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Flashcards in SC10 Deck (28):
1

what are cancer initiating cells

a cell in a healthy individual which is mutated enough that is becomes a tumour

2

What are the for and against for SCs as cancer initiating cell hypothesis

For: SCs are long lived, can accumulate mutations and have pootential to proliferate indefinitely.
Against: Quiescence is tightly controlled, progenitors are also highly prolierative.

3

Give an example of SC giving rise to cancer

CML: chronic myeloid leukemia
clonal bone marrow disroder, caused by over proliferation of mature granulocytes and their precursors

4

give an example of a progenitor giving rise to cancer

AML: acute myeloid leukemia
myeloblast progenitor cells are mutated preventing differentiation combined with disruption of proliferation genes leading to cancer.

5

What is the cancer SC hypothesis

Hyp: cancer (like most tissues) contains a heirachal organisation of cells, including CSCs, which have SC properties such as self-renewal and ability to give rise to progeny of all cell types found in a particular cancer.
** CSCs by definition can therefore replenish the tumour and are resistant to chemo which are theorised to kill differentiating cells

6

What is evidence for CSC hypothesis

1. AML has cells that can give rise to the tumouir repeatedly in otherwise healthy mice
2. CSCs that can give rise to new tumours have been identified by CD133 in solid tumour colon cancer

7

what is the consequence if there are CSC

therapies that target CSCs could prevent relapse.

8

where have CSCs been identified

in several solid tumours inc.
brain, breast, colon, ovary, pancreas etc.

9

what are three possible origins of CSC

Adult SC (mutation)
mutation in developing
De-differentiation
Heirachy

10

how could CSC originate from adult SCs

combo of high division rate and long life is a good background for mutation accumulation, a primary factor driving cancer initiation

11

how could CSCs originate from developing SCs

mutation in developing SC popualtions shared by many descendants, daughter cells are therefore closer to becoming tumours

12

How could CSCs develop from de-differentiation?

a fully differentiated cell could undergo several mutations that drive it back to a stem like state, suggest that any cell could become a CSC (although difficult).

13

how could CSCs orignate from a heirachy

tumour is a heterogenous population of mutant cells with several lineages of CSCs opotcal to specific envrionments allowing tumour adaptation

14

What is a major cause of tumour lethality

metastasis
*not all tumours can do this

15

Describe EMT

epithelial mesenchymal transition
* EMT is a process where epithelial cells lose their cell polarity/cell-cell adhesion and gain mirgratory invasive properties to become MSCs.

16

what is EMT important for

many processes such as mesoderm formation and wound healing

17

what is EMT relevant to

the acquisition and maintenance of SC like characteristics and is sufficient to endow differentiated normal and cancer cells with SC properties.

18

what could tumour cells undergoing EMT be precursors for?

metastatic cancer cells or CSCs

19

What are circulating tumour cells

biomarker of cancer progression
cells that have left the primary site of tumour growth but have yet to invade new tissues (potentially CSCs)

20

what are the two types of circulating tumour cells

traditional: confirmed cancer cells with epithelial origin.
Met/cytokeratin negative: CSC or cells undergoing EMT thought to be resistant to treatment and more prone to metastasis.

21

what are the problems with the CSC hypothesis

1. CSCs cant be studied in most tumours.
2. differences between CSCs and SCs: normal SCs are are, stable and dont accumulate mutations as mostly quiescenct, the oppositive in Cancer cells.
3. identification of CSC based on demonstration of distinct phenotype that allows prospective enrichment, however in many cases this definition doesnt hold.
4. assays have a large influence on result so samples are variable.

22

what are the present challenges in CSCs

1. identify whether each tumour cell has a heirachy of cells
2. adequate experimental assays must be identified.
3. adequate clinical end points need to be developed.

23

How have CSCs been targetted with salinomycin

2009
salinomycin selectively reduces the proportion of breast CSCs in mice 100X relative to paciltaxel, combined with autophagy inhibitors to prevent cancer cell survival via autophagy.

24

how have CSCs been targetted with nanobombs

2015
Nanobombs are packaged nanoparticles with miR-34a and ammonium bicarbonate (causes bread to swell), delivered to CSCs in mouse prostate. irradiation causing nanoparticles to swell and burst endosome, dispersing RNA which lowers level of CD44 linked to tumour development and crucial to CSC survival

25

how have CSCs been targetted with CD123 specific Ab.

impairs AML SC homing to the BM and reduces repopulation.
which have CD123 highly expressed.

26

What is the clonal evolution of cancer

in cancer new sub types can arise and take over the original cancer.
genetic heterogenity can be used to recreate tumours history.
if role of sub populations is fully understood could give an idea about CSCs and make treatment more effective.

27

What does model of CSC as CIC suggest
- what can change this

onky a small sub population of cancer cells have tumourigenic potential. which has previously been backed up with evidence showing 1/million melonoma cells can cause cancer in immunocompromised (NOD/SCID) mice.
- how the assay is done can change these results

28

What is the experiment on immuno comprimised mice with changing assay and what did this show

1. NOD/SCID mice (No B/T-cells)-170 days 1/3 mice got tumours.
2. NOD/SCID (No B/T/NK cells) - 90 days all mice got tumours.
- injection wiht matricgel support = 100 days all mice got tumours.
** shows results dependent on assay done, suggests CSCs are not as rare as previously thought and that potentially many cells can be CSCs.