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Molecular Medicine > Unit 3 - Cell Biology of Cancer > Flashcards

Unit 3 - Cell Biology of Cancer Flashcards

1
Q

function of CTLA-4

A

brake on T-cell activation

functions to regulate T-cell activation

cancer cells benefit from reduced T-cell activation

MAb vs CTLA-4 releases the brake, allowing enhanced T-cell killing of tumour cells

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2
Q

PD-I

A

required for T-cell activation

acting through a different mechanism PD-I also acts as a brake on tumour-directed cells

MAb vs PD-I also ‘releases the brake’, allowing enhanced T-cell killing of tumours

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3
Q

use of MAbs

  1. MAb vs CTLA-4
  2. MAb vs PD-I
A

treatment with MAb has led to dramatic clinical outcomes - remissions and cures of metastatic cancers

  1. releases brake ⇒ enhanced T-cell killing of tumour cells
  2. releases brake ⇒ enhanced T-cell killing of tumour cells
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4
Q

CAR T-cell therapy

A

Chimeric Antigen Receptor

T-cells (specialised WBCs) are isolated from a patient and a custom designed gene, that expresses a new cells surface molecule that recognises the tumour and activates the T cell to kill it, is introduced into cells

cells containing the gene are grown in culture to prepare an inoculum

CAR T-cells are infused back into patient

T-cells target cancer cells for killing

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5
Q

MOA of CAR T-cell therapy

A
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6
Q

what is cancer

A

a disease that originates at the cellular level but tumoue function as complex tissues that integrate multiple cellular functions and mechanisms to promote tumour survival and growth

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7
Q

what is needed to identify the cellular origin of tumours

A

histology

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8
Q

how do cellular properties change as cancer develops/progresses

A

acquisition of adaptive phenotypes through mutation and genome instability couples with recruitment and modification of non-cancer cells to form tumour microenvironments

⇒ for diagnosis and prognosis + understanding therapeutics, knowledge of the cellular basis of cancer is good pragmatic knowledge (personalised therapy)

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9
Q

6 Hallmarks of Cancer

A
  1. sustained proliferative signalling
  2. evading growth suppressors
  3. activating invasion and metastasis
  4. enabling replicative immortality
  5. inducing angiogenesis
  6. resisting cell death
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10
Q

metastasis

A

migration of tumour cells from primary tumour to secondary sites

responsible for 90% of cancer deaths

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11
Q

how do cells spread

A

via blood, lymph and through proximity

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12
Q

where might secondary tumours form

A

lung, bone, liver, brain

lymph nodes

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13
Q

what are secondary tumours

A

tumours of primary tissue irrespective of tumour site

e.g. breast cancer within liver

histochemistry can identify tumour type and aid design of treatment

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14
Q

invasion-matastasis cascade - 7 steps

A
  1. localised invasion
  2. intravasation (into circulation)
  3. transport
  4. arrest (in a secondary location)
  5. extravasation (out of circulation and into tissue - colonisation)
  6. proliferation
  7. colonisation

utilise mechanisms related to pathways of embryonic development and wound healing

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15
Q

malignancy

A

penetration of tumour c ells beyond basement membrane id definitive of malignancy

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16
Q

EMT

A

epithelial → mesenchymal transition

change in phenotype

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17
Q

properties of epithelial cells

A

polygonal morphology

network of cell-cell junctions

apical-basal polarisation

limited mobility/motility

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18
Q

mesenchymal cells - properties

A

migratory

variegated morphology/spindle shaped

loosely organised

present in connective tissue/stromal tissue e.g. fibroblasts

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19
Q

key components of EMT

A

expression of embryonic transcription factors e.g. Snail, Slug, Twist, Zeb 1/2

loss of e-cadherin function

loss of tight junctions

acquisition of motility through CT

protease secretion

growth factor receptor expression

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20
Q

EMT - change in markers

A

Epithelial cells express epithelial markers and do not express mesenchymal markers

Twist - down regulation of epithelial cell markers and upreg of mesenchymal markers

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21
Q

anchorage-dependent signalling

E-cadherin

A

functions as a cell adhesion molecule

Maintains epithelial cell phenotype by signalling cell-cell interactions via IC domain

loss leads to dysregulation of β-catenin, a transcription factor regulated by localisation in the cell

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22
Q

β-catenin

A

integrated into cadherin-actin adherens junctions complexes

a normal component of Wnt signaling pathway

upon loss of cell adhesion it translocates to nucleus to activate TCF/LEF family transcription factors - loss causes cell to move into a different phenotypic state

regulated by molecular association e.g. E-cadherin and APC and by inhibitors e.g. ICAT (inhibition of β-catenin and TCF4)

cytoplasmic levels are maintained through ubiquitin-dependent proteolysis via the β-catenin destruction complex

mutation/misexpression correlated with cancer progression

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23
Q

familial adenomatous polyposis

A

proliferation of polyps in colon

1 in 30,000

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24
Q

APC gene

A

function = regulation of β-catenin through the proteolytic pathway

tumour suppressor gene

autosomal dominant mutations

maintains epithelial cell phenotype in colonic crypts

integrates cellular architecture, motility with cell cycle regulation and gene expression

also functions in mitosis and loss contributes to CIN

(cells live for 4 days)

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25
Q

transcription factors and metastasis

A

especially embryonic TFs

regulate differentiation and de-differentiation

Tcf/Lef, Slug, Snail

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26
Q

cell surface receptors and metastasis

A

EGF

E-cadherin

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27
Q

motility regulating proteins and metastasis

A

GTPases, PI3K and PIP3

cytoskeleton proteins

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28
Q

EC proteases

A

matrix metalloproteases break down EC matrix providing space to move

mesenchymal type cells

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29
Q

progression of EMT

A
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30
Q

invasion-metastasis cascade

LOCALISED INVASION

A

EMT

motility

proteases

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31
Q

invasion-metastasis cascade

INTRAVASION

A

EMT

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32
Q

invasion-metastasis cascade

TRANSPORT

A

physical transport in circulation

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33
Q

invasion-metastasis cascade

ARREST

A

physical occlusion/adherence

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34
Q

invasion-metastasis cascade

EXTRAVASION

A

motility

proteases

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35
Q

invasion-metastasis cascade

PROLIFERATION

A

growth regulation

growth factor receptors

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36
Q

invasion-metastasis cascade

COLONISATION

A

vascularisation

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37
Q

overview of invasion-metastasis cascade

A

utilises mechanisms related to pathways of embryonic development and wound healing via EMT

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38
Q

the Hayflick limit

A

somatic cells have limited doubling potential

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39
Q

how do some cells have limitless replicative potential

A

cells relieved of senescence pathways

e.g. p53, Rb mutations

undergo crisis after some number of doublings

about 50 for human cells

crisis is associated with chromosome damage due to erosion of telomeres (tips)

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40
Q

where can telomeres be found

A

at the termini of chromosomes

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41
Q

sequence element iterated at telomeres

A

a repetitive sequence element is iterated for 5-40 kb in mammals

TTAGGG

3’ single strand extension of G-strand, 2-3 repeats, 20-30 in us

nicks in C-strand every 2-3 repeats

Partially fully stranded, partially nicked

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42
Q

what makes telomere structure distinctive

A

unique chromatin composition and topological arrangement

T-loop shields terminus from exposure

shelterin complex of chromatin proteins also shield terminus (DNA ends are recognised by the cell as damage so this configuration of the telomeres shields the 3’ end of the chromosome and encases it in this chromatin complex)

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43
Q

function of telomeres

A

REPLICATION OF 5’ ENDS

DNA replication = 5’ → 3’ direction and is initiated by a primer

the extreme 5’ end cannot be primed and requires another mechanism for replication

telomerase provides this mechanism

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44
Q

which end needs to be extended

A

DNA is melted by a DNA helicase - stabilised by RPA protein

DNA always requires extension of a 3’ hydroxyl - 5’ to 3’

Gap leads to shortening of chromosome in a round of DNA replication - cause of crisis

By extending the 3’ end, the loss of 5’ material doesn’t matter

CARRIED OUT BY TELOMERASE

45
Q

function of telomerase

A

telomere replication is mediated by the enzyme telomerase

46
Q

describe structure of telomerase

A

ribonucleoprotein enzyme containing

  • hTERT reverse transcriptase
  • hTR RNA template
47
Q

what does telomerase do and when is it active

A

adds nucleotides to 3’ end of chromosomal DNA

telomerase is selectively active in germ line and limited cells types

it is NOT active/has limited activity in most somatic cells and telomeres thus shorten throughout the replicative life of a cell lineage

48
Q

Protein vs RNA activity

what can they do together

A

protein - enzymatic activity

RNA - template activity

together they can polymerase a template into sequence onto the end of a DNA fragment

49
Q

life span of cells - impact of telomerase activity

A

Limited life span of cells - cells eventually become senescent because chromosomes were undergoing damage

This is because telomerase is selectively active in germ cells and not expressed in most somatic cells, so telomere erosion is occurring

Chromosomes are shorter in older people

50
Q

function of telomeres

A

suppression of recombination

free DNA ends are recognised as damage by cells

non-homologous recombination can be induced at breaks

telomeres are specially packaged to prevent recognition of chromosome ends as DNA breaks

51
Q

what happens to broken chromosomes

A

they will often undergo fusion with themselves after DNA replication or with another chromosome

Fusion events produce chromosomes with 2 centromeres - during mitosis, a chromosome with 2 centromeres can attach to opposite poles of the mitotic spindle and be pulled in opposing directions and ultimately be broken

Improperly segregate chromosome fragments

Fusion, bridge formation and mitosis, breakage, formation

Severe TOXIC GENOTYPIC STRESS ON THE CELLS

Ultimately destined to die but some cells with broken chromosomes can mend them and survive

52
Q

telomerase is essential for

A

unlimited growth of most cancer cells

53
Q

4 targeted approaches - telomere-based therapeutics

A

hTERT inhibitors

template antagonists

telomere disruptors - DNA

telomere disruptors - shelterin complex

54
Q

hTERT inhibitors

A

direct enzyme inhibition

slow telomere erosion

55
Q

template antagonists

A

oligonucleotides complementary to RNA template

GRN183L in clinical trials

56
Q

telomere disruptors - DNA

A

G-quadriplex promoters alter telomere structure

inhibit telomerase and may uncap

RHPS4 in preclinical development

57
Q

telomere disruptors - shelterin complex

A

potential route to telomere uncapping

58
Q

difference between normal somatic cells and cancer cells

A

While normal somatic cells do not express telomerase, cancer cells DO

They are successful because they have adapted a strategy

59
Q

unusual configuration of telomeres

A

G-quartet

atypical base pairing between guanine residues in a square format

double looped G quartet structure containing 4 bp strands

Target of drug development - nucleic acid inhibitors disrupt G quartet structures

60
Q

gene therapy - telomere-based therapeutics

A

virus dependent on telomerase expression to selectively kill cancer cells

telomelysin in trials

Synthetic virus is constructed which is cytotoxic but ONLY IN PRESENT OF TELOMERASE, so normal cells would not be affected

61
Q

immunotherapy - telomere-based therapeutics

A

hTERT is processed and presented by MHC

induce immune cells that attack presenting cells - telomerase vaccine

Proteins present in cytoplasm and in human cells are digested by MHC, and presented on cell surface (immune recognition of cell process)

Cancer cells would express something on their cell surface

62
Q

as part of combination therapy - telomere-based therapeutics

A

hTERT inhibition is slow but could be a factor in combo therapy (Imetelstat)

Long term - cancer cells can be severely inhibited

63
Q

EMT - 7 steps

A
  1. loss of e-cadherin function
  2. dysregulation of β-catenin pathway
  3. loss of tight junctions
  4. acquisition of motility
  5. transcription factor expression
  6. protease secretion
  7. growth factor receptor expression
64
Q

telomeres and cellular lifespan

A

somatic cells have limited replicative potential - lack of telomerase expression

tumour cells reactivate telomerase expression to support limitless replicative potential

telomeres manage and protect chromosome ends

telomerase reverse transcriptase (TERT) maintains ends by addition of telomere repeats

telomere structure, shelterin complex protects ends from recognition as DNA termini

cancer cell specificity provides target of opportunity for therapeutics

65
Q

what are solid tumours and what do they require

A

organ systems requiring vasculature for survival

tumours arise in highly vascularised regions

cells locared > 0.2 mm from vessel do not grow

hypoxia leads to necrosis in tumour cores

tumours actively promote angiogenesis

66
Q

how to recruit vascular tissue

key molecule

A

capillaries are formed from endothelial cells

VEGF - vascular endothelial growth factor - key molecule involved in angiogenesis

67
Q

other important angiogenic factors

A
68
Q

what do cancer cells secrete

A

VEGF - but it is immobilised in ECM

69
Q

how to activate VEGF

A

MMPs, Matrix Metabolic Proteases, (MMP-9) proteolyse ECM and give riseto angiogenic swithc

MMPs can be produced by inflammatory mast cells and macrophages - co-opting normal cell functions for tumorigenesis

70
Q

balancing angiogenesis - what are its inhibitors and where are they found

A

normally tightly regulated - development and wound healing

ECM contains inhibitors of angiogenesis - thrombospondin-I (Tsp-I), fragments of ECM proteins

other circulating proteins inhibit angiogenesis - IFN, interleukins, TIMP-2

71
Q

inhibitors of angiogenesis in ECM

A

Tsp-I

fragments of ECM proteins

72
Q

inhibitors of angiogenesis - circulating proteins

A

IFN

interleukins

TIMP-2

73
Q

how are tumours successful

A

they evolve a complex of mechanisms that tip the balance toward local angiogenesis and metabolic permissiveness

74
Q

anti-angiogenic therapies

A

requirement of angiogenesis for tumour formation makes this a very active area of therapeutic development

alone they are limited in effect on survival - marginal improvements

combination strategies now being undertaken

75
Q

summary of role of angiogenesis in tumour progression

A
76
Q

enabling characteristic - tumour promoting inflammation

A

inflammatory responses play decisive roles at different stages of tumour development, including

initiation

promotion

malignant conversion

invasion

metastasis

immune cells that infiltrate tumours engage in an extensive and dynamic crosstalk with cancer cells

induction of angiogenesis - production of MMP by macrophages

77
Q

genome instability - what products of inflammation may be mutagenic

A

ROS and RNI (rxn to cytokines)

78
Q

how is proliferative signalling induced

A

induced by cytokines released in inflammation

79
Q

pro-survival (anti-apoptotic) signalling - how are they induced

A

can be induced by cytokine pathways

80
Q

nature of tumours

A

organs with differentiated cell compartments and functions

81
Q

parenchyma of tumour

A

core of neoplastic epithelial cells - carcinoma

82
Q

stroma of tumour

A

surrounding/supporting mesenchymal cells

83
Q

describe cellular structure of tumour

A

Surrounded by stromal tissue

Vasculature, endothelial cells, pericytes surround vessels

Then there are infiltrating immune cells

Cancer associated fibroblasts - type of cells that are migratory through the cancer

Contribute to vitality of tumour

84
Q

inflammatory cells

A

contribute proteases that resist invasion

85
Q

cytokines

A

activate VEGF

86
Q

pericytes

A

in communication with the endothelial cells that stabilise the induced vasculature

87
Q

cancer-associated fibroblasts

A

secrete multiple growth factors that contribute to epithelial cell growth as well as growth of other cells

88
Q

cancer stem cells and tumours

A

common constituent of many if not most tumours

89
Q

CSCs - how do they work

A

defined operationally through their ability to efficiently seed new tumours upon inoculation into recipient host mice

90
Q

what is unique about cells with properties of CSCs

A

more resistant to various commonly used therapeutic treatments

many have bona fide stem cell like characteristics - ability to transdifferentiate into endothelial-like cells (vasculature) recently documented in glioblastomas

91
Q

glioblastomas and CSCs

A

CSCs have the ability to transdifferentiate into endothelial-like cells (vasculature) - recently documented in glioblastomas

92
Q

model of solid tumour stem cells based on breast cancer

A
93
Q

reprogramming energy metabolism - warburg effect of cancer cells

A

cancer cells depend on glycolysis (rather than ox phos in mitochondria)

glycolysis is typical in anaerobic conditions

94
Q

what does the warburg effect allow

A

tumours to be visualised by 18F-deoxyglucose

may aid growth in hypoxic environments - HIF I pathways (cellular response to hypoxia is mediated by HIF I - Activating glycolytic activity through HIF I pathway in addition to helping cells in a low O2 environment, the glycolytic pathway produces lots of biosynthetic intermediates - positive feature for tumour cells to increase conc of metabolic intermediates to allow for increased overall metabolism of tumour cells)

may provide richer range of biosynthetic precursors for increased overall metabolism

potential application of glycolytic inhibitors e.g. 2-deoxyglucose now in clinical trials, glucose transport inhibitors

95
Q

HIF I pathways

A

cellular response to hypoxia is mediated by HIF I

Activating glycolytic activity through HIF I pathway in addition to helping cells in a low O2 environment, the glycolytic pathway produces lots of biosynthetic intermediates - positive feature for tumour cells to increase conc of metabolic intermediates to allow for increased overall metabolism of tumour cells

96
Q

cancer depends on

A

genetic variety - a positive role for genome instability in tumour formation - diversity of genome and phenome provide a positive role for tumour development by creating more opportunity for tumours to adapt

mutation and aneuploidy thus play direct roles in tumour progression throughout the developemnt of the tumour

⇒ tumour cells are adapted to their ‘ad hoc’ niches - with attendant ‘achilles heels’ e.g. oncogene dependence

97
Q

epigenetic mutation

A

non-sequence dependent alterations in gene function

activation/silencing

Chromosome associated proteins that are associated with specific - propagated from one cell to another

98
Q

aneuploidy

A

aberrant chromosome numbers

consequence of defects in chromosome segregation

99
Q

aneuploidy and cancer

A

aneuploidy is causative of cancer

100
Q

low levels of aneuploidy

A

promote tumorogenesis

101
Q

high levels of anueploidy

A

do not promote tumorogenesis

too disruptive

102
Q

aneuploidy leads to

A

increased rates of mutagenesis through enhanced recombination and defective DNA damage repair

103
Q

critical players in generation of aneuploidy and in cancer therapeutics

A

mitosis and mitotic spindle formation

104
Q

spindle poisons, novel antimitotic drugs

A

vinblastine/vinca alkaloids

taxol and taxanes

epithilones

Eg5 inhibitors

105
Q

therapeutic potential

A
106
Q

MCQ

A
107
Q

MCQ - inhibitors of telomerase

A
108
Q

MCQ - inflammatory mechanisms promote tumour establishment by, for example

A

Molecular Medicine (7 decks)

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