Lecture 4 - Cancer and Stem cells

Question 1

Define pluripotency

Answer 1

Ability to generate all cell types of an embryo including germ cells

Question 2

Describe the cell cycle

Answer 2

4 phases and a resting phase of G0

M phase, division Cdk1 cyclin A/B
G1 phase, interphase Cdk4/6 cyclin D
G0 phase, resting
Cell enlarges
S phase, interphase Cdk2 cyclin E
DNA synthesis (replication)
G2 phase, inyerphase Cdk2 cyclin A

Uncontrolled proliferation = cancer

Question 2

Describe the cell cycle

Answer 2

4 phases and a resting phase of G0

M phase, division Cdk1 cyclin A/B
G1 phase, interphase Cdk4/6 cyclin D
G0 phase, resting
Cell enlarges
S phase, interphase Cdk2 cyclin E
DNA synthesis (replication)
G2 phase, inyerphase Cdk2 cyclin A

Uncontrolled proliferation = cancer

Question 3

What is an oncogene?

Answer 3

A gene capable of transforming a normal cell into a tumour cell

Question 4

What do Tumour-suppressors do?

Answer 4

Restrict proliferation

Question 5

What is cancer driven by?

Answer 5

Cancer is driven by the activation of oncogenes and sometimes involves the inactivation of tumour-suppressor genes

Question 6

What carcinogenic and environmental factors can cause cancer?

Answer 6

Chemical - Smoking
Parasites - Schistosoma, Clonorchis
Radiation - UV, Ionising radiation
Viruies - HPV, EBV, HBV

Question 7

What are the differences on cells within the same tumour ?

Answer 7

Differentiation state

Proliferation rate

Migratory and invasive capacity

Size

Therapeutic response - some are more refractory to chemotherapy

Tumourigenicity =Intra-tumour heterogeneity

Question 8

What is the Stochastic model ?

Answer 8

A general model for Cancer.

All tumour cells are equipotent and a proportion of them stochastically (randomly) proliferate to fuel tumour growth while other tumour cells differentiate=targets for anti-cancer treatments.

All the cells are tumour-initiating, have the same potency and can self-renew or differentiate

Question 9

What is the Cancer stem cell model ?

Answer 9

Only a small subset of tumour cells has the ability for long-term self-renewal and these cells give rise to committed progenitors with limited proliferative potential that eventually terminally differentiate.

Question 10

How do CSC survive chemotherapy?

Answer 10

CSCs are more dormant, so escape chemo because they are slower than fast-proliferation cells. It will survive to allow tumours to grow back with heterogeneity.
Drugs target fast stem cells

Question 11

What are the differences between normal SCs and Cancer SCs ?

Answer 11

Normal stem cells:
Self-renewal (homeostasis)
Differentiation (maintenance of organ functionality)
Ability for functional reconstitution

Cancer stem cells:
Self-renewal (tumour growth)
Differentiation (tumour heterogeneity(resistance))
Ability to initiate a tumour

They are both regulated by signaling pathways (e.g. WNT, colon cancer)

Question 12

How does tumourigenesis work ?

Answer 12

Also known as oncogenesis or carcinogenesis, refers to the process by which normal cells transform into cancerous cells using mutations.

Question 13

What is In vitro potential?

Answer 13

Establishment of cell lines that can self-renew and differentiate

Question 14

What is In vivo potential ?

Answer 14

The ability to give rise to cancer following transplantation into animals

Question 15

How can we give mice leukameia ?

Answer 15

CD34+CD38- AML stem cells give rise to Leukaemia
A Sub-lethal radiation to an immunocompromised mouse followed by a Transplantation of these AML causes Leukaemia.

Question 16

What is a Glioblastoma (GBM) ?

Answer 16

most prevalent and lethal primary brain tumour
Aggressive and invasive
Treatment: surgical resection, radiation+chemotherapy (e.g. temozolomide (TMZ))
Recurrent
Average survival time=12-18 months - only 25% of glioblastoma patients survive more than one year, and only 5% of patients survive more than five years.
GBMS are heterogenous

Question 17

Features of the GBM stem cell lines?

Answer 17

Can self-renew
Can differentiate (GFAP = glial cells, Dcx = neural precursors)
But variable differentiation potential depending on tumor

Question 18

How to cause GBM tumours in vitro?

Answer 18

Can take blastoma stem cells (GBM stem cells) and isolate them with FGF2 and EGF, Stereotactic inject them into the animal brain and end up with tumours just like the GBM ones

Question 19

What are the main approaches to study cancer ?

Answer 19

Xenograft models
Cancer cell lines
Genetically modified animals (oncogenes/tumour suppressor mutations)

Question 20

What are the limitations of in vitro modelling of tumorigenesis?

Answer 20

failure to capture the transition from a normal to a tumourigenic phenotype in a tractable manner and in a human context
Lack of mechanistic insight

Question 21

What is a neuroblastoman?

Answer 21

A common solid tumour in infants and young children
Originates in an embryonic cell type called the neural crest which generates peripheral neurons
Aggressive neuroblastomas express high levels of the transcription factor MYCN

Ectopic overexpression of MYCN in normal neural crest cells gives rise to neuroblastoma-like tumours

Primary development locations of neurobatomas are the spinal (nerve root), adrenal gland and top of kidney.

Question 22

What is the neural crest ?

Answer 22

The neural crest cells originate from the ectoderm.
It is a group of cells that migrate around to different parts of the developing embryo in order to differentiate into different cells.

During migration, neural crest cells undergo epithelial-to-mesenchymal transition, which allows them to detach from the neural tube and migrate along defined pathways to their final destinations. These pathways include the cranial, cardiac, trunk, and enteric neural crest streams, each of which gives rise to specific cell types and tissues.

The Neural plate bends into a circle above the noctochord

Question 23

How do neural crest arise ?

Answer 23

The neural crest arises during early embryonic development through a process called neurulation, which involves the formation of the neural tube from the ectoderm, the outermost layer of the embryo.

They arise in response to WNT and BMP signals, overexpression of these = neuroblastoma

Question 24

What happens to neural cells once they have been induced?

Answer 24

Once the neural crest cells have been induced, a series of transcription factors and signalling pathways are activated to regulate their migration and differentiation. For example, the transcription factor Sox10 regulates the expression of genes involved in cell fate determination and migration.

Question 25

What causes GBMs to DIE in mice?

Answer 25

Indatroline