L8 - Invasion And Metastasis

Question 1

Describe the invasion-metastasis cascade.

Answer 1

1. Primary tumor formation
2. Localised invasion
3. Intravasation
4. Transport through circulation
5. Arrest in microvessels of various organs
6. Extravasation
7. Formation of a micrometastasis
8. Colonisation-formation of a macrometastasis

Question 2

What is metastatic inefficiency?

Answer 2

The sequence of steps in the invasion-metastasis cascade is completed infrequently.

Question 3

What is the least-efficient step of invasion-metastasis cascade?

Answer 3

Colonisation

Depends on the adaption of disseminated cancer cells to the microenvironment of this tissue

Question 4

How do we differentiate a benign tumor vs metastasized tumor?

Answer 4

Stain with laminin (green)

A differentiated tumor (benign) have visible, clean borders/boundaries, make them easy to remove via surgery

Vs

Invasive tumor can observe basement membrane has broken down which shows that cells have started to metastasize

Question 5

Patterns of invastion

Answer 5

• One by one in single file
• Collective invasion

Question 6

As melanoma cells are moving together through a collagen matrix (blue), they still
adhere to one another through adherent junctions that are formed by ___________
molecules (red).

Answer 6

E-cadherin

Answer 7

Fibroblast —> immune cells
Tissue immafiomyeloid stajjcells

Question 8

What do macrophages secrete?

Answer 8

Metalloproteinase (MMP) is released.
Dissolve the ECM molecules that confined individual cells, creating space for carcinoma .

Question 9

How are MMPs released?

Answer 9

• MT1-MMP (protease) enable carcinoma cells to degrade basement membrane
• direct contact with stroma. MT1-MMP cleaves pro-MMP2-2 made by stromal cells, convert into active, soluble protease
• MT1-PPM partially cleaves collagen I
  Activated MMP-2 degrades the initially formed collagen i have for change

Question 10

When are cells able to carry out locomotion?

Answer 10

• exposure to mitogenic growth factors
• Epithelial cells: induced by hepatocyte growth factor (HGF)
• eg. Breast cancer : induced by EGF

Question 11

Describe the steps leading up to the locomotion of cells.

Answer 11

1. Cytoplasm extends, protrusion from cell surface of lamellipodia (actin polymerization at plus end)
2. Cell surface protease degrade ECM
3. Secrete integrins to construct new attachment with ECM
4. Break adhesion at lagging edge (myosin II —> contraction)
5. Re-deploy cytoplasm and plasma membrane at leading edge

Question 12

What is EMT?

Answer 12

Epithelial to mesenchymal transition

Question 13

What is TNF-alpha?

Question 14

What are the factors that determine where the higher likelihood of metastasis happens?

Answer 14

“Seed and soil” hypothesis: finding compatible home

• availability of supportive factors for survival and proliferation
• specific chemical messages from target organs (difference between microenvironment)
• capillaries form vascular beds expressing tissue specific molecules on their luminal surface and offering docking sites
• negative interaction: tissue repel cancer cells

Question 15

What do mammary carcinoma cells within a primary tumor express and what is the resulting product?

Answer 15

TGF-beta which induce the production of angiopoietin-like protein 4 (Angptl4)

Question 16

Describe the extravasation process.

Answer 16

1. Cancer cell circulates in the blood vessel
2. It adheres to the endothelium
3. Blocks the flow of platelets which help to degrade the endothelial cells
4. Platelets also lead to angiogenesis
5. Transendothelial migration by degrading basement membrane and extracellular matrix with MMPs, cell division
6. Infiltration into target tissue by adapting to microenvironment

Question 17

What is the rate limiting step of metastasis?

Answer 17

Colonization

Question 18

Describe the evolution of colonization?

Answer 18

1. Genetically heterogenous primary tumor population seeds equally heterogenous micrometastases
2. Removal of primary tumor
3. Residual micrometastases —> metastatic dissemination
4. New dispersed cells all share common origin —> secondary “shower”, similar genetics

Question 19

What is the significance/importance of EMT for cancer cells?

Answer 19

• for motility and invasiveness that cannot be achieves in normal tissues
• EMT is also used during embryogenesis

Question 20

Describe the gene expression of important epithelial and mesenchymal cell markers.

Answer 20

E-cadherin: strong cell-cell adhesion, repressed during EMT
Cytokeratins: repressed during EMT
Vimentin: intermediate filament component in mesenchymal cells cytoskeleton ( increase in tumor cells)
Fibronectin: extracellular matrix protein secreted by mesenchymal cells (increase in tumor cells)