L10 Metastasis, genetic variation and stem cells

Question 1

Metastasis

Answer 1

the spread of cancer cells from one site to another site

Question 2

Angiogenesis

Answer 2

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

Question 3

Hypoxia induces VEGF which induces sprouting

Answer 3

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

Question 4

Initial stages of metastasis involve an EMT

Answer 4

see onenote

cells lose epithelial characteristics and become migratory - allows them to invade the surrounding tissue and enter the vasculature, a process called intravasation

Question 5

How can we find genes that regulate metastasis?

Answer 5

see onenote

Question 6

TF Twist promotes metastasis

Answer 6

see onenote slides

twist promotes invasiveness and metastasis

Question 7

Twist drives EMT

Answer 7

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

Question 8

Metastasis involves an EMT

Answer 8

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

Question 9

E-cadherin is a tumour suppressor

Answer 9

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

Question 10

Circulating tumour cells in the vasculature

Answer 10

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)

Question 11

Formation of secondary tumour involves MET

Answer 11

see onenote diagram

involves CTCs leaving the blood vessel (extravasation) to seed the new tumour

growth of the second tumour thought to involve MET

Question 12

What is more dangerous? CTCs or CTMs?

Answer 12

see onenote

CTMs appear to be much better at metastasising

Question 13

The CellSearch system

Answer 13

designed to detect circulating tumour cells

blood samples taken from patient

immunomagnetically sorts the cells, immunostains them and presents them for inspection

Question 14

Principle of CellSearch system

Answer 14

see onenote

Question 15

Counting CTCs has prognostic value

Answer 15

see onenote

does seem to be a good way of tracking the progress of some types of cancer

Question 16

Cancer heterogeneity and clonal evolution

Answer 16

see onenote

a tumour is genetically heterogenous (made up of cells with different mutations) and this genetic makeup evolves over time

Question 17

sequencing of a cancer reveals the evolutionary tree of mutations

Answer 17

see onenote

able to piece together a family tree of cell lineages

Question 18

Evolution and genetic variation

Answer 18

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)

Question 19

Chromosomal instability leads to aneuploidy

Answer 19

CIN = gain/loss of whole chromosome or fractions of chromosomes

aneuploidy = abnormal number of chromosomes

Question 20

How can aneuploidy arise?

Answer 20

see onenote

1. mitotic checkpoint defects
2. merotelic attachments
3. multipolar mitotic spindles

Question 21

single cell RNAseq of glioblastoma

Answer 21

see onenote slides

great variability at the chromosome and gene level

Question 22

sequencing reveals colorectal cancer “landscape”

Answer 22

see onenote

Question 23

colorectal carcinoma and APC

Answer 23

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)

Question 24

BRAF is a MAP Kinase

Answer 24

see onenote

Question 25

BRAF and melanoma

Answer 25

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

Question 26

Cancer heterogeneity and clonal evolution - BRAF inhibitor

Answer 26

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

Question 27

cancers arise from tissues with stem cells

Answer 27

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

Question 28

Cancer stem cell hypothesis

Answer 28

see onenote slides

cancer stem cells may explain relapse

stem cells divide slowly making them less susceptible to chemotherapies that target rapidly dividing cells