L9 - Cancer and Stem Cells Flashcards
What are the 4 carcinogenic causes of cancer?
Chemical - Smoking - Beta-naphthylamine Parasites - Schistosoma - Clonorchis Radiation Viruses - HPV - EBV - HBV
What are tumours?
They are heterogenous
What is intra tumour heterogeneity?
Cells within the same tumour often exhibit differences in terms of
- Differentiation state
- Proliferation rate
- Migratory and invasive capacity
- Size
- Therapeutic response
- Tumorigenicity
What is inter tumour heterogeneity?
Heterogeneity between tumours
What does the stochastic model say all cells are?
Tumour-initiating
Have the same potency
Can self-renew or differentiate
What does the stochastic model say the characteristics of tumour cells are?
All tumour cells are equipotent
A proportion of them stochastically proliferate to fuel tumour growth
A proportion of them differentiate to create targets for anti-cancer treatment
Tumours often tend to recur – differential resistance to treatments
What does the cancer stem cell model show?
Only a small subset of tumour cells has the ability for long-term self-renewal
Give rise to committed progenitors with limited proliferative potential - eventually terminally differentiate
What are the therapeutic implication of cancer stem cells?
They have a slow cell cycle/dormant
Treat with drug that only kills proliferating cells – CSCs are therefore drug resistant
Slow growing CSCs have escaped treatment - tumour grows back with heterogeneity
What are the common features between normal stem cells and cancer stem cells?
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
- Ability to initiate a tumour
They are both regulated by the same signalling pathways
By which two methods can cancer cells be used to form tumours?
Reprogramming of specialised cells to a cancer stem cell like entity
- Gives rise to a heterogenous cancer
Oncogenic transformation of pre-existing stem cells
How are cancer cells captured?
In vitro potential – establishment of cell lines that can self-renewal and differentiate
In vivo potential – ability to give rise to cancer following transplantation into animal
What is acute myeloid leukaemia?
Blood cancer affecting myeloid lineage
What are the characteristics of HSCs?
HSC – haematopoietic stem cells
The express cell surface markers - CD34 +CD38
They are slow growing
Found in the bone marrow niche
What method is used to assess HSC ability?
Take immunocompromised mice
Sub-lethal radiation – no haematopoietic system in mice
Transplantation of a single HSC can rescue haematopoietic system
How are leukaemia stem cells formed?
Normal HSC (CD34+ and CD38-) undergoes transformation events to form a leukaemia stem cell
- Can self-renew
- Can differentiate
Can take immunocompromised mice
Sub-lethal radiation – no haematopoietic system in mice
Transplantation of a single leukaemia stem cell can give rise to leukaemia in the mouse
What is glioblastoma?
Most prevalent and lethal primary brain tumour
Aggressive and invasive
Recurrent
How is glioblastoma treated?
Surgical resection
Radiation and chemotherapy
- E.g. temozolomide
What is the average survival time of glioblastoma patients?
12-18 months
Only 25% of glioblastoma patients survive more than one year
Only 5% of patients survive more than five years
Characteristic of GBM stem cells?
Heterogenous
Driven/resemble normal neural stem cells
How do you isolate GBM stem cells?
Using the same conditions used to capture neural stem cells in vitro
Plate dissociated cells on laminin in the presence of FGF2 and EGF
What different factors can GBM stem cell colonies express?
Nestin and Sox2 – undifferentiated markers
Under expression of differentiated markers
- Can self-renew
- Can differentiate
- GFAP - glial cells
- Dcx - neural precursors
- But variable differentiation potential depending on tumour
What does a stereotactic injection of GBM stem cells into brain of mice give?
GBM like tumour
How do you find suitable treatments for glioblastoma?
Apply drug screens in order to find suitable treatment
Indratraline
- Severe effect on GBM stem cells
- Less severe effect on foetal NS cells
What are the 3 main in vitro approaches to studying cancer?
Xenograft models
Cancer cell lines – proliferate indefinitely
Genetically modified animals (oncogenes/tumour suppressor mutations)
What are the limitations of the 3 main in vitro approaches to studying cancer?
Failure to capture the transition from a normal to a tumourigenic phenotype
Lack of mechanistic insight
What is the method used to study a cancer phenotype?
Established cancer stem cell lines reprogrammed into induced pluripotent stem cell state
Or hESCs that have had oncogenic mutations introduced
Either method leads to in vitro differentiation to cell type of interest
Examine phenotype – e.g. proliferation, impaired differentiation
What is a neuroblastoma?
Common solid tumour in infants and young children
Where do neuroblastomas originate?
In an embryonic cell type - 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
What do neural crest cells arise in response to?
WNT and BMP signals
- hPSCs form neural crest cells when exposed to WNT and BMP signals
- hESCs from a neuroblastoma phenotype when exposed to WNT, BMP and MYCN overexpression
