Session 2 - Invasion and metastasis Flashcards
Define invasion
infiltration of local tissues by of cancer cells
define metastasis
a secondary tumour that grows separately from the primary and has
arisen from detached transported cells
What do benign tumours do instead of metastasizing?
Benign tumours tend push in an expansile fashion into
their surroundings rather than infiltrating as malignant cells do and benign tumours NEVER
metastasise.
Why do cancers primary sites need to shed a large number of cells before they can successfully metastasize?
Metastasis is exceedingly infefficient
Is metastasis cancer specific?
Normal physiological mechanisms are hijacked by cancer cells, for example white blood cells use similar mechanisms to move between and through tissues and placental trophoblastic cells invade into the myometrium and endometrium and can even spread to distant sites (e.g. lung).
What are the four main steps of metastasis?
Initial growth and Invasion
Transport to distant sites
Thriving in a new site
Escape immune destruction at each step
What is involved in initial growth and invasion (two steps)
Detachment: either small groups or individual cells must break apart from the main tumour mass
Invasion: these cells must then travel through adjacent tissues
How do cancer cells transport to different sites?
Blood vessels
Lymphatic vessels
Body cavities
How do cancer cells establish themselves in a new site? (three steps)
- Must escape blood or lymphatic vessels ( extravasation)
- Grow at a distant site or escape into surrounding distant tissues (if in body cavity)
- Grow in size at new site
What has to happen to cells for invasion to occur?
Epithelial to mesenchymal transition (alter from epithelial cell phenotype to a more motile stromal cell type)
Give three key features of cancer required for effective invasion
Altered adhesion,
Altered proteolysis,
Increased motility
Give two changes in adhesion required for cancer cells to escape?
Cell to cell
Cell to stroma
Give two molecules involved in cell to cell altered adhesion
Cadherins
Immunoglobulin like receptors
Give a molecular change involved in cell to stroma altered adhesion
Integrins are modified
What are two important types of proteolysing enzymes in invasion?
MMPs and Serine protease
What do MMPs do?
MMP-2 and MMP-4 can digest
collagen type 4 in basement membrane, which is important for early invasion of carcinoma cells
What do serine proteases do?
Important examples include urokinase-like plasminogen activator (uPA), tissue plasminogen activator (tPA) and plasmin
How do cancer cells alter their motility?
Growth factors and cell adhesion molecules can signal into the cell and affect the
state of the actin cytoskeleton, which is important in mediating cell movement.
These signaling pathways interact with the cytoskeleton via the a small G-proteins
that are part of the Rho family
Give an overview of invasion process
Proteolysis creates a new space for a cancer cell to move into
Cells push out cytoplasmic processes at the front of the cell in the direction of travel
New adhesions to stroma are formed in these cytoplasmic extensions using integrins to anchor the cell in a new
position
Integrin signaling to Rho proteins leads to changes in actin filaments to form actin stress fibres
Stress fibres generate traction to pull the back of the cell forwards
De-adhesion at back of the cell (via down-regulation of cadherins if the back of the cell is connected to another
cancer cell or integrins if the back is connected to stroma) allows the cell to be pulled forwards
Why is cancer called “cancer”?
malignant
tumours tend to form an irregular craggy mass, while benign tumours, which have a
pushing and expansile pattern of growth, tend to be smooth.
What is “tethering”?
Malignant cells infiltrate surrounding tissues, resulting in these tumours getting tethered to
surrounding structures. This is clinically useful for diagnosing a lump as malignant. An important example is nipple inversion in breast cancer.
In what type of tissue direction are cancer cells likely to sprad?
Malignant cells tend to infiltrate along paths of least resistance, e.g. between tissue planes
and along neurovascular bundles
Give three ways in which cancer cells are transported to different sites
Blood vessels
Lymphatics
Body cavities
What are two types of entry point for cancer cells moving into blood vessels?
Capillaries and venules (often new vessels which have arisen due to cancer-induced angiogenesis)
Why don’t cancer cells invade arteries?
arteries are resistant to invasion, possibly because of their elastin content, which is not easily
degraded)
What must cancer cells do to get into a blood vessel?
Degrade the basement member and penetrate the endothelium
Why are lymphatics easier to move into than blood vessels?
No basement membrane
What is the name for tumours creating lymphatics
Lymphangiogenesis
Give four examples of cancers traversing body cavities
Colon cancer can invade the peritoneum o Lung cancer can invade the pleurae o Brain cancer can invade the ventricles o Rarely pericardium can be invaded by tumours in the mediastinum
Give three reasons cells in transit are so vulnerable
Embolic trauma
Antibodies
ROS
What protects cancer cells moving through blood vessels from emboic trauma?
Platelets (is this why aspirin is effective in preventing cancer?)
Give a clinical feature of cancer transport
Spread in body cavities can lead to an inflammatory exudate, which can be tested biochemcally to determine if it is an exudate and can be sent for cytology to look for malignant cells
Where do peritoneal effusions gravitate to, and what site does this mean is a likely location for cancer?
Pouch of douglas, which can be felt during a rectal or vaginal examination
What is a distinguishing sign of cancer in lymphatics?
Malignant cells can remin in and extensively permeate lymphatic vessels leading to localized oedema
How do cancer cells undergo extravastion?
They lodge in capillaries and venules
They attach to the endothelium
They then penetrate the endothelium and vascular basement membrane
What are three adhesion molecules important for extravasation?
- Selectins
Immunoglobulin-like adhesion molecules
Integrins
How do cancer cells penetrate the basement membrane?
Proteolytic enzymes as described above (MMPs, serine proteases)
Expansile growth in the capillary may also lead to cells breaking out of a vessel
Where does most of the inefficiency of metastasis come from?
due to failure of cells to successfully colonise the new site. Non-progressive
small deposits can often occur, known as micrometastases (these deposits are sometimes referred to as dormant)
What two features determine site of a metastasis?
- Purely mechanical embolic mechanism, e.g. bowel cancer hepatic portal
circulation lodges in liver capillary bed liver metastasis - Seed/soil, i.e. new tissue must have appropriate environment to support the growth
of a metastasis.
What is the relationship between metastasis and tumour size?
Likely hood of metastasis relates to size of tumour because large numbers of cells need to be shed to generate “seeds”
What are the four most common areas of spread of of blood borne metastasis?
Lung
Bone
Liver
Brain
Give some sites which should be a major site for metastasis but are not
Kidneys get 25% of cardiac output, but few
metastases but the smaller adrenals are a
favourite target of bronchial carcinoma
Cardiac and skeletal muscle account for 40% of
body mass, yet get few metastases
Gastric carcinoma ovaries
GIT gets 10% of cardiac output but few
metastases grow there, although melanoma
occasionally does
Spleen virtually never gets metastases.
Suggest five reasons certain sites may not be appropriate hosts for metastatic cancer?
Balance of local growth factors and growth
inhibitors in a tissue
Local injury might favour metastasis due to
exposed vascular basement membrane or
altered expression of endothelial adhesion
molecules
Presence of chemotactic factors in a tissue
Differing surface recognition mechanisms in
different tissues
Mechanical factors e.g. muscle contraction
could lead to cancer trauma
What two pieces of evidence suggests immune involvement in metastasis?
Immunocompromised people have a higher risk of cancer
Rarely, cancers can regress due to destruction by immune cells, especially melanoma
Give three ways in which cancer cells initiate an immune response?
They can express novel proteins due to mutations
They can express proteins normally only seen in embryos or in “immunologically privileged” sites such as testes
and brain
They can express proteins, often altered by mutation, at extremely high levels
Give three stages at which the immune system modulates cancer
Elimination
Equilibrium
Escape
What is elimination of cancer by immune system?
getting rid of early tumours (also known as immunosurveillance)
What is equilibrium of immune system with cancer?
a state where a cancer has become established but is held in check by the immune system
(sometimes known as dormancy)
What is escape?
where a cancer has developed strategies to evade the immune system and thrive – cancer progression
a. Clonal evolution down regulation of tumour antigens
b. Kill immune cells
c. Grow faster than immune killing
What is the most important role of immunse system in metastasis moderation?
killing of cells during
the metastatic journey (one of the reasons metastasis is inefficient) and suppression of metastases from establishing
themselves.
Why are micrometastasis often dormant?
Due to immunosupression
