What is metastasis and why is it so harmful?
- Metastasis is the process by which some of the tumour cells leave the primary tumour, travel to a distant site via a circulatory system, and establish a secondary tumour. It is one of the hallmarks of cancer. *
- Primary tumours are only responsible for 10% of cancer deaths. However they can be sometimes harmful – exert pressure/invade on surrounding tissues, obstruct passageways (e.g. colon), stop vital functions from occurring.
- 90% of cancer death is due to metastasis:- as they can cause damage in other parts of body
- E.g. brain, bones, lung liver - which would have harmful consequences on vital functions.
- Metastasis can also cause secondary infections – bacteria can colonise the damaged tissue walls and damaged blood vessels can lead to haemorrhage.
What factors determine the secondary site selection in metastasis?
- Seed and soil theory – ‘when a plant goes to seed, its seeds can only grow if they fall on congenial soil’. I.e. the ability of the tumour’s colonisation will depend on interactions between cancer cells (seeds) and microenvironment (soil) – i.e. area they invade.
- Appropriate growth factors or extracellular matrix environment – they signal to mass of tumour for individual cells to move to another location. E.g. VEGF, platelet derived growth factor.
- Compatible adhesion sites on the endothelial lumenal surface.
- Selective chemotaxis at which the organ producing some soluble attraction factors to the tumour cells – chemical attractants on host cells to bring the tumour cells induces a chemical response so that tumour cells will enter.
- Carrier platelets can target tumour cells to damaged tissues which are easier to invade.
Give an overview of the steps of the metastatic cascade.
- Cells become malignant
- Invasion of the BM
- Intravasation of blood vessels (or lymph vessels)
- Extravasation into new tissues.
- Colonisation and proliferation – most inefficient as majority of cells die here.
Describe how cells become malignant in metastasis.
- Acquisition of the invasive and metastatic phenotype is an early event in cancer progression.
- How do cells become malignant/metastatic?
- –> Cell change their appearance by undergoing the epithelial-mesenchymal transition (EMT) where they adopt a feature of mesenchymal cells.
- –> EMT also happens in embryogenesis and wound healing.
- –> It involves reorganisation of the actin cytoskeleton which will the cells the ability to move.
- –> Also involves changes in protein expression - E-cadherin’s + cytokeratins expression is repressed (markers of ECs) while is vimentin (component of mesenchymal cytoskeleton) is induced as well as N-cadherin. CDH1 gene that encodes E-cadherin is repressed by methylation.
- –> E-cadherin acts to adhere epithelial cells to one another. N-cadherin replaces it and it makes carcinoma cells more attracted to stroma, as well as being much weaker and promoting cell motility they cause the cells to become invasive.
- –> There are also changes in integrin expression and alterations in cytoskeleton will active Ras which mediates actin/myosin cell movement.
- –> The EMT is reversible and once cells settle in new environment they undergo a MET.
Explain invasion of the BM and what enzymes mediate this?
Cells will break through the basal lamina and enter the stroma/connective tissue.
Mediated by:-
- Matrix metalloproteinases (MMP) – are zymogen proteases secreted from stromal cells.
- - They act to dissolve the ECM molecules (such as collagen and fibronectin) and hence give space for the epithelial cells to move around.
- - MMPs have roles in normal cell division, as every time a new cell is created space in ECM has to be created for it.
- - However in EMT in cancer, the MMPs carry out a continuous proteolysis.
- - 16 members in the family, with zinc ion in their catalytic domain (hence the ‘metallo’). - Urokinase plasminogen activator (uPA) - it’s a non-MMP protease secreted by macrophages which will bind EC receptors and help activate MMPs.
- - It cleaves plasminogen –> plasmin that goes onto cleave and activate other MMPs. It is bound on surface of tumour cells by means of a specific receptor.
Once in stroma, the carcinoma can interact with platelets, lymphocytes and other blood components. They have close contact with capillaries, giving them a lot of nutrients and oxygen etc.
Describe the process of intravasation.
Once the tumour cells are in the stroma, they can squeeze through endothelial cells to enter the blood stream.
Before invading BM, carcinomas can dispatch angiogenic factors to induce formation of new blood vessels in stroma.
Describe the process of migration. Why is it so dangerous to tumour cells and how do they overcome it?
– They travel through blood/lymph circulatory systems to other parts of body.
Migration is very dangerous for cancerous cells due to:=
— The cells need stromal support and if they don’t get it they undergo apoptosis.
— Sheer force of the blood is also dangerous and can damage cells.
— Presence of immune cells (macrophages and complement proteins) in the blood is dangerous.
— High oxygen levels which is toxic for most cancer cells.
- –> Cancer cells are often escorted by platelets in the blood, which will shield them from the mechanical stress and immune cells. The platelets may also help guide them to damaged tissues which are easier to invade.
- Can also migrate through the lymph system - almost all tissues have lymphatic vessels that cancerous cells can enter. Tumours can induce lympangiogenesis by secreting VEGF-C.
Describe the process of extravasation.
- The tumours will travel in the blood until they get stuck in a capillary bed.
- Or they can be homed to tissues by chemokines – e.g. HIF1-a induces expression of CXCR4 in some breast cancers which will take them to lung/liver.
- Cells adhere to capillary bed to fibrinogen by P-selectin along with interactions between integrins and E-cadherins.This causes arrest of cells in capillary beds.
- Their binding to endothelial layer exposes glycoproteins which the cancer cells can digest via MMPs and they can invade stroma.
- Or the tumour may grow so large that it destroys the vessel wall.
Describe the process of colonisation.
- Once in tissue, they will start to form tumour mass and ‘colonise’.
- -This a very inefficient process since cancerous cells are new to this foreign environment.
- Most of the ‘micro-metastases’ will not survive or they can lie dormant for many years. (conventional chemotherapies do not target these dormant cells)
- The foreign environment is harsh as it lacks the growth and survival factors that cancer cells require.
- Cancer cells will also need to induce angiogenesis to successfully form a secondary tumour – hypoxic conditions will upregulate angiogenic factors.
