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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
transcription factors and metastasis
especially embryonic TFs regulate differentiation and de-differentiation Tcf/Lef, Slug, Snail
26
cell surface receptors and metastasis
EGF E-cadherin
27
motility regulating proteins and metastasis
GTPases, PI3K and PIP3 cytoskeleton proteins
28
EC proteases
matrix metalloproteases break down EC matrix providing space to move mesenchymal type cells
29
progression of EMT
30
invasion-metastasis cascade LOCALISED INVASION
EMT motility proteases
31
invasion-metastasis cascade INTRAVASION
EMT
32
invasion-metastasis cascade TRANSPORT
physical transport in circulation
33
invasion-metastasis cascade ARREST
physical occlusion/adherence
34
invasion-metastasis cascade EXTRAVASION
motility proteases
35
invasion-metastasis cascade PROLIFERATION
growth regulation growth factor receptors
36
invasion-metastasis cascade COLONISATION
vascularisation
37
overview of invasion-metastasis cascade
utilises mechanisms related to pathways of embryonic development and wound healing via EMT
38
the Hayflick limit
somatic cells have limited doubling potential
39
how do some cells have limitless replicative potential
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)
40
where can telomeres be found
at the termini of chromosomes
41
sequence element iterated at telomeres
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
42
what makes telomere structure distinctive
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)
43
function of telomeres
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
44
which end needs to be extended
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
function of telomerase
telomere replication is mediated by the enzyme telomerase
46
describe structure of telomerase
ribonucleoprotein enzyme containing * hTERT reverse transcriptase * hTR RNA template
47
what does telomerase do and when is it active
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
Protein vs RNA activity what can they do together
protein - enzymatic activity RNA - template activity together they can polymerase a template into sequence onto the end of a DNA fragment
49
life span of cells - impact of telomerase activity
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
function of telomeres
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
what happens to broken chromosomes
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
telomerase is essential for
unlimited growth of most cancer cells
53
4 targeted approaches - telomere-based therapeutics
hTERT inhibitors template antagonists telomere disruptors - DNA telomere disruptors - shelterin complex
54
hTERT inhibitors
direct enzyme inhibition slow telomere erosion
55
template antagonists
oligonucleotides complementary to RNA template GRN183L in clinical trials
56
telomere disruptors - DNA
G-quadriplex promoters alter telomere structure inhibit telomerase and may uncap RHPS4 in preclinical development
57
telomere disruptors - shelterin complex
potential route to telomere uncapping
58
difference between normal somatic cells and cancer cells
While normal somatic cells do not express telomerase, cancer cells DO They are successful because they have adapted a strategy
59
unusual configuration of telomeres
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
gene therapy - telomere-based therapeutics
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
immunotherapy - telomere-based therapeutics
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
as part of combination therapy - telomere-based therapeutics
hTERT inhibition is slow but could be a factor in combo therapy (Imetelstat) Long term - cancer cells can be severely inhibited
63
EMT - 7 steps
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
telomeres and cellular lifespan
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
what are solid tumours and what do they require
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
how to recruit vascular tissue key molecule
capillaries are formed from endothelial cells VEGF - vascular endothelial growth factor - key molecule involved in angiogenesis
67
other important angiogenic factors
68
what do cancer cells secrete
VEGF - but it is immobilised in ECM
69
how to activate VEGF
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
balancing angiogenesis - what are its inhibitors and where are they found
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
inhibitors of angiogenesis in ECM
Tsp-I fragments of ECM proteins
72
inhibitors of angiogenesis - circulating proteins
IFN interleukins TIMP-2
73
how are tumours successful
they evolve a complex of mechanisms that tip the balance toward local angiogenesis and metabolic permissiveness
74
anti-angiogenic therapies
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
summary of role of angiogenesis in tumour progression
76
enabling characteristic - tumour promoting inflammation
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
genome instability - what products of inflammation may be mutagenic
ROS and RNI (rxn to cytokines)
78
how is proliferative signalling induced
induced by cytokines released in inflammation
79
pro-survival (anti-apoptotic) signalling - how are they induced
can be induced by cytokine pathways
80
nature of tumours
organs with differentiated cell compartments and functions
81
parenchyma of tumour
core of neoplastic epithelial cells - carcinoma
82
stroma of tumour
surrounding/supporting mesenchymal cells
83
describe cellular structure of tumour
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
inflammatory cells
contribute proteases that resist invasion
85
cytokines
activate VEGF
86
pericytes
in communication with the endothelial cells that stabilise the induced vasculature
87
cancer-associated fibroblasts
secrete multiple growth factors that contribute to epithelial cell growth as well as growth of other cells
88
cancer stem cells and tumours
common constituent of many if not most tumours
89
CSCs - how do they work
defined operationally through their ability to efficiently seed new tumours upon inoculation into recipient host mice
90
what is unique about cells with properties of CSCs
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
glioblastomas and CSCs
CSCs have the ability to transdifferentiate into endothelial-like cells (vasculature) - recently documented in glioblastomas
92
model of solid tumour stem cells based on breast cancer
93
reprogramming energy metabolism - warburg effect of cancer cells
cancer cells depend on glycolysis (rather than ox phos in mitochondria) glycolysis is typical in anaerobic conditions
94
what does the warburg effect allow
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
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
96
cancer depends on
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
epigenetic mutation
non-sequence dependent alterations in gene function activation/silencing Chromosome associated proteins that are associated with specific - propagated from one cell to another
98
aneuploidy
aberrant chromosome numbers consequence of defects in chromosome segregation
99
aneuploidy and cancer
aneuploidy is causative of cancer
100
low levels of aneuploidy
promote tumorogenesis
101
high levels of anueploidy
do not promote tumorogenesis too disruptive
102
aneuploidy leads to
increased rates of mutagenesis through enhanced recombination and defective DNA damage repair
103
critical players in generation of aneuploidy and in cancer therapeutics
mitosis and mitotic spindle formation
104
spindle poisons, novel antimitotic drugs
vinblastine/vinca alkaloids taxol and taxanes epithilones Eg5 inhibitors
105
therapeutic potential
106
MCQ
107
MCQ - inhibitors of telomerase
108
MCQ - inflammatory mechanisms promote tumour establishment by, for example

Molecular Medicine (7 decks)

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