Cancer Bio (Michaelis Lecture 2 - Cancer heterogeneity)

Question 1

What is heterogeneity?

Answer 1

The quality or state of being diverse in character or content

Question 2

What is the cancer stem cell hypothesis?

Answer 2

• not all cancer cells from a given tumour are equal
• Only a few cancer stem cells have non-limited self renewal capacity
• CSCs responsible for tumor growth, resistance, and recurrence

Question 3

What are the characteristics of cancer stem cells?

Answer 3

• self renewable
• last a life time
• display low sensitivity to toxins
• may outlive anti-cancer therapy in dormancy
• may colonise other sdistal body sites

Question 4

The CSC hypothesis would give an explanation for what 2 phenomena?

Answer 4

1) Local recurrences of cancer long after treatment
2) (Dormant) metastases are formed long after treatment (in breast cancer metastases can occur >10 years after initial treatment)

Question 5

Are CSCs dormant? What impact does their activity have on therapy?

Answer 5

• Adult stem cells characterised by long-term dormancy
• CSCs dormancy may be associated with decreased chemotherpy sensitivity
• May explain recurrences

Question 6

Are CSCs resistant to chemotherapy?

Answer 6

Some evidence to show CSCs chemo resistance but not conclusive:

• Some breast cancer, CML, T-cell acute leukaemia stem cells have shown resistance to chemo drugs

Question 7

How does imatinib act as a targeted anticancer therapy? Which cancer does it treat and how?

Answer 7

• Breakthrough therapy in treating chronic myeloid leukaemia (CML)
• Inhibits the BCR-ABL fusion protein (encoded by Philadelphia chromosome)

Question 8

What is the problem with imatinib related to CSCs?

Answer 8

• BCR-ABL positive patients usually have recurrence of the disease after treating with imatinib
• Likely due to dormant imatinib-resistanct stem cells

Question 9

How are cancer stem cells recognised in leukemias and why is this possible for leukemias but harder in solid tumours?

Answer 9

• In leukaemia, CD34 and 38 are used as haematopoietic stem cell markers
• Able to do in leukaemias as the cells of origin are known to be stem cells:
  > Cancers that begin in hematopoietic stem cells or progenitor cells
• Harder to do in solid tumours as tissue of origin not known/do not always arise from stem cells

Question 10

Using acute myeloid leukaemia as an example, how frequent are CSCs?

Answer 10

• Mouse leukaemias transplanted into histocompatible recipients > 1 in 10 is tumourigenic

Question 11

What is stem cell plasticity?

Answer 11

The ability of stem cells to differentiate into other cell types

Question 12

Are cancer stem cell populations stable or is the conversion to non stem cells reversible? Describe the 2 models that show each is a possibility

Answer 12

1) Hierarchial model
- Stem cells of an original population divide and differentiate into different cell types and more stem cells

e.g RED1 —> BLUE1, YELLOW1 AND RED2

2) Stochastical model
- Stem cells differentiate into non-stem cells, some of which revert back to stem cells

e.g RED1 –> BLUE1 –> YELLOW1 –> RED1

Question 13

How may cancer stem cells divide to maintain stem cell population? (Hierarchial model)

Answer 13

Asymmetric division

• One stem cell divides to give one stem cell and a differentiated cell
• This new stem cell then does the same etc etc etc

Question 14

What is epigenetics?

Answer 14

The study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself

Question 15

What are the 2 main mechanisms of epigenetics?

Answer 15

1) DNA methylation
- can activate or repress genes

2) Histone tail modification

Question 16

What are the 2 categories of oncogenic changes that result in cancer cell plasticity?

Answer 16

1) Genetic changes/mutations - irreversible

2) Epigenetic changes - reversible

Question 17

What is clonal evolution? How does it explain intra tumour hetergeneity?

Answer 17

• Tumours highly genetically and epigenetically unstable
• Induction of many mutations in cancer cell population affecting proliferation rates
• Selections pressures influence survival of different cancer cell phenotypes by natural selection

Question 18

Name some cancer cell selection pressures

Answer 18

• hypoxia
• starvation
• anti-cancer therapies
• microenvironment (tissue location/invasion/metastasis)
• immune system

Question 19

What complications does clonal evolution have on cancer treatment?

Answer 19

1) Metastatic tumours may require different treatment to primary tumour
2) Different cells of the same tumour may require different treatment