Lecture 9 - metastasis

Question 1

Describe the metastatic cascade

Answer 1

Metastasis is a multi-step process.
Metastasis encompasses tumour growth/angiogenesis, detachment/invasion, transport in circulation, arrest in distant organs, extravasation, and establishment at secondary sites.
Invasion is an early step in the metastatic cascade.
Encompasses whole organism/host
Primary tumour is growing, angiogenesis required to exceed certain size to access oxygen/nutrients from blood, once tumour reaches certain size some of these cells migrate out ofthe tumour - detach and invade, get into the bloodstream or the lymphatic vessels and through those networks are transported around the body and arrest in distant organs/ Once they arrest in distant organs they have to adhere to the vessel wall in that distant site, then have to extravasate, invade back through the endothelial layer into the surrounding tissue. Then have to establish a microenvironment suitable for the metastasis to grow, then have to proliferate and once the metastasis reaches a certain size also needs angiogenesis

Question 2

Describe modes of metastasis

Answer 2

A minority of tumour cells have metastatic potential (red) Cancer stem cell theory.
The capacity to metastasise is displayed by the whole tumour cell population.
Gene expression profiling of breast primary tumours predicts disease outcome. A poor-prognosis signature predicts the development of metastases, compared to a good-prognosis signature.
Poor prognosis tumours harbour subpopulations of cells with a tissue-specific expression profile.
Acquisition of many mutant genes not necessarily required for metastasis because EMT-TFs are pleiotropic.

Question 3

What are Circulating tumour cells (CTCs)?

Answer 3

Cancer cells transiting in blood/lymphatic vessels following intravasation.
Inefficient – hostile environment, most die due to anoikis, lack of stromal support, hydrodynamic shear forces.
CTCs may recruit platelets and form microthrombi to mitigate this.
CTC burden predicts survival of metastatic breast cancer patients.
Immobilization using antibodies, e.g. EpCAM (CellSearch), microfluidic devices based on cell size (in development).
Problem: rare, persist for very short time in circulation.

Question 4

Describe Dispersion via the lymphatic system

Answer 4

Invasion and intravasation into lymphatic vessels at tumour periphery.
Lymphatic vessels drain into blood system.
Easy to detect by IHC.
Routine for breast cancer prognostic determination.
Removal of draining lymph nodes does not affect patient survival.
Useful surrogate markers.
Easy to detect cells in lymph nodes when have metastasised
Prognosis - How many cells have arrived in lymph nodes, how many lymph nodes have metastatic cancer cells in them
only useful as prognostic indicators = cutting out lymph nodes has no effect on patient survival
Surrogate markers – can’t target them therapeutically but useful for prognostic determination
The bigger the tumour at the time of diagnosis the poorer the prognosis
The more lymph nodes contain cancer cells the worse the survival outcome

Question 5

Describe extravasation

Answer 5

Penetration of arterial wall (mechanisms as per invasion/intravasation).
Alternative: proliferation in lumen.
Endothelial cells lining blood vessels in different organs express different adhesion molecules.
Tumour cells expressing the corresponding receptor may arrest in specific locations.
Metastasis depends on two parameters:
Frequency that cells are trapped.
Adaptation to new microenvironment.
The cancer cells penetrate the arterial wall
Can get trapped in capillary vessels and proliferate in the lumen, displaces endothelial layer and gain access to surrounding tissue

Question 6

Describe the Fates of cells in micrometastases

Answer 6

Death (most cells undergo apoptosis).
Quiescence or dormancy.
Single solitary cell (G0-G1 arrest).
Micrometastatic lesion that cannot recruit blood supply (angiogenic dormancy) is kept at sub-clinical level by immunosurveillance, or anti-growth signals from normal tissue ECM.
Resume proliferation (growing micrometastasis).
Colonization is rate-limiting step in metastatic cascade.

Question 7

Explain the process of priming the metastatic niche

Answer 7

Signals from primary tumours ‘prepare’ distant sites by forming a ‘pre-metastatic niche’.
Hypoxia in the primary tumour triggers production of lysyl oxidase (LOX).
LOX induces structural changes at the secondary site.
Structural changes at the secondary site recruit bone marrow-derived cells (BMDCs).
BMDCs colonize secondary site and upregulate integrins, cytokines, accelerate angiogenesis.
High LOX in primary tumours correlates with increased risk of metastasis and death.
Potential therapeutic target: block LOX to prevent initiation of the pre-metastatic niche.