30
Q

Explain the mode of action of Fulvestrant

A
  • “pure” anti-estrogen (no agonism)
  • prevents dimerisation, activation
  • increases degradation
  • Selective ER down-regulator (SERD)
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31
Q

What is epigenetics?

A
  • changes that affect gene expression without changing DNA base sequence e.g. histone modifications (acetylation, methylation) or DNA modifications (cytosine methylation -> promotor repression)
  • can be inherited by daughter cells
  • alter the accessibility of DNA for transcription

Acetylation opens chromatin domains (more susceptible to transcription) whereas methylation closes chromatin domains

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32
Q

Mode of action for HDAC inhibitors

A

HDACs (histone deacetylases) remove acetyl groups from histones
It is an attractive drug target
HDAC inhibitors have proven to be effective, but unsure of MOA
Induce apoptosis, is ant-angiogenic and causes cell cycle arrest

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33
Q

What is the splicing mutation in Rb (retinoblastoma)?

A

Skipping of exon 22 gives rise to a non-functioning protein - the G->C mutation means that the single base mutation at the intron-exon boundary stops exon 22 being recognised by splicing factors

34
Q

How do microRNAs (miRs) repress gene expression?

A

Short RNA molecules which bind to (almost) complementary sequences in the 3’UTRs of target mRNAs

  • > inhibition of translation (protein synthesis)
  • > mRNA degradation
  • oncomirs - repress TS genes
  • tumour suppressor miRs - repress oncogenes
  • mutations of miRs or of targets can lead to dysregulation: incorrect binding, changes in microRNA levels
35
Q

Explain protein turnover

A
  • proteins are degraded when no longer needed - tagged by the addition of peptides such as ubiquitin - tags proteins for degradation by the proteasome
  • MDM2 targets p53 for ubiquitination

A posttranslational modification

36
Q

How is RAS mutated?

A

Mutations affecting codons 12,13 or 61 leads to constitutively active RAS protein
Therefore, GTPase regulating pathways for proliferation and survival can go ahead without a ligand
Leads to GTP (active) binding over GDP binding

37
Q

What does more MDM2 mean?

A

Less p53

38
Q

What is BCR

A

a serine threonine kinase and GTPase

39
Q

What is ABL

A

a signalling TK (tyrosine kinase)

40
Q

What causes BCR and ABL to fuse and what are the consequences of this?

A
  • Reciprocal translocation of chromosomes 9 and 22 fuses CBR and ABL - the fusion protein has TK activity, that’s no longer regulated (lots of signalling = cancer)
  • this is very frequently associated with chronic myeloid leukaemia (CML)
41
Q

What TKIs target BCR and ABL? (tyrosine kinase inhibitors)

A

Imatinib (Gleevec), Nilotinib (Tasigna), Dasatinib (Sprycel)

42
Q

What are the details of a partial deletion of EDFR?

A

EGFR variant III lacks most of extracellular domain
Mutation (deletion) of 801 base pairs (267 amino acids)
Variant III is present in 20-60% of glioblastoma

43
Q

What is the consequence of partial deletion of EGFR (truncated) via Variant III?

A

Constitutively active - constantly signalling cell to proliferate

44
Q

What metabolises tamoxifen to its active products?

A

(Tamoxifen = produrg)

CYP2D6 (cytochrome 450 family member)

45
Q

What can alter tamoxifen metabolism in some individuals?

A

Significant proportion of the population have inherited a gene that encodes a less active protein
Poor metabolisers require an increased dose to compensate (double dose recommended)

46
Q

How can HPV lead to cervical cancer?

A
  • produces oncogenic proteins E6 & E7
  • E6 targets p53 for degradation
  • E7 inhibits Rb
47
Q

How can Helicobacter pylori lead to gastric carcinoma and mucosa associated lymphoid tissue (MALT) lymphoma?

A
  • lives in the stomach
  • causes gastric and duodenal ulcers (inflammation)
  • Increases ROS and RNS in stomach - free radicals cause DNA damage -> mutation
48
Q

How do parasites cause cancer?

A
  • flatworms, tapeworms (and their eggs) can cause inflammation:
  • schistoma haematobium (flatworm) infection is associated with bladder cancer
  • opisthorchis viverrini (flatworm) = bile duct cancer
  • tapeworms in other mammals e.g. cats or dogs
  • Malaria (protozoa) = Burkitt’s lymphoma (causative?)
49
Q

What can the compound benzo[a]pyrene cause?

A

Inhaled through smoking
Converts to an epoxide in the lungs - benzo[a]pyrene diol epoxide
This reacts with guanine so guanine adduct is mis-read as thymine leading to adenine being incorporated into DNA instead during DNA replication (instead of cytosine) - this causes mutations in DNA of p53 and RAS gene

50
Q

How can microRNAs be exploited for cancer therapies?

A
  • block oncomirs: stop microRNAs downregulating tumour suppressor genes
  • increase tumour suppressor microRNAs: downregulate oncogenes
51
Q

How are miRNAs stopped?

A

1) - anti-miRs (antagomirs) to inactivate oncomirs
- oligonucleotides complementary to miRsbind and sequesters (isolates) oncomirs
- microRNA sponges mop up oncomirs
- microRNA mask to lock oncomirs: oligonucleotide complementary to target mRNA - binds to mRNA to blovk access to miRs

THEREFORE, 3 approaches: isolate, mop up, block

2) upregulate tumour suppressor miRs: oligonucleotides to mimic TS miRs

52
Q

Barriers to successful use of miR therapies?

A

1) Stability: unmodified oligonucleotides only last a few mins in the blood stream as nucleus is ready to digest them. But a chemical (e.g. phosphothioate) modification and/or incorporation into liposomes or nanocarriers can increase half -life
2) Excretion: PS modifications -> albumin binding, slower renal clearance
3) Cellular uptake and targetting: large size and polarity = difficult to cross cell membranes - incorporate into carriers to facilitate active uptake by cells

53
Q

Biological barriers for miRNA therapies?

A
  • high doses required: usually one anti-miR per miR and thousands of oncomirs per cell
  • transient inhibition: repeated doses required
  • off target effects: multiple targets for each miR, context specific (some miRs can act as oncomirs and TS miRs in different contexts)
54
Q

Discuss the future directions for cancer gene therapy

A

1) pro-drug metabolising enzyme therapy: phosphorylates pro-drugs to toxic nucleosides - target to dividing cells using gamma retrovirus vector or by targetting to cancer cell surface antigen
2) Viral oncolysis (virotherapy): viruses engineered to only replicate in cancer cells
3) Targeting the tumour microenvironment: prevent angiogenesis by modifying normal cells
4) Gene therapy to reduce toxicity (higher dose ca be given): effectively increase therpaeutic index, e.g. MGMT gene (removes alkylating DNA modifications) confers resistance to alkylating agents

55
Q

What produces monoclonal antibodies (Mabs)?

A

B lymphocytes

56
Q

What are polyclonal antibodies?

A

Come from many clones of B lymphocytes and target multiple epitopes of the antigen (extracted from the blood of immunised animals)

57
Q

What are MAbs used for?

A
  • make cells visible to the immune system
  • stop cells dividing e.g. against cancer cell gowth factor receptors
  • target therapies e.g. conjugated to enzyme, drug or radioisotope (deliver drugs)
  • diagnosis e.g. testing for expression of hormone receptors
58
Q

Name MAb used as a drug in cancer

A

Rituximab

  • targets CD20 on B cells
  • caused antibody dependent cell mediated cytotoxicity (ADCC)
  • causes complement mediated cytotoxicity (CDC)
  • Kills B cells in lymphomas and leukemias (incl healthy B cells)
59
Q

Explain where MAbs are used as delivery systems

A

1) Radioimmunotherapy (RIT) to deliver therapeutic radioisotopes: Ibritumomab tiuxetab in conjugation with yttrium-90 or indium-111 for NHL (aplpha-CD20 on B cells)
2) Antibody Drug COnjugates (ADC): MAb delivers a drug to a target e.g. trastuzumab emtansine (inhibits HER2 and delivers emtansine)
3) Antibody Directed Enzyme pro-durg therapy (ADEPT) - not get on the market: the MAb delivers an activating enzyme to the target so Prodrug is only activated where it is needed

60
Q

What are the advantages of monoclonal antibodies?

A

_ for therapeutic antibody use is it essential: good specificity, large quantities, well defined purity - no contaminants

61
Q

How were early MAbs made?

A

Derived from animal spleen cells fused with cancer cells

  • full size antibodies
  • recognised as foreign by patient’s immune system
62
Q

What are the benefits of recombinant MAbs?

A
  • reduce immune response problems as:
  • not recognised as foreign
  • different species have signiciacnt different in Fc region which can be recognised by immune system
  • antibodies that look “human” will go unnoticed
  • therefore, use human antibody with mouse Fv region = chimeric antibodies
  • use human antibody with mouse CDR = reshaped antibodies
63
Q

Why can’t we use completely human antibodies?

A
  • low yiels, potential for contamination (e.g. viral)
  • ethical issues using human tissue
  • geneticall modify mice with genes for human antibodies e.g. Panitumumab against EGFR
  • recombinant antibodies using micro organisms to synthesise MAbs (e.g. phage display)
64
Q

What additonal benefits can be found by recombinant MAbs?

A
  • reduce size and complexity by excluding unnecessary amino acids e.g. fc region
  • smaller molecules extravasate and distribute more easily
  • remove unwanted immunological functions e.g. Fc activation of ADCC and CDC (but these can be useful, as for rituximab)
  • add additional functions e.g. ADEPT
  • easier to produce by recombinant methods: reduce production costs
65
Q

How are recombinant antibodies fabricated?

A

Fragments are based on either a Fab fragment or an Fv fragment of an antibody

66
Q

What are the disadvantages of using antibody fragments?

A
  • reduced binding activity
  • loss of ummune effector function (e.g. ADCC, CDC): not necessarily a bad thing
  • redued circulation:half-life controlle by Fc region and glycosylation - can modify fragment to improve characteristsics (e.g. PEGylate)
67
Q

What is the aim of third generation antibodies or SMIPs?

A
  • Aim to reduce size even further by removing non-essential regions and allow the molecules to penetrate better into tumour associated antigens and mount an immune response - important to retain effector functions (e.g. effector cells, complement binding)
  • an example is TRU-015; like rituximab it recognises CD20 but has been stripped back (still contains antigen binding region and a constant region with effector function)
68
Q

What is the basis of cancer vaccines?

A
  • a tumour-associated antigen (TAA) to induce an immune response specifically against tumour cells - difficult as host immune system is often compromised
  • induction of cytotoxic T lymphocytes: to kill cancer cells by expressing tumour associaed antigens or APC (antigen presenting cells) by expressing CD40L or CD80, or to attract APCs by secreting chemokines or cytokines sch as GM-CSF, lymphotactin or iterleukins.
69
Q

Lets talk about the prostate cancer vaccine more specifically

A
  • expolits the fact that prostatic acid phosphatase (PAP) is only found in prostate cancer cells
  • immune cells from the patient are removed and exposed to a fusion protein of PAP and GM-CSF (granulocyte macrophage colony stimulating factor) acts as a growth factor and stimulates the maturation of the monocyte into the activated APC which activates T cells to kill those cells in the patient that display PAP
70
Q

Where did DFTF probably originate? ( Devil Facial Tumour Disease)

A

miRNAs and expression patterns from protein coding genes support this
Schwann cells in the peripheral nervous system

71
Q

What can we learn about human cancers from the devil and the dog?

A
  • Spread as allografts (skin grafts), by biting or mating
  • cancers behave as sexual parasites
  • genetically distinct from their hosts
72
Q

General function of MHC (MLA in humans)?

A 
Present antigens on the surface of the cell such that they are visible to the immune system 
Three different MHC in mammals: MHC class I and class II and HLA in humans
73
Q

How do MHC molecules produce APCs?

A
  • antigens are derived from the degradation of proteins by the proteasome, where they travel to the endoplasmic reticulum to form complexes with the chaperone proteins such as TAP, and associate with MHC class I molecules
  • MHC proteins then translocate to the cell surface to present antigens to CD8+ T cells
74
Q

Describe the structure of MHC class I molecules

A
  • has three domains: alpha 1 and alpha 2 form peptide binding groove; alpha 3 is a transmembrane domain which can also interact with cytotoxic T lymphocytes (CD8 +CTLs)
  • beta- microglobulin is encoded separately, but associates with the alpha domains to form the functional complex
75
Q

What are the transmissible tumor cell characteristsics?

A

MHC proteins themselves and factors that associate with them, are downregulated in both DFT and CTVT, to reduce the visibility of cancer cells to the host’s immune system.

  • DFT cells downregulate genes that allow antigen presents - e.g. TAP and beta-microglobulin
  • CTVT doesnt express MHC molecules at all during growth period
  • Its not that the genes aren’t there they just aren’t being expressed
  • there are other mutations that allow CTVT to fly under the host’s radar
76
Q

What are the host characteristics for transmissible cancers?

A
  • no evidence of compromised immune system
  • DLA (MHC in dogs) genotype influences growth of tumour
  • devils underwent recent population bottlenecks: smaller genetic pool so reduces genetic diversity therefore, foreign cells are less foreign
77
Q

What have we learnt from the evolutionary response to cancer cells?

A
  • IgM might be a good place to start for novel therpaies
  • currently most immunotherapies are based on IgG
  • IgM has the advantage of prolonged surveillance for cancer cells where it can bind to cancer precursors as well as cancer cells, and induce apoptosis
  • IgM-based therapies have been tested experimentally and show promise against neuroblastoma and melanoma in particular
78
Q

What is an alternative mode of action for vincristine?

A
  • induces a strong inflammatory response triggered by DAMPs (damage associated molecular patterns)
  • induces an immune response
  • kick strats regression of cancer
  • CCR5 is upregulated, and this is thought to be the central regression as it attracts T lymphocytes, natural killer cells and myeloid cells which can mount a defence against cancer - can kill cells and sensitive tumours for further treatment
79
Q

What is the molecular biology of DFTD?

A
  • ERBB (EGFR) inhibitorrs found to be effective (lapatinib, erltotinib, apitinib)
  • DFT cells express high levels of ERBB2 and ERBB3 and of STAT3
  • hyperacivated ERBB-STAT3 reduces MHC class I related genes B2M, SAHA-UC (class I MHC gene)
80
Q

Are there transmissible human cancers?

A
  • in utero transmission maternal-> foetal and foetal -> foatal
  • organ transplant - rare with screening
  • injury during surgery: sarcoma transmitted from patient to surgeon

Cancer (6 decks)

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