Neoplasia 3

Question 1

MECHANISMS OF INVASION AND METASTASIS

Answer 1

1. INVASION. Increased net protease activity causes active degradation of basement membrane and ECM.
   eg. matrix metalloproteinases- type IV collagenase, urokinase.
2. MIGRATION.
   - Mediated by coordinated changes in cytoskeleton and adhesion structures.
   - Stimulated by autocrine growth factors and ECM cleavage products eg. collagen fragments.

Question 2

TUMOUR METASTASIS PATHWAYS

Answer 2

1. TRANSCOELOMIC- (kissing metastasis) Thoracic/abdominal surface tumours. There are few barriers to their spread.
   eg. mesothelioma, ovarian adenocarcinoma.
2. HAEMATOGENOUS- sarcomas (mesenchymal)
3. LYMPHATIC- carcinomas (epithelial- skin/glands)

Regional lymph node involvement is suggestive of WIDESPREAD DISEASE.

Question 3

MESOTHELOMIA

Answer 3

Neoplastic cells spread all over available surfaces, but do not metastasise by lymphatic or haematogenous routes.
Tumour cells can reimplant locally but don’t metastasise to distant sites.
Use the transcoelomic pathway.

Question 4

THE METASTATIC CASCADE

Answer 4

A cascade of steps involved in the haematogenous spread of a tumour.

1. CLONAL EXPANSION
2. Forms a METASTATIC SUBCLONE
3. INTRAVASATION- enters blood vessels
4. TUMOUR CELL EMBOLUS in blood vessels. Platelets may protect the embolus and encourage metastasis.
5. EXTRAVASATION- leaves blood vessels.
6. METASTATIC DEPOSIT
7. ANGIOGENESIS
8. GROWTH

Question 5

TUMOUR EMBOLI

Answer 5

Tumour cells form small emboli once they have entered vessels by intravasation.
Emboli are recognised and attacked by host lymphocytes.
They are then surrounded by platelets- HIDDEN.

EXIT SITE of tumour cells is dependent on:

1. Pattern of drainage of primary tumour.
2. Tumour cell/endothelial cell adhesion molecule interaction.
   - Microenvironment suitability.

Tumours often metastasise to specific sites eg. prostate carcinomas often metastasise to bone.

Question 6

HAEMATOGENOUS SPREAD

Answer 6

More commonly seen in veins than in arteries.
Veins are thin walled, so intra and extravasation is easier.
Possibly:
VENA CAVA -> LUNGS (-> ARTERIES)
PORTAL SYSTEM -> LIVER

Adrenal tumours move from the adrenal veins to the vena cava.

Question 7

HAEMATOGENOUS VS TRANSCOELOMIC SPREAD

Answer 7

In haematogenous spread of tumour cells, masses will be seen THROUGHOUT the organ- in the belly and on the surface.
In transcoelomic, masses are seen only on the SURFACE of the organ.

Question 8

WHERE SHOULD THE FIRST AREAS CHECKED FOR METASTASIS BE?

Answer 8

-Regional lymph nodes
-Liver
Lungs

Question 9

ROUTES OF TUMOUR METASTASIS

Answer 9

From tissues to blood, lymphatic vessels.
Can then travel to spleen.
Liver, lungs and regional lymph nodes should be the first areas checked for metastasis- Rich blood supply/lymphatic drainage.

Question 10

SUPPRESSION OF METASTASIS

Answer 10

Metastatic potential is the cumulative effect of many genetic alterations.
There are a small number of identified genes involved in suppression of metastasis:
Gene encoding E-CADHERIN- E-cadherin is a component of adherence junctions.
It therefore suppresses metastasis by stopping tumour cells separating and metastasising.

Question 11

NECESSITIES FOR SUCCESSFUL TUMOUR GROWTH

Answer 11

Solid tumours greater than 1-2mm diameter. Angiogenesis is switched ON. This allows the tumour to INDUCE and SUSTAIN NEW TUMOUR VASCULATURE.

Complex:

• Recruitment of endothelial cells from pre-existing vessels.
• Endothelial cell proliferation
• Directed migration through the ECM
• Maturation and differentiation of the capillary sprout.
• > ANGIOGENESIS.

Question 12

ANGIOGENESIS

Answer 12

Stimulation of HOST blood vessel growth.
Seen in solid tumours over 1-2mm diameter.
Requires oxygen and nutrients.
(Vascular Endothelial Growth Factor VEGF, acidic and basic fibroblastic growth factors)

Question 13

CONTROL OF ANGIOGENESIS

Answer 13

Control is a balance between angiogenesis stimulating (VEGF) and angiogenesis inhibiting (eg. thrombospondin) factors.
Tumour protease activity can be important in angiogenesis control. It causes breakdown of basement membrane/ECM proteins, allowing release of angiogenic/antiangiogenic ECM-bound factors, including VEGF.

Question 14

NORMAL TISSUE VASCULATURE

Answer 14

The mature network of blood vessels is stable, with structure and function of wall and network being appropriate to location (eg. arteries vs veins)

Question 15

TUMOUR VASCULATURE

Answer 15

An evolving network of unstable vessels, with ABNORMAL structure and function, inappropriate to the vessel location.

Question 16

STAGES IN TUMOUR ANGIOGENESIS

Answer 16

• Endothelial cell recruitment
• Endothelial cell proliferation
• Directed migration through the ECM
• Maturation and differentiation of the capillary sprout.

Question 17

CHARACTERISTICS AND FUNCTIONS OF TUMOUR VASCULATURE

Answer 17

• Tumour blood vessels are dilated, tortuous and permeable.
• Vessel leakiness means perivascular fibrin can be involved in tumour stroma formation.
• Endothelial cells produce growth factors -> Platelet Derived Growth Factor (PDGF), IL-1 (interleukin) -> STIMULATE TUMOUR CELL GROWTH.

Tumour associated lymphatics are essential for metastasis of solid tumours to regional lymph nodes.

In human tumours, there is a strong correlation between levels of VEGF and lymphatic metastasis.