Brain cancer Flashcards
What percentage of all cancers do brain tumors make up?
3%
What is the average age for peak rate of brain tumour cases?
85-89
Why might the average brain tumour age be skewed?
Glioblastomas are more common in the elderly
TRUE or FALSE?
The brain tumor incidence has been rising (by about 34%) since the 1990s
TRUE
Where are most benign brain tumors found?
Meninges
Meningiomas
What is the most common type of brain tumour?
Glioblastoma
What is the 5-year survival rate for glioblastomas?
Very bad (10% or less)
If you had chemo, surgery and radiation therapy for a glioblastoma what would your average survival be?
15 months
What are the obstacles to effective treatment of GBM?
Heterogeneity: different people have different mutations and different cells in the tumours
Glioma stem-like cells are treatment-resistant
Invasion
What are the sources of heterogeneity in GBM?
Inter- and Intratumoral
Molecular (genetic, transcriptional, epigenetic, cell signaling)
Cellular (GSC and lineage progression)
Therapy-induced (heterogeneity in recurrent GBM)
Describe the concept of intertumoural heterogeneity
Each tumour has:
- Different mutations (e.g. abberations in DNA copy number, gene expression, and DNA methylation)
- Epigenetic changes
- Transcriptional changes
What are the three critical signalling pathways where genetic abberations are found?
- RTK/RAS/PI3K
- P53. Normally stop cells from dividing by becoming activated in response to stress signals (e.g. oncogenes). In most tumours this is downregulated
- CDKN2A
What is the most common mutation in brain cancers?
Amplification in EGF Rs
What are transcriptional sources of intertumoural heterogeneity?
Abberation in gene expression of EGFR, NF1, and PDGFRA/IDH1
Each define a different subtype of tumour
Expression of which molecule is associated with the proneural subtype?
PDGFRA/IDH1
Expression of which molecule is associated with the classical subtype?
EGFR
Expression of which molecule is associated with the mesenchymal subtype?
Loss of NF1
The theory of neural subtype of glioblastomas is a scientifically supported theory
TRUE or FALSE
FALSE
It was actually an artifact
What are sources of epigenetic intertumoural heterogeneity?
Methylation
Histone modification
Higher order structures
Close or open chromatin
How many subgroups of GBMs could be found if looking at DNA methylation patterns?
6
What is the most common mutation in brain cancers?
IDH1 gene, which codes for an enzyme, and whose mutation causes too much methylation
What is the survival like for patients witch IDH1 mutation?
Increased suvival
What are FISH studies and what have they revealed about intratumoural heterogeneity?
Fluorescence in situ hybridization (FISH)
Test that “maps” the genetic material in human cells, including specific genes or portions of genes.
PDGFRA and EGF receptor amplifications were found in the same tumour but not in the same cells
What problem does intratumoural heterogenity pose for treatment?
Different diagnoses will be given depending on where you sample the tumor
If you use a specific targeted therapy you may only inhibit some cells and not others
What have copy number analysis and RNA-seq revealed about molecular intratumoural heterogeneity?
Different regions of a brain tumor harbors different aberrations and alterations in gene copy numbers
Different regions harbour distinct transcriptional profiles
Within the tumour you have samples which classify into different subtypes
What is 5 ALA?
A substance that, if given to brain cancer patients, causes the tumour to fluoresce
What have single cell RNA-seq of molecular intratumoural heterogeneity shown?
Single cells from the same tumor present distinct transcriptional profiles and can be categorized into different subgroups
What have functional alalyses of GBM clones shown about cellular intratumoural heterogeneity?
Clones display different markers, proliferation, and differentiation
Even though they come from the same tumour
What are the theories as to how heterogeneity occurs?
- Survival of the fittest
- Glioblastoma stem-like cells (GSCs)
- Plasticity driven by the microenvironment (e.g. hypoxic microenverionment select specific mutations)
- Branched tree model
Explain the survival of the fittest theory for heterogeneity
Clonal evolution
Tumor cells divide and acquire mutations
Upon a selective pressure the most fit clone(s) will survive and cause tumor relapse
Explain the GSC theory for heterogeneity
SCs divide asymmetrically and generate
- SCs
- More differentiated tumor cells that can acquire mutations.
Upon treatment, resistant SCs will survive and cause tumor relapse
Explain the Plasticity driven by the microenvironment model for heterogeneity
microenvironment –> epigenetic mechanisms –> cells with different tumorigenic properties
Explain the branched tree model for heterogeneity
Mutations shared by all tumor cells proceed from the founder clone which is depicted as the trunk of the tree.
The branches are composed by tumor cells that acquire mutations present only in a subset of the tumor cells.
What is the evidence for therapy induced heterogenity?
Low grade gliomas and their recurrences are highly divergent with 43% of tumours carrying mutations not detected at recurrence
Emergence of treatment-resistant subclones displaying TMZ-induced hypermutator phenotype, i.e. TMZ imposes distinct evolutionary trajectories
TRUE or FALSE?
When recurrent tumours are found in a different location they are the same type of tumour as the first one
FALSE
To summarize, what are the things that influence heterogeneity?
Treatment
Location
Microenvironment
Cellular hierarchy
Where does adult neurogenesis occur?
Dentate gyrus of the hippocampus
Subventricular zone of the lateral ventricle
How did people figure out the involvement of GSCs in tumour development?
The tumour cells had stem cell markers and could become different neurons
If you implant CD133- cells they won’t make a tumour but CD133+ caused tumours
What is the marker for stem cells?
CD133
What are properties of glioma stem-like cells?
Required functional characteristics:
- Sustained self-renewal
- Persistant proliferation
- Tumour initiation
Common (but not defining characteristics):
- Frequency in tumour
- Stem cell marker expression
- Ability to differentiate along multiple lineages
What is the evidence of GSC as the origin of tumour heterogeneity?
Barcoded tumour cells --> Passaged them (also doing DNA seq) --> supported the idea of a neural evolution of the tumour (similar to neural stem cell division not survival of the fittest)
What is the possible reason for therapeutic resistance in tumours?
Chemotherapy: glioma stem cells can quiesce, these approaches only target dividing cells
Radiotherapy: Stem cells have the ability to initiate check point inhibition and repair their DNA
In order to cure a cancer what cells do you have to target?
The stem cells
What are the 3 methods of cancer invasion?
Via brain parenchyma
Via blood vessels
Via white matter tracts
Which molecules are involved in tumour vascular homing?
SDF-1/CXCR4
Bradykinin
What are SDF-1 and CXCR4 and how have they been shown to be involved in vascular homing?
SDF-1 is a chemokine and CXCR4 is its receptor expressed by tumour cells
If you put SDF-1 in media (to ruin the gradient) or knock down the CXCR4 receptor, the neural stem cells/tumour cells don’t migrate much
How is bradykinin part of vascular homing?
Brain tumors have bradykinin receptor 2
It is important for tumor migration
Give bradykinin –> increase the Ca2+ signal in the cells –> migrate towards higher bradykinin gradient
Which molecule is important for perivascular invasion?
Ephrin-B2
What are the 3 mechanisms which help tumour cells use blood vessels to invade new regions?
Vascular homing
Perivascular invasion
Overcoming barriers to perivascular invasion
What is the role of Ephrin-B2 in perivascular invasion?
Ephrin-B2 repels migrating cells
Tumour cells are proven to no longer be sensitive to Ephrin B2
If you knock out Ephrin B2 tumour cells stop migrating and forming tumours
Overexpressing ephrin B2–> transform neural stem cell to tumour cell
How do tumours overcome barriers to perivasuclar invasion?
Astrocyte end feet control how blood vessels constrict.
Tumour cells displace astrocyte end feet –> astrocytes lose control on the vasculature–> Glioma cells then take control of the vasculature (cause diameter of blood vessels to increase)
What happens exactly when tumour cells cause astrocytes to lose control of vasculature?
Leakage of serum into parenchyma
Loss of tight junctions
Degradation of basement membrane
What is glioblastoma survival like compared to other cancers?
Much worse
What are current treatments for glioblastoma?
Surgery (when possible), radiation, chemo (temozolomide)
No major breakthrough apart from TMZ and no success with targeted therapy in trials
Define grade
How abnormal the tumour cells are to normal cells
Define stage
How far the tumour has spread
How do tumour cells form
- Cell of origin can be a neural progenitor or even a differentiated astrocyte or neurone which can dedifferentiate
- Pre-neoplastic cell (not studies yet)
- Neoplastic cells
How does methylation affect transcription?
It represses the expression of neighbouring genes
How does methylation work?
DNA methyltransferases methylate cytosine –> recognised by editor enzymes –> mediate the transformation of 5 methyl cytosine to 5 hydroxyl methyl cytosine (on the way to demethylation)
Readers (chromatin remodelling factors) recognise 5 methyl cytosine and lead to further changes in chromatin structure
What are the pros and cons of the different models used for identifying good glioblastoma treatment targets?
Genetically modified GBM:
Pros: allows for careful modelling
Cons: TIME (though tech is improving fast), how faithful (mouse v. human), availability of drugs, BBB
Patient-derived primary GBM cells:
Pros: TIME, may be used to make decision regarding therapy regimen
Cons: depends on availability of targeting agents; in vitro clonal selection (intra-tumour heterogeneity), cells cannot be derived from every tumour, engraftment issues , BBB
What are the types of targets for GBM therapy?
- Tumour subtype/stage-specific targets (e.g. IDH1 mut)
a. Target mut IDH1 in the initial tumour
b. When tumour comes back you could, in principle, perform further (epi)genomic analysis and identify stage specific targets - Targets common to multiple GBM subtypes/subclones
Example: a number of oncogenic signals could be shared by different tumour subtypes (e.g. Myc transcription factors)
What are the problems with the two types of tumour targets?
Subtype specific:
Time from molecular analysis to therapy
Availability of experimental models/drugs
Little interest from pharma given small nr. Of patient + issue of costs for health services
Common mutations:
Limited number, might be difficult to target
Toxicity to normal cells
