eBook Chapter 2 - Tumour Biology

Question 1

What are the 4 properties of a malignant cell?

Answer 1

1. detachment from primary mass
2. invasion of ECM e.g. basement membrane
3. adhesion to endothelium and extravasation
4. colonisation of and survival in secondary organ

Question 2

Malignant is associated with the loss of what 4 processes?

Answer 2

1. density dependent inhibition of growth
2. contract inhibition of movement
3. anchorage dependence
4. adhesion

Question 3

What are the 6 steps of the metastatic cascade?

Answer 3

1. Detachment from the primary tumour mass (which requires reorganisation of the cell-cell and cell-matrix adhesion complexes)
2. Invasion through the basement membrane into adjacent stroma (which requires secretion of MMPs, restructuring the ECM and migration of the cells)
3. Intravasation into the blood vessels (this requires interaction of cancer cells with endothelium
4. survival of cancerous cell sin blood stream and avoidance of the immune system
5. extravasation through integration with the endothelial lining inside vessels (and interaction with selectins and integrins)
6. establishment of micro-metastases at the secondary site

Question 4

Describe EMT and its transcription factors

Answer 4

Epithelial Mesenchymal Transition

• program that regulates invasion and metastasis
• physiologically, it is implicated in various stages of embryonic development and wound healing
• tumour epithelial cells switch to EMT to increase their mobility allowing them to invade and metastasise
• EMT is a reversible process and is governed by transcription factors including Snail, Slug, Twist and Zeb1/2.

Question 5

Describe normal adhesion
How it is loss in cancer
The consequences for its loss
(Next flashcard details E-cadherin loss)

Answer 5

• normally, epithelial cells are helps together by adhesion complexes
• there are 3 types of complexes that support cells: tight junctions, adheres junctions and desmosomes
• adhesion molecules of the cadherin family are the main adhesion receptors in adherens junctions and desmosomes, tight junctions are controlled by junctional adhesion molecules (JAMS)
• adhesion receptors are down regulated in metastatic cancer cells
• in particular, downregulation of E-cadherin is common via inactivating mutations, epigenetic silencing, proteolytic cleavage and proteosomal degredation. Additionaly E-cadherin loss cold be part of EMT

Question 6

Describe in detail the loss of E-cadherin

Answer 6

• E-cadherin is anchored to actin filament of cytoskeleton by alpha and beta-catenins
• if free beta-catenin accumulates in the cytoplasm it is phosphorylated in combination with the APC protein and is degrading in the proteasome.
• beta-catenin is also a key player in Wnt signalling pathway
• when APC gene is mutated, beta-catenin accumulates in cuytoplasm, migrates to the nucleus and associates with Tcf/LEF and other TFs thus activating EMT programme

Question 7

Describe tissue invasion

Answer 7

• invasion of tissues requires matrix metalloproteinases (MMPs), secreted by stromal and tumour cells, degrade ECM and allow the malignant cell to invades and move by amoeboid of mesenchymal movement

Question 8

Describe hypoxia and its consequences

Answer 8

• cells in the middle of the tumour mass become hypoxic as the diffusion limit for oxygen is about 100um
• cells growing away from the source of oxygen undergo selection and only those able to adapt sivirve
• hypoxia drives changes in metabolism and induces tumour angiogenesis
• cancer cels can reprogram their glucose metabolise, even in the presence of oxygen, if it gives them a growth advances over normal cells, this is called the glyolytic switch and involves the upregulation of glycolysis
• HIFs are the major players in the initiation of the glycolytic switch
• in hypoxic condition, HIFs accumulate and are transported t the nucleus where they bind to hypoxia responsive elements and induce transcription of glycolysis enzymes (e.g. GLUT1) and angiogenesis genes (e.g. VEGF, Ang2, NOS, PDGF-B0)
• thus hypoxia induces angiogenesis so tumours undergo the angiogenic switch, secreting factors that cause continous sportuong of the normally quiescent vasculature
• there are different mechanism of tumour vascularisation including, recruitment of EPCs, insuscetive angiongeneic, sprouting angiotensin, vasculogenic mimicry, vessel co-option
• the newly formed vessels in tumours are immature, branched and distorted with an uneven diameter. this leads to erratic blood flow and leakiness
• the site of metastasis are determined by many factors and even cells that do metastasise do not necessarily survive and colonise the secondary tissue. metastasis is very inefficient