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Molecular Oncology > Day 7: Cancer stem cells, intratumor heterogeneity, clonal growth, growth dynamics, population screening > Flashcards

Day 7: Cancer stem cells, intratumor heterogeneity, clonal growth, growth dynamics, population screening Flashcards

HC 17, 18, 19

1
Q

HC17: The intestinal stem cell niche: cells and signals

A

In base of the crypt
> Niche cells: Paneth cells and mesenchymal cells like fibroblasts
> Niche signals: Wnt, Notch, EGF, and ECM proteins (morphogens)
> Notch and EGF from Paneth cells
> Wnt from Paneth cells and mesenchymal cells (different types of Wnt ligands)

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2
Q

Classic development CRC

A

APC loss, hyperproliferation to adenoma, than KRAS, Smad4 and TP53 to CRC

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3
Q

Intratumor heterogeneity

A

All the normal cell types from the niche found back in tumor
> also cancer stem cells
> multilineage differentiation
> non-malignant cells in micro-environment
> stem cell like cells: cancer stem cells

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4
Q

Distinction cancer stem cells in breast cancer based on CD44 and CD24

A

High CD44 and low CD24

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5
Q

Cancer stem cells character

A

Can form new tumor after injection in NOD/SCID mice
> CSCs found in multiple tissues

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6
Q

CD133 expression in CSCs

A

High expression
> has better outgrowth
> can differentiate into other tumor cell types

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7
Q

CD133+ cancer cells in xenograft

A

CSCs: outgrowth of new tumor

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8
Q

Spherical cancer cells in vitro resemble

A

CSCs > retain stemness

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9
Q

CK20 marker and character of these cells

A

For differentiated cell: can be increased when differentiation factors added to CSC culture medium
> these cannot form new tumors because differentiated

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10
Q

Wnt activity as CSC marker

A

High Wnt activity for CSCs
> Wnt reporter contruct: TOP-GFP with TCF promotor: Wnt reactive
> green cells in xenograft

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11
Q

Tumor induction capacity is .. for many malignancies

A

Low, only few cells can develop outgrowth: CSCs

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12
Q

Single CSCs display:

A
  • Self-renewal
  • Multilineage differentiation potential
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13
Q

CSCs in established cancer: CD133 and prognosis

A

High CD133+ cells: bad prognosis and low survival rate

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14
Q

Higher expression Lgr5 in TOP-GFP+ cells > ?? (Lgr5 promotor sensitive for b-catenin–TCF)

A

CSCs

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15
Q

CSCs and chemotherapies

A

Better resistance against it
> 5-FU and oxaliplatin (FOLFOX)
> CD133+ cells better resistant

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16
Q

Why are CSCs therapy resistant

A
  • Express high levels of anti-apoptotic proteins
  • Primed to respond to DNA damage
  • Protected by the niche
  • Express higher levels of drug efflux transporters
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17
Q

CSCs and immune escape

A
  • Express molecules that repress T-cells
  • Promote pro-tumor phenotype of macrophages
  • Adenosine production to inhibit T-cells and NK-cells
  • Promote M2 proliferation (tumorigenic macrophage)
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18
Q

CSC therapy response in conventional therapy

A

Differentiated cells die and CSCs survive: outgrowth and differentiation (repopulation)

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19
Q

CSC specific therapy

A

Target CSC to remain with differentiated cells which can be eliminated later

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20
Q

Are there successful cancer stem cell depletion therapies?

A

No, not yet because
> Tumor initiation or established tumor?
> Tumor heterogeneity: hard to specifically target
> Cancer stem cell plasticity: role micro-environment

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21
Q

… cells are required for metastasis

A

CSCs

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22
Q

CSC plasticity in established cancers: Lgr5 expression coupled to DTR test (toxin receptor) and with metastasis

A

> Give mice DT (toxin, only cells with DTR die)
Deplete CSCs
However, when treatment stopped: tumor grows back with the same rate as control: plasticity (can shift cell types)
CSCs are essential for metastasis: liver metastases: after CSC depletion and DT test and stopped treatment, metastatic tumor did not come back

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23
Q

iCaspase-9 gene coupled to Lgr5 promotor (Wnt target): apoptosis inducer. Treat mice with cancer with dimerizer so that iCasp9 dimerizes and induces apoptosis: effect?

A

In treated cells: proliferation cells takes place in non-stem cells (this is normally not the case
> first decrease in size but then growth again
> High level plasticity: differentiated cells can return to undifferentiated state
» towards Lgr5+ CSCs again
> Reversion from differentiated population to CSC population

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24
Q

Cell plasticity in tumors is strongly dependent on …

A

the micro-environment
> differentiated cells become stem cell like again: reversion

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25
CSC niche shown with TOP-GFP marker
a-SMA for myofibroblasts > TOP-GFP cells close to a-SMA cells: niche! > Differentiated cancer cells without myofibroblasts injected: no regerneration CSCs > Injected with myofibroblasts: regeneration CSCs! (nude mice) > Factors from micro-environment induce stemness in cancer cells > CSC is not an intrinsic propery > Myofibroblasts induce CSCs in vivo
26
CSCs are tumor initiating cells. What is their role in established cancers based on their location?
In vivo clonogenicity located at surface of the tumor > stem cell functionality > interactions with micro-environment on surface of tumor
27
Correlation stem cell marker expression and stem cell functionality (in cancer)
No correlation > homogeneous expression across tumor (centre and surface tumor cells)
28
Presence fibroblasts and stem cell functionality correlation (in cancer)
Significant > On outiside tumor; a-SMA+ cells (fibroblasts) > induce stem cell functionality on surface of tumor
29
Xenograft with only the centre tumor cells of primary tumor taken
Were not clonogenic in primary tumor but still outgrowth because signals micro-environment > expression stem cells markers also in centre of the tumor > low TOP-GFP in primary tumor, decreased outgrowth potential
30
CSC functionality in initiation tumor and established tumor
CSC marker expression: tumor initiation Presence of niche: clonogenicity in established tumor
31
Functional stem cell properties are ... dependent in established cancer tissue
location
32
Prevent plasticity in tumors
Therapy: target CSCs and tumor micro-environment (niche cells) > prevent tumor relapse
33
Cancer stem cells have been identified in multiple cancer types using tumor initiation assays in immunodeficient mice. Do the identified cancer cell sub-populations reflect the cancer cells with stem cell functionality within established tumor tissue?
No, cancer stem cell functionality in established cancers is dependent on the niche signals from the micro-environment
34
HC18: Lineage tracing in intestinal lining
Stem cells fuel clonal growth > mark the stem cells (stem cell markers like LGR5)
35
Confetti staining lineage tracing of crypt base stem cells
Cells per crypt are renewed by stem cells > crypts turn into a single color each > one stem cells will imprint the entire crypt > villi are fueled by multiple crypts, multiple colors
36
Why do crypts turn monoclonal? Randomness:
In crypt base, limited space for set amount of stem cells (with Paneth cells) > some stem cells get pushed out upon division > until one color from the confetti staining remains (one clone from set starting point will make up for all stem cells in crypt, the rest pushed out) > one color lost per division: random which one remains as the last one (50% chance between 2) >> no preference for a certain cell
37
Stem cell competition results in ...
clonal fixation (monoclonal crypt in stem cells)
38
Neutral drift dynamics
- Division of one stem cell pushes out another for differentiation - No bias in this: neutral drift (random 50/50) - Stain one stem cell in all crypts red, mostly disappears but some crypts develop entirely red - Clone size increases over time when becoming fixated
39
Clone size and clonal fixation
More fixation, larger size
40
Clonal competition in cancer when first hit: loss of APC (conventional development pathway)
Hyperproliferation > bias towards the clonal survival of the APC mutated stem cell and the loss of other wild-type stem cells > APC mutant wins most of the times: but not always
41
Chances of growth dynamic results when one APC mutant in the stem cell crypt
- Mutant cells can be extinct and pushed out: 45% - Mutant outcompetes it and fixation of crypt: only APC mutants: 55% > Limited ability of fixative effect
42
Normal competition between two WT stem cells in clonal dynamics to win and push other out, and with APC+/- and APC-/-
WT/WT > 50% APC+/- /WT > 62% APC-/- /WT > 79% APC-/- /APC+/- > 69%
43
APC-/- stem cells: why benefit over WT stem cells?
They actively disadvantage WT cells
44
Probability to reach fixation in 5 stem cell situation crypt with: - KRAS G12D - APC-/- - APC+/- -WT
KRAS G12D (70%) > APC -/- (55%) > APC +/- (40%) > WT (20%) - Important in prevention tumor formation: especially in inherited deficiencies - Early oncogenic mutations provide limited clonal advantage over other stem cells in niche (crypt)
45
APC mutants in WT organoid stem cell niches in co-culture
Outcompeted by APC mutants > WT organoids are disappearing
46
APC mutant stem cells disadvantage WT stem cells, how?
Secrete Wnt antagonists
47
Wnt antagonists made in vitro APC-/- organoids and in vivo in adenoma
Notum, Wif1, Dkk2
48
Function Wnt antagonists
Inhibit Wnt or Wnt receptor more upstream (extracellular)
49
LiCl as treatment
Lithium Chloride inhibits Gsk3b (part of b-catenin destruction complex) > inhibited destruction complex > stimulated Wnt pathway for WT stem cells > outcompete APC mutant > disadvantage of WT stem cells by APC mutants overcome > rescue loss of stemness in vivo
50
Lgr5 expression in Notum+ stem cells and Notum+ stem cells treated with LiCl
Notum+: low Notum+ LiCl+: recued expression, no different to control
51
LiCl effect on biased drift
Reduce advantage of APC mutants > lower clone size (lower clone fixation) > reduced polyp burden, less polyps formed in mice when APC deficient (FAP)
52
Neutral drift to biased drift to corrected drift to treated
Neutral drift > APC mutation Biased drift > LiCl treatment Corrected drift > Removal of mutant ISCs (intestinal stem cells) (prevent ougrowth adenomas in patients with inherited risk: FAP)
53
Intestinal stem cells compete for .... in crypt
the space in the niche (to not get pushed out)
54
Some mutations cause super-competition in ISC niche. What is super-competition.
Active inhibition of neighbouring cells (with Wnt antagonists) which can lead to complete disappearance of WT stem cells: fixation of mutant stem cell clone (but this potential is limited!, 55% in APC -/-)
55
APC-/- Culture Medium (CM) induces ... in WT stem cells
Differentiation
56
Chemo-preventive strategies like LiCl can .... the advantage of mutant stem cells
Reverse to normal (random)
57
HC19: Mortality rate and incidence CRC in Netherlands is ...
High
58
Development CRC in time
Slow progress over years
59
Polypectomy in adenomatous polyp stage leads to...
No development of cancer
60
When patients are symptomatic of CRC, then:
Already in advanced CRC stage
61
5-years survival rates for stage 1 and stage 4 CRC
1: >90% 4: <10% > survival rate depends on stage
62
Strategies to reduce CRC-related mortality
- Prevention: reduce risk factors, no alcohol, smoking, reduce processed foods - Screening: testing asymptomatic persons for disease or risk factors
63
Screening criteria CRC
- Important health problem - Patient should directly benefit upon identification: follow-up treatment should be available > Suitable test available > Accepted treatment for patients with recognized disease > Test should be acceptable to population - Identification early stage - Condition with important health problem: high incidence and mortality for CRC
64
Population-based screening for CRC
Search for asymptomatic individuals in population with disease markers > detect CRC in earlier stage > detect and remove advanced precursors (big polyps, to reduce mortality)
65
Screening types CRC
- FIT (stool test) - Sigmoidoscopy - Colonoscopy - Molecular markers: not very promising - (also colonography or colonocapsule)
66
Stool test CRC
- Polyps shed blood - Blood markers in stool test: cancer marker
67
Fecal immunochemical test (FIT) (stool)
- Antibodies to detect human Hb only - Non-invasive, 1 stool sample - Done at home and sent to lab - Reduced CRC related mortality with 22%!
68
Sigmoidoscopy
- Inspection left side of colon > if positive > colonoscopy > Every 3-5 years > reduce CRC-related mortality: 31% - Annama to get feces out the colon - Complication risk of 0-0.003% - Low participation rate: 32%, makes it less effective
69
Colonoscopy
Reference standard: through entire colon > detection and removal in one procedure > effect on CRC incidence: 18% reduction, not significant mortality reduction in NL, but with 50% when everyone participates (prediction)! > higher participation grade in US > Participation 22% in NL > complication risk 0.1-0.3%: perforation and bleeding: is severe: instant surgery needed > invasive procedure
70
Factors in choice of screening program
- Features - Participation rate - Yield of test - Risk and burden - Capacity endoscopy - Costs >> choice differs for each country
71
National Bowel Cancer Program Netherlands
All Dutch citizens 55-75 years > FIT every 2 years > Participation rate lowered when coronavirus outbreak: lowered governmental trust
72
Participation rate by age and gender in CRC screening programs
-Men are less willing worldwide > higher risk men in CRC though (counterinuitive) - Participation rate trend is negative overall over years - Blood in stool test > 5% > ask for follow-up with colonoscopy - More in increased age
73
FIT positivity rate by age and gender
FIT positivity increases with age and more with men
74
Possible findings when follow-up colonoscopy after positive FIT
- Nothing - Serrated and non-advanced adenomas - Advanced adenomas - Colorectal cancer
75
What happens when polyps found (adenomas, serrated or advanced) when colonoscopy?
Easy removal with resection > small chance of developing CRC
76
Stage discovery distribution of screened and unscreened CRC
Before screening program > a lot stage 4 and little stage 1 Screening > a lot stage 1 and low stage 4 >> mortality rates are dropping, slow downwards trend CRC incidence and mortality
77
Possible pitt falls in CRC screening
- Sensitivity for adenomas and sessile serrated lesions - Type of screening test and willingness to participate - Inducing more inequity in health care: persons with highest social economic status and more healthy lifestyle are the ones participating in screening, but they have approx. better outcomes as risk probability > extra attention needed for other groups - FIT screening is based on detection of blood in stool sample: not all lesions bleed
78
Cancers can be missed in FIT"FIT interval CRC
CRC between 2 screening rounds > 0.10% of iCRC after negative FIT > sensitivity of the test is 75%
79
Future perspective CRC screening
- Find protein biomarkers in feces for stool test - Fecal DNA marker test: used in US > downside: lower-cost effectiveness and more false positives - Risk stratification: select patients better based on risk factors - Barriers in participation researched and decision-making

Molecular Oncology (7 decks)

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