Cancer stem cells and bioengineering

Question 1

What properties of stem cells make them potentially cancerous?

Answer 1

• long lived → can accumulate mutations
• already have the potential to proliferate indefinately

Question 2

What is the cancer stem cell hypothesis?

Answer 2

the cancer stem cell hypothesis - cancers as most tissues contain a hierarchical organisation of cells. Most tumour cells die naturally, however cancer stem cells “replenish” the tumour and are resistant to chemotherapy

Question 3

What do we tend to focus on when recognising cancer stem cells?

Answer 3

we tend to focus on the cells that survive chemotherapy instead of expression of specific markers as the level of expression can vary inbetween cancers as well as in the same cancer

Question 4

Do you have particular population of cancer stem cells for all cancers?

Answer 4

for some cancers you don’t have a particular stem cell population for example ALL , it seems like any cell can become cancerous , we are starting to think that where the cell is is actually more important than what the cell is

Question 5

What is EMT an MET?

Answer 5

• EMT (epithelila-mesenchymal transition)- allows the cells to break away from the original tumours
• MET happens in the receiving tissues

Question 6

What are some characteristics of cancer stem cells?

Answer 6

• self renewal
• asymetric cell division
• interaction with CSC niche
• mechanism to escape therapy

Question 7

What do we consider cancer stem cells?

Answer 7

chemoresistant cells with the ability to drive relapse formation are considered cancer stem cells

Question 8

Describe clonal evolution of cancers

Answer 8

the mutations that intiated the cancer can be found in all cancerous cells but then we can develop subpopulations with different mutations

Question 9

Compare healthy and cancerous stem cells

Answer 9

• they both give rise to more of themselves and progeny
• tissue stem cells are rare, quiescent and highly stable, however this is not necessarily the case for CSC
• CSC do not have to derive directly from stem cells

Question 10

How can cancerous cells escape therapy?

Answer 10

• pumps are able to extrude a therapeutic agent
• queiescence - chemotherapy will typically kill proliferating cells
• mitochondrial transfer - cancer cells can offload their damaged mitochondria so the reactive oxygen species don’t kill them

Question 11

Can immune system recognise the cancerous cells?

Answer 11

cancer cells express different variants of genes and specific oncogenes → cancer specific antigens can be recognised by the immune system

Question 12

What does cancer evolution lead to?

Answer 12

• cancer evolution leads to:
  
  • negative selection of cells with neo antigens
  • down regulation of antigens
  • over expression of PDL1 whcih anergises PD1+ T cells
• these processes happen at different pace in different areas → cancer heterogeneity

Question 13

What kind of metabolic pathways do PSCs and HSCs use?

Answer 13

• PSCs get some ATP from glycolysis and use the TCA for genetic regulators (for example Acety Co A)
• Hematopoetic stem cells high in glycolysis (anaerobic) but they are usually quiescent and they want to have little oxygen to reduce the reactive oxygen species

Question 14

What happens in healthy stem cells when ROS levels rise?

Answer 14

even when the oxygen species rise the good stem cells will be able to recover from the damage and repair their DNA and damaged proteins for example using autophagy

Question 15

Are ROS always a disadvantage?

Answer 15

reactive oxygen species are not always bad, for example highly proliferative cancer cells have high levels of reactive oxygen species but they also have methods for dealing with them so if we are able to identify those mechanisms there is potential for therapeutics targets (metabolic vulnerability)

Question 16

Give an example of how the different ROS levels direct what nutrients are important for the cell

Answer 16

for example glutathione is very important for cell with high oxygen reactive species (it is an antioxidant) so cysteine which is essential to make that molecule becomes of great value to the cells

Question 17

What is the difference between neutral drift and clonal evolution

Answer 17

• neutral drift:
  
  • cell extrinsic, physical determinants of stem cell dominance
  • eg intestinal crypts
  • the stem cells that “compete” with each other arevirtually the same
  • it’s just luck of being more inside or outside the crypt
• clonal evolution
  
  • cell-intrinsic changes confer advantage to some cells oveer others
  • eg clonal haemotopoesis; cancer resistence of therapies

Question 18

What are organs on chip?

Answer 18

Artificial human organs, or organ-on-chip technologies, simulate a whole organ’s cell make up and physiology. They act as alternatives to animal models in drug safety testing

Question 19

What are some advantages of using organs on chip?

Answer 19

• Organs-on-chips house live human cells on scaffolds that are physiologically, mechanically, and structurally similar to the emulated organ
• The living cells used in tests last much longer on the chip than in traditional laboratory methods, and require lower infection doses compared to traditionally used model systems.

Question 20

What are microfluidics?

Answer 20

microfluidics - tiny capilaries that transport cells/assays and stuff

Question 21

What can we find out from microfluidics?

Answer 21

• cells need to squeeze through so you can see what happens to them after they do it
• how long does it take it to squeeze through? for example leukemia cells tend to be stiffer than the healthy cells