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EXMD504 > 8. Tumour Microenvironment > Flashcards

8. Tumour Microenvironment Flashcards

1
Q

why is there variability in cancer survival rates? (4)

A
  1. some organs more/less necessary
  2. how easily it is detected (location, screening)
  3. patient variability
  4. molecular characteristics of tumour, pathways
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2
Q

5 things that affect heterogeneity of cancer

A
  1. genetic
  2. epigenetic
  3. phenotypic
  4. microenvironment
  5. clinical response
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3
Q

4 types of cancer

A
  1. carcinoma
  2. sarcoma
  3. lymphoma, leukemia
  4. brain cancer
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4
Q

what type of cells are involved in carcinoma?

A

epithelial cells

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5
Q

what type of tissue is involved sarcoma?

A

supporting tissue (bone, cartilage, fat, connective tissue, muscle)

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6
Q

what type of cells are involved in lymphoma/leukemia?

A

cells of blood and lymphatic origin

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7
Q

3 main characteristics of cancer

A
  1. loss of growth control
  2. local invasion
  3. altered tissue organization
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8
Q

quantitative element of loss of growth control

A

number of cells

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9
Q

qualitative element of loss of growth control

A

differentiation and orientation of cells

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10
Q

3 aspects of somatic mutation theory

A
  1. mutations are necessary for cancer to arise
  2. mutations cause uncontrolled proliferation
  3. cancer is irreversible
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11
Q

what is assumed if mutations cause uncontrolled proliferation?

A

if mutations cause uncontrolled proliferation, this assumes the default state of a cell is quiescence (i.e. dormant/inactive)

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12
Q

why does SMT say that cancer is irreversible?

A

if solely caused by mutations, mutations cannot be undone therefore cancer is irreversible

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13
Q

what does SMT imply about cancer overall?

A

SMT implies that cancer is a cellular disease

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14
Q

development of cancer via SMT (7 steps)

A
  1. DNA damage
  2. mutation
  3. self-sufficient growth
  4. resistance to apoptosis
  5. invasion
  6. tumour
  7. metastasis
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15
Q

are mutations actually sufficient for cancer development? evidence?

A

mutations are NOT sufficient for cancer development

many mutations are found in normal skin, so must be another factor contributing to cancer

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16
Q

describe normal proliferation of epithelial cells

A

epithelial cells normally highly proliferative
- high turnover to eliminate damaged cells
- proliferative in specific zones

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17
Q

what controls proliferation of epithelial cells normally?

A

stem and progenitor cells control proliferation of epithelial cells

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18
Q

normally, epithelial cells are proliferative in specific zones but how does this change in tumours?

A

in tumours, these zones get larger

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19
Q

what does carcinoma develop from?

A

pre-malignant stages

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20
Q

how long can it take carcinomas to develop?

A

years to decades

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21
Q

describe the experiment to determine whether mutations are sufficient for cancer development in any cell

A

introduce oncogenes and tumour suppressors in diff cell populations –> not all will form tumours

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22
Q

describe the experiment with Prom1+ cells

A

Prom1+ usually have big generative ability over time

but not all Prom1+ cells were equally susceptible
- Quiescent cells were less vulnerable
- Generative cells were more vulnerable

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23
Q

what does damage-induced stem cell activation lead to?

A

damage-induced stem cell activation sensitizes cells to promote tumour formation

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24
Q

with the results from the experiment looking at whether mutations alone are sufficient for cancer development, what does this tell us about tumour formation?

A

events outside of epithelium/tissue repair responses can sensitize tissues to form a tumour

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25
Q

how is inflammation related to cancer incidence?

A

inflammation associated with INCREASED cancer incidence

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26
Q

how does inflammation increase cancer incidence?

A
  1. stromal cells accumulate and activate –> PRO-TUMOURIGENIC
  2. changes microenvironment
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27
Q

what is the correlation btwn impaired immunity and cancer

A

incidence of lung, GI, reproductive, and skin cancers is higher in IMMUNOSUPPRESSED organ transplant patients

but incidence of breast cancer is lower

THEREFORE, immune responses are highly variable btwn cancer types and people –> no definitive link

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28
Q

is cancer irreversible?

A

some evidence of tumour regression

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29
Q

9 mechanisms that could cause tumour regression

A
  1. silencing oncogenes/activating tumour suppressors
  2. epigenetic mutations
  3. tumour inhibition by growth factors, cytokines
  4. induction of differentiation
  5. hormonal mediation
  6. elimination of carcinogen
  7. tumour necrosis or apoptosis
  8. angiogenesis inhibition
  9. immune mediation
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30
Q

what cannot cause tumour regression?

A

mutations “un-mutating”

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31
Q

what is the theory after SMT?

A

Tissue Organization Field Theory (TOFT)

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32
Q

3 components of TOFT

A
  1. Mutations lead to cancer by disrupting morphostats
  2. mutations that induce proliferation are not needed for carcinogenesis
  3. genetic instability is only a BYPRODUCT of carcinogenesis
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33
Q

what does it mean for cancer to be caused by disruption of morphostats?

A

mutations don’t change proliferation, just disrupt the homeostasis of tissue to affect growth control

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34
Q

SMT vs TOFT

A

These theories are opposite and incompatible

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35
Q

what does TOFT imply about cells?

A

implies cells are inherently proliferative

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36
Q

what does TOFT imply about where carcinogenesis occurs?

A

implies carcinogenesis occurs at the TISSUE level, not cellular

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37
Q

what does TOFT imply about reversibility/irreversibility of carcinogenesis?

A

TOFT states that carcinogenesis is REVERSIBLE

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38
Q

describe the epithelial defense against cancer

A

NORMAL epithelial cells have an intrinsic ability to suppress/eliminate adjacent tumour cells

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39
Q

how do normal epithelial cells suppress tumour epithelial cells? (5)

A
  1. competition btwn more/less fit cells
  2. non-cell autonomous functions
  3. apical extrusion
  4. apoptosis
  5. senescence
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40
Q

how is apical extrusion initiated?

A

cells can distinguish mechanical differences btwn its neighbours

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41
Q

3 steps of apical extrusion

A
  1. altered oncogenes = altered cytoskeleton
  2. normal cells can detect the stiffness of mutant cells
  3. normal cells can contract and SQUEEZE the stiff/mutant cells out of the epithelium into lumen or cause APOPTOSIS
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42
Q

what is basal extrusion?

A

tumour cells pushed further into the tissue, out of the epithelium until it reaches stroma –> cells stay in contact with ECM so it can stay alive

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43
Q

describe the competition in apical extrusion. what does this explain?

A

mutant cell is the LOSER, basal cell is the WINNER –> therefore cancer is rare

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44
Q

what regulates the epithelial defense?

A

regulated by micro/systemic environment

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45
Q

how does the systemic environment regulate epithelial defense?

A

obese –> less efficient at removing tumour cells

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46
Q

what happens to tumour microenvironment in obese tissue

A
  • aligned collagen –> more stiff
  • increased inflammation
  • cannot extrude mutant cells –> stay in epithelium
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47
Q

what does competition btwn normal and mutant cells lead to?

A

competition leads to senescence of damaged cells

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48
Q

what is competition controlled by?

A

competition is controlled by p53

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49
Q

how does p53 mediate competition?

A

based on relative p53 levels –> low p53 cells WIN and suppress cells with high p53

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50
Q

how is p53-mediated competition related to p53-mediated DNA damage?

A

p53-mediated competition is INDEPENDENT of p53-mediated DNA damage

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51
Q

what do the breast duct and myoepithelium do?

A

breast duct produces milk, myoepithelium is contractile to squeeze milk

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52
Q

what happens in stage 0 of breast cancer? (3)

A
  • basic structure of ducts are arranged in pre-invasive lesions
  • ducts maintain some organization with myoepithelium
  • ducts become more solid
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53
Q

why do breast ducts become more solid in breast cancer?

A

cells extruded to lumen may be surviving, making it more solid

54
Q

what occurs in stage 1-3 of breast cancer?

A

myoepithelium starts to break down, allowing for invasion

55
Q

what is the main indicator of whether breast cancer is invasive or not?

A

if myoepithelium breaks down –> INVASIVE

56
Q

how do myoepithelial cells prevent dissemination/invasion? (3 steps)

A
  1. tumour cells start to invade
  2. myoepithelium captures/restrains/pulls tumour cells back in
  3. myoepithelium prevents invasion even once tumour cells have unattached
57
Q

why does the prevention of dissemination by myoepithelium show that the tumour microenvironment is important?

A

normal tissue in the surroundings can restrain tumour properties and characteristics

58
Q

are the hallmarks of cancer reliant on mutant cells or microenvironment? what is the significance?

A

most of the hallmarks of cancer are INDEPENDENT of mutant cells and rely on interactions with microenvironment

therefore, more than just the mutant cell is involved

59
Q

what kinds of cells are found in tumours? (general types and 6 specific types)

A

cells with pro AND anti-tumourigenic properties

  1. malignant cancer cells
  2. immune cells
  3. fibroblasts
  4. adipocytes
  5. vasculature
  6. tissue-specific cells
60
Q

how can we predict patient outcome in relation to stromal micronevironment

A

isolate stromal regions –> look at gene expression patterns associated with patient outcomes

61
Q

do normal tissues have microenvironment?

A

yes, but modified with tumour

62
Q

describe co-evolution of tumour and microenvironment

A

as tumour evolves, microenvironment also evolves

63
Q

how does microenvironment change with diff tumours?

A

tumours have diff compositions, proportions, and activation states of stroma at diff times

stroma supports metabolic requirements of tumour

64
Q

describe the microenvironment in metastatic disease

A

cancer cells disseminate to other areas where the microenvironment hasn’t evolved to support the cells –> cells cannot be supported in the same way

65
Q

what are cancer associated fibroblasts (CAF)?

A

fibroblasts that have been reprogrammed within the tumour microenvironment to promote tumour progression accomplish hallmarks of cancer

66
Q

2 things that CAFs indicate

A
  1. heterogeneity of stroma
  2. tumour and its microenvironment have high plasticity
67
Q

where do CAFs come from?

A

can come from anything –> many mechanisms can produce them

68
Q

are CAFs one cell type?

A

no, it is just a term to broadly describe many cell types with diff functions

69
Q

when and how do CAFs interact with cancer cells?

A

during INVASION

CAFs directly ASSOCIATE WITH and LEAD cancer cells

70
Q

2 ways that CAFs help cancer cells invade?

A
  1. CAF remodels ECM
  2. CAF has dynamic adhesions with cancer cells to pull/drag them
71
Q

what is one of the main products from fibroblasts?

A

collagen deposition

72
Q

why are tumours typically stiffer than normal tissue?

A

fibroblasts induce collagen deposition

73
Q

is collagen deposition/stiffness uniform for a tumour?

A

no, not fully uniform throughout tumour

74
Q

2 consequences of increased stiffness of tumour cells

A
  1. modulates growth properties
  2. allows tumour cells to be more motile
75
Q

experiment to determine that increased stiffness allows tumour cells to be more motile

A

put normal cells and tumour cells on matrices with diff stiffness
- invasion on stiff matrix
- no invasion on soft matrix

76
Q

how is the recognition of stiffness by normal cells related to mutation type?

A

INDEPENDENT of mutation type

77
Q

how does oxygen affect tumour progression? (4)

A

HYPOXIA impacts:
1. vascularization
2. treatment resistance
3. EMT
4. metastasis

78
Q

why are tumours not so affected by hypoxia?

A

tumour cells are good at adapting to stress –> to promote survival

79
Q

what is one of the most abundant cell types?

A

macrophages

80
Q

2 states of macrophages

A
  1. tissue-resident
  2. M1/M2
81
Q

where do tissue-resident macrophages come from?

A

deposited in tissue during embryonic development

82
Q

where do tissue-resident macrophages reside?

A

in diff compartments: stromal, epithelial

83
Q

role of tissue-resident macrophages

A

suppress/engulf apoptotic cells

84
Q

why do tissue-resident macrophages suppress/engulf apoptotic cells

A

apoptotic cells secrete factors that induce inflammation but want to PREVENT inflammation

85
Q

M1 vs M2 macrophages

A

M1 = anti-tumour
M2 = pro-tumour

86
Q

what determines whether M1 or M2 macrophage is activated?

A

naturally anti-tumourigenic but integrates multiple signals from microenvironment to control activation (but actually more complex, less binary)

87
Q

what do tumour-associated macrophages do?

A

allow for tumour cell proliferation and migration

88
Q

4 steps in the function of TAMs

A
  1. TAM secretes EGF
  2. EGF activates EGFR on tumour cells
  3. upregulates VEGF/VEGFR signaling in surrounding tumour cells
  4. tumour cell proliferation and migration
89
Q

in addition to proliferation and migration, what do TAMs do?

A

stimulate invasion and promote survival disseminated cells

90
Q

how do TAMs promote survival of disseminated cells? (3 steps)

A
  1. tumour cells are shed into abdominal cavity
  2. normally, they will die BUT macrophages associate and activate program to bind epithelial cells
  3. allows shed cells to interact with peritoneal cavity and cause disease
91
Q

how do macrophages stimulate invasion and metastasis? (3 steps)

A
  1. cell recruits macrophages with CCL2
  2. macrophage responds with Wnt1 as pro-survival factor
  3. allows reciprocal signaling btwn epithelial cell and macrophage so epithelial cell can be supported upon dissemination
92
Q

how do macrophages affect ECM? what is the effect of this?

A

ECM is organized parallel to the edge of the tumour so cells usually travel along the ECM
- macrophages remodel ECM to direct the cell AWAY from the tumour for metastasis

93
Q

what is immune surveillance?

A

immune system can recognize tumour cells and modulate tumour growth

94
Q

immune response in normal cells vs transformed cells

A

normal cells usually NOT immune-responsive

transformed cells express tumour-associated antigens that can be recognized by the immune system

95
Q

what can tumour-associated antigens be?

A

mutant proteins, junk material, etc.

96
Q

what happens when immune cells recognize the tumour associated antigens?

A

present antigens to T cells for elimination

97
Q

describe the equilibrium that is reached in immune surveillance

A

reaches equilibrium where
A. tumour cells have adapted
B. cells with strongest tumour antigens have been eliminated

98
Q

describe the tumour at equilibrium

A

tumour is neither regressing nor progressing

99
Q

can the immune system/tumour leave equilibrium?

A

yes –> immune system is modified/edited to allow tumour growth (escape phase)

100
Q

3 stages of immunoediting

A
  1. eilimination
  2. equilibrium
  3. escape
101
Q

what happens in the first phase of immunoediting?

A

ELIMINATION –> vulnerable tumour cells are cleared by the immune system, resistant tumour cells survive

102
Q

what causes the equilibrium phase of immunoediting?

A

EQUILIBRIUM –> driven by strong selective pressure from adaptive immune system + T cells

103
Q

what causes the escape phase of immunoediting?

A

global IMMUNOSUPPRESSIVE state with anti-inflammatory cytokines

104
Q

how can we use immunoediting as a way to find treatments?

A

find therapeutics that make the immunoediting process stay in the equilibrium phase

105
Q

describe T cell activity in tumour cells

A

in the tumour, they follow the same biological and physiological rules as normal but mechanisms are induced to PREVENT OVER-ACTIVATION –> leads to T cell exhaustion

106
Q

what happens with T cell exhaustion?

A

T cells become less responsive to antigens and less efficient

107
Q

how is T cell activity suppressed in cancer?

A
  1. immune checkpoints induced by cancer and stromal cells will suppress T cell activity
  2. neutrophils and Treg with suppressive functions in tumour microenvironment
108
Q

what is an immune hot tumour?

A

immune cells are active INSIDE the tumour

109
Q

what is an immune cold tumour?

A

immune cells are active on the PERIPHERY of the tumour

110
Q

how do immune hot and immune cold tumours change the cancer?

A

change the response and treatment

as well, varies throughout the tumour

111
Q

why does immune hot and immune cold change throughout tumour?

A

diverse immune-epithelial interactions change hot/cold

112
Q

benefit of targeting the tumour microenvironment

A

stroma is genetically stable compared to tumour cells –> less likely to become resistant

113
Q

what is the problem with targeting the tumour microenvironment and example?

A

may deplete stromal cells required for anti-tumour function

ex. angiogenesis inhibitors may not work bc they block the anti-tumourigenic effects of the microenvironment

114
Q

goal of immunotherapy

A

improve or induce immunological surveillance recognition and destruction of cancer cells –> i.e. RE-EDUCATE immune system

115
Q

5 immunotherapeutic approaches

A
  1. adoptive cell transfer
  2. checkpoint inhibitor
  3. MAb
  4. cancer vaccines
  5. cytokines
116
Q

describe adoptive cell transfer

A

take T cells from patient, re-engineer to express receptor for tumour antigen and give back to patient

117
Q

result of adoptive cell transfer?

A

increases proliferation and activity of T cells against tumour cells with the antigen

118
Q

what was the first adoptive cell transfer treatment?

A

recognize CD19 on B cells for lymphoblastic leukemia

119
Q

what is the purpose of immune checkpoints?

A

prevents over-activation of immune system

120
Q

what do immune checkpoint blockers do?

A

allows immune system to target cancer cells

121
Q

CTLA4 checkpoint inhibitor

A

normally, CTLA4 inhibits T cell activity by outcompeting co-stimulatory CD28 for CD80/CD86

use anti-CTLA4 to increase T cell activity

122
Q

PDL1 checkpoint inhibitor

A

normally, PDL1 is expressed on tumour cells to inhibit T cell activity

use anti-CPDL or anti-PDL1 to increase T cell activity

123
Q

where are immune checkpoint inhibitors most effective?

A

effective in immune HOT tumour where immune cells are in contact with epithelial cells

124
Q

describe MAb

A

use antibodies against markers on tumour cells to remove tumour cells

125
Q

describe destruction of tumours with antibodies

A

increase the association btwn tumour cell and T cell with bispecific antibodies

126
Q

example of destruction of tumours with antibodies in pancreatic cancer

A

pancreatic cancer cells express EpCAM on their surface

Ab recognizes EpCAM on cancer cell and CD3 on T cell –> brings cancer cell in direct contact with T cell

127
Q

describe cancer vaccines

A

vaccinate against cell surface markers on cancer cells

128
Q

how can we re-educate the stroma? explain

A

reprogram TAMs

  1. TAMs normally require CSF-1 for differentiation and survival
  2. use CSF-1 INHIBITOR to restore TAMs to anti-tumour activity
129
Q

why is re-educating the stroma helpful?

A

can be used prophylactically to prevent macrophages from become pro-tumour

130
Q

issue with immunotherapy

A

immune hot tumours are more responsive –> must turn cold tumours into hot tumours in combo with cytotoxic therapies

EXMD504 (12 decks)

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