Metastasis

Question 1

What is metastasis?

Answer 1

Spread of cancer cells from place of origin in the body

Question 2

What happens to the chance of metastasis as tumour size increases?

Answer 2

Chance of metastasis increases

Question 3

Is metastasis a regular or rare event?

Answer 3

Rare

Question 4

Describe the mechanism of invasion + metastasis

Answer 4

1) Primary tumour formation leads to angiogenesis

2) Localised invasion
= Tumour cells start moving towards blood vessels

3) Intravasation
= Tumour cells breaks pass endothelial cell barrier
= Interact w/ blood components (e.g. platelets, lymphocytes)
= A lot of cancer cells are lost due to these interactions

4) Transport through circulatory system
= Can get stuck in capillaries that are highly vascularised

5) Extravasation
= Cancer cells migrate out of blood vessel

6) Formation of micrometastasis
= Need environment suitable for proliferation
= Small tumour produced

7) Colonisation - Formation of macrometastasis

Question 5

Is metastatic efficiency high or low?

Answer 5

Low

Cancer cells are lost at each stage of metastasis
Death rates in micro metastasis can overcome proliferation -> preventing formation of macrometastasis

Question 6

Name the 3 types of secondary tumours

Answer 6

Single, dormant cancer cells

Micrometastasis

Active, angiogenic metastasis

Question 7

Is tumour dormancy different or the same in different tumour types?

Answer 7

Different

Question 8

What other system besides circulatory can metastatic cells travel through?

Answer 8

Lymphatic system

Question 9

Describe the “seed and soil” theory

Answer 9

Tumours need to have the right microenvironment to grow

Micrometastasis in certain tissues

Question 10

What are the problems w/ the “seed and soil” theory?

Answer 10

Doesn’t explain ALL tumour metastasis

Contralateral metastasis = rare (why only 1 kidney/breast but not the other?)

Question 11

How can cancer cells move from epithelial tissue -> mesenchymal tissue (blood + connective)?

Answer 11

Epithelial-mesenchymal transition (EMT)
= Lose epithelial phenotype
= Gain mesenchymal phenotype

Question 12

Describe EMT model

Answer 12

Epithelial state
= Contains E-cadherins -> link cells together
= E-cadherin linked with plasma membrane via cytoplasmic tail
= Cytoplasmic tail linked w/ beta-catenin which is linked w/ alpha-catenin

E-cadherin releases beta-catenin
Beta-catenin translocates into nucleus + binds to TFs
-> mesenchymal change

Question 13

What evidence supports EMT?

Answer 13

Cellular changes
Western blots

Loss of epithelial markers
= E-cadherin
= beta-catenin
= alpha-catenin
= cytokeratin

Gain of mesenchymal markers
= Fibronectin
= Vimentin
= N-cadherin

Change also associated w/ expression of twist (transcription factor)

Question 14

How do primary tumours + secondary tumours have the same histopathology?

Answer 14

EMT may be reversible (depending on stromal signals)

Mesenchymal-epithelial transition (MET)

Allows secondary tumours to stay static + grow

Question 15

Name the 2 forms of metastasis in bone

Answer 15

Osteolytic = bone (Ca deposit) breakdown

Osteoblastic = bone overgrowth

Question 16

What type of cancer initiates osteolytic metastasis?

Answer 16

Breast cancer

Question 17

How does breast cancer initiate osteolytic metastasis?

Answer 17

Secrete PTHrP (parathyroid hormone related peptide)

• > Activates osteoclasts by inhibiting osteoperigin (OPG = inhibitor of osteoclasts)
• > Osteoclasts digests bone
• > Release growth factors from stroma which goes to tumour cells

Question 18

Describe the metastasis + drug resistance model

Answer 18

As secondary tumour is formed from DTCs, few cells become drug resistant

Under targeted therapy, drug-sensitive cancer cells express factors (therapy-induced secretome) that fight back

• > Accelerate growth of drug-resistant cells
• > Supports survival of drug-sensitive cells

Drug-resistant cells left can cause relapse

Question 19

What are heterogeneous disseminated tumour cells (DTCs)?

Answer 19

Cancer cells that have left the primary tumour + survived in the circulation to land in a distant organ