Session 2 - Invasion and metastasis

Question 1

Define invasion

Answer 1

infiltration of local tissues by of cancer cells

Question 2

define metastasis

Answer 2

a secondary tumour that grows separately from the primary and has
arisen from detached transported cells

Question 3

What do benign tumours do instead of metastasizing?

Answer 3

Benign tumours tend push in an expansile fashion into
their surroundings rather than infiltrating as malignant cells do and benign tumours NEVER
metastasise.

Question 4

Why do cancers primary sites need to shed a large number of cells before they can successfully metastasize?

Answer 4

Metastasis is exceedingly infefficient

Question 5

Is metastasis cancer specific?

Answer 5

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).

Question 6

What are the four main steps of metastasis?

Answer 6

Initial growth and Invasion
Transport to distant sites
Thriving in a new site
Escape immune destruction at each step

Question 7

What is involved in initial growth and invasion (two steps)

Answer 7

Detachment: either small groups or individual cells must break apart from the main tumour mass
 Invasion: these cells must then travel through adjacent tissues

Question 8

How do cancer cells transport to different sites?

Answer 8

Blood vessels
 Lymphatic vessels
 Body cavities

Question 9

How do cancer cells establish themselves in a new site? (three steps)

Answer 9

• 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

Question 10

What has to happen to cells for invasion to occur?

Answer 10

Epithelial to mesenchymal transition (alter from epithelial cell phenotype to a more motile stromal cell type)

Question 11

Give three key features of cancer required for effective invasion

Answer 11

Altered adhesion,
 Altered proteolysis,
 Increased motility

Question 12

Give two changes in adhesion required for cancer cells to escape?

Answer 12

Cell to cell

Cell to stroma

Question 13

Give two molecules involved in cell to cell altered adhesion

Answer 13

Cadherins

Immunoglobulin like receptors

Question 14

Give a molecular change involved in cell to stroma altered adhesion

Answer 14

Integrins are modified

Question 15

What are two important types of proteolysing enzymes in invasion?

Answer 15

MMPs and Serine protease

Question 16

What do MMPs do?

Answer 16

MMP-2 and MMP-4 can digest

collagen type 4 in basement membrane, which is important for early invasion of carcinoma cells

Question 17

What do serine proteases do?

Answer 17

Important examples include urokinase-like plasminogen activator (uPA), tissue
plasminogen activator (tPA) and plasmin

Question 18

How do cancer cells alter their motility?

Answer 18

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

Question 19

Give an overview of invasion process

Answer 19

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

Question 20

Why is cancer called “cancer”?

Answer 20

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.

Question 21

What is “tethering”?

Answer 21

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.

Question 22

In what type of tissue direction are cancer cells likely to sprad?

Answer 22

Malignant cells tend to infiltrate along paths of least resistance, e.g. between tissue planes
and along neurovascular bundles

Question 23

Give three ways in which cancer cells are transported to different sites

Answer 23

Blood vessels
Lymphatics
Body cavities

Question 24

What are two types of entry point for cancer cells moving into blood vessels?

Answer 24

Capillaries and venules (often new vessels which have arisen due to cancer-induced angiogenesis)

Question 25

Why don’t cancer cells invade arteries?

Answer 25

arteries are resistant to invasion, possibly because of their elastin content, which is not easily
degraded)

Question 26

What must cancer cells do to get into a blood vessel?

Answer 26

Degrade the basement member and penetrate the endothelium

Question 27

Why are lymphatics easier to move into than blood vessels?

Answer 27

No basement membrane

Question 28

What is the name for tumours creating lymphatics

Answer 28

Lymphangiogenesis

Question 29

Give four examples of cancers traversing body cavities

Answer 29

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

Question 30

Give three reasons cells in transit are so vulnerable

Answer 30

Embolic trauma
Antibodies
ROS

Question 31

What protects cancer cells moving through blood vessels from emboic trauma?

Answer 31

Platelets (is this why aspirin is effective in preventing cancer?)

Question 32

Give a clinical feature of cancer transport

Answer 32

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

Question 33

Where do peritoneal effusions gravitate to, and what site does this mean is a likely location for cancer?

Answer 33

Pouch of douglas, which can be felt during a rectal or vaginal examination

Question 34

What is a distinguishing sign of cancer in lymphatics?

Answer 34

Malignant cells can remin in and extensively permeate lymphatic vessels leading to localized oedema

Question 35

How do cancer cells undergo extravastion?

Answer 35

They lodge in capillaries and venules
They attach to the endothelium
They then penetrate the endothelium and vascular basement membrane

Question 36

What are three adhesion molecules important for extravasation?

Answer 36

• Selectins
   Immunoglobulin-like adhesion molecules
   Integrins

Question 37

How do cancer cells penetrate the basement membrane?

Answer 37

Proteolytic enzymes as described above (MMPs, serine proteases)
 Expansile growth in the capillary may also lead to cells breaking out of a vessel

Question 38

Where does most of the inefficiency of metastasis come from?

Answer 38

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)

Question 39

What two features determine site of a metastasis?

Answer 39

1. Purely mechanical embolic mechanism, e.g. bowel cancer  hepatic portal
   circulation  lodges in liver capillary bed liver metastasis
2. Seed/soil, i.e. new tissue must have appropriate environment to support the growth
   of a metastasis.

Question 40

What is the relationship between metastasis and tumour size?

Answer 40

Likely hood of metastasis relates to size of tumour because large numbers of cells need to be shed to generate “seeds”

Question 41

What are the four most common areas of spread of of blood borne metastasis?

Answer 41

Lung
Bone
Liver
Brain

Question 42

Give some sites which should be a major site for metastasis but are not

Answer 42

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.

Question 43

Suggest five reasons certain sites may not be appropriate hosts for metastatic cancer?

Answer 43

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

Question 44

What two pieces of evidence suggests immune involvement in metastasis?

Answer 44

Immunocompromised people have a higher risk of cancer

 Rarely, cancers can regress due to destruction by immune cells, especially melanoma

Question 45

Give three ways in which cancer cells initiate an immune response?

Answer 45

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

Question 46

Give three stages at which the immune system modulates cancer

Answer 46

Elimination
Equilibrium
Escape

Question 47

What is elimination of cancer by immune system?

Answer 47

getting rid of early tumours (also known as immunosurveillance)

Question 48

What is equilibrium of immune system with cancer?

Answer 48

a state where a cancer has become established but is held in check by the immune system
(sometimes known as dormancy)

Question 49

What is escape?

Answer 49

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

Question 50

What is the most important role of immunse system in metastasis moderation?

Answer 50

killing of cells during
the metastatic journey (one of the reasons metastasis is inefficient) and suppression of metastases from establishing
themselves.

Question 51

Why are micrometastasis often dormant?

Answer 51

Due to immunosupression