L10 Metastasis, genetic variation and stem cells Flashcards
Metastasis
the spread of cancer cells from one site to another site
Angiogenesis
tumours recruit blood vessels
signals from tumour can cause nearby blood vessel to sprout new branches which invade the tissue. Once the tumour is vascularised its growth becomes exponential and is able metastasise
Hypoxia induces VEGF which induces sprouting
see onenote
tumour grows, central cells become starved of oxygen. this condition is sensed by a protein called hypoxia inducible factor 1-alpha
VEGF - vascular epithelial growth factor
Initial stages of metastasis involve an EMT
see onenote
cells lose epithelial characteristics and become migratory - allows them to invade the surrounding tissue and enter the vasculature, a process called intravasation
How can we find genes that regulate metastasis?
see onenote
TF Twist promotes metastasis
see onenote slides
twist promotes invasiveness and metastasis
Twist drives EMT
see onenote
during early Drosophila development, twist is expressed in cells on the ventral side of the embryo
these cells are initially epithelial but Twist expression causes them to break free of their neighbours and become migratory
in twist mutants, this process fails
Metastasis involves an EMT
see onenote
during early stages of metastasis, epithelial tumour cells undergo an EMT which allows them to break free of the epithelial state and invade surrounding tissue and enter the vasculature
twist is a prognostic marker for many cancers
E-cadherin is a tumour suppressor
Loss of e-cadherin is a common feature of cancer cells
hereditary loss-of-function mutations in CDH1 (i.e. ecadherin) greatly increase risk of diffuse gastric cancer
Circulating tumour cells in the vasculature
see onenote
tumour cells that enter the blood stream are called circulating tumour cells (CTCs)
CTCs can also circulate as clusters, also called circulating tumour microemboli (CTMs)
Formation of secondary tumour involves MET
see onenote diagram
involves CTCs leaving the blood vessel (extravasation) to seed the new tumour
growth of the second tumour thought to involve MET
What is more dangerous? CTCs or CTMs?
see onenote
CTMs appear to be much better at metastasising
The CellSearch system
designed to detect circulating tumour cells
blood samples taken from patient
immunomagnetically sorts the cells, immunostains them and presents them for inspection
Principle of CellSearch system
see onenote
Counting CTCs has prognostic value
see onenote
does seem to be a good way of tracking the progress of some types of cancer
Cancer heterogeneity and clonal evolution
see onenote
a tumour is genetically heterogenous (made up of cells with different mutations) and this genetic makeup evolves over time
sequencing of a cancer reveals the evolutionary tree of mutations
see onenote
able to piece together a family tree of cell lineages
Evolution and genetic variation
see onenote
the more genetic variation there is in a tumour, the more opportunity there is for evolution
mutations that lead to more variation will help a cancer evolve
cancers often acquire mutations in genes involved in DNA damage response
loss of such proteins leads to increased mutation rate and chromosomal instability (CIN)
Chromosomal instability leads to aneuploidy
CIN = gain/loss of whole chromosome or fractions of chromosomes
aneuploidy = abnormal number of chromosomes
How can aneuploidy arise?
see onenote
- mitotic checkpoint defects
- merotelic attachments
- multipolar mitotic spindles
single cell RNAseq of glioblastoma
see onenote slides
great variability at the chromosome and gene level
sequencing reveals colorectal cancer “landscape”
see onenote
colorectal carcinoma and APC
see onenote
people that inherited
one faulty copy of APC are predisposed to cancer
APC is part of the complex that targets beta-catenin for destruction so loss of APC overactivates Wnt pathway and causes tumour growths (adenomas)
BRAF is a MAP Kinase
see onenote
BRAF and melanoma
see onenote slides
mutation in BRAF, result in constitutive activation of MAPK pathway
Vemurafenib (Zelboraf) selective inhibitor of mutant BRAF Val600 and treatment show major tumour responses
Cancer heterogeneity and clonal evolution - BRAF inhibitor
if bottlenecks are due to chemo, it can mean that one is selecting for cell types that are resistant and will therefore cause relapse and require different drugs
cancers arise from tissues with stem cells
arise from tissues that are self-renewing e.g. epidermis, bone marrow
stem cells can be very few in number but in the long term are responsible for maintenance of the tissue
Cancer stem cell hypothesis
see onenote slides
cancer stem cells may explain relapse
stem cells divide slowly making them less susceptible to chemotherapies that target rapidly dividing cells
