Molecular Basis of Cancer 2

Question 1

What is meant by cells having limitless replicative potential?

Answer 1

Feature of cancer cells
Has unrestricted proliferative capacity
Able to divide indefinitely without undergoing cellular senescence and mitotic catastrophe.

Question 2

What are the six hallmarks of cancer?

Answer 2

Sustain proliferative signalling
Evade growth suppressors
Activate invasion and metastasis
Enable replicative immortality
Induced angiogenesis
Resist cell death

Question 3

What are the two barriers in non cancerous cell for replicative immortality?

Answer 3

Senescnes - cells exisintg long term in a non growing but viable state.
Crisis - apoptopic death of cells

Question 4

What is a telomere?

Answer 4

Consists of short nucleotide sequences, guanine rich, that are repeated multiple times, act as a cap over the chromosome
Are maintained by telomerase enzymes
Tends to decrease repeat length from gamete to older individuals, suggesting reduced during each division, progressive shortening of telomeres over lifespan.
Loss of telomeres results in cell senescence.

Question 5

What is the normal process by which cell senescence occurs in non-cancerous cells with a functional p53 gene?

Answer 5

Replication - telomerase expression maintains telomere length
Replication - telomerase is not active - telomeres are progressively shortened - continues for 50-70 divisions
Expression of functional p53 protein
Then checkpoint activation and cellular senescence oocurs as telomeres too short.
Senescent cell.

Question 6

What happens in a cell with shortened telomeres and non functional p53?

Answer 6

Shortened telomeres
No expression of functional p53
Activation of salvage and non-homolough end joining pathways
Results in dicentric chromosomes.
Undergoes metaphase and anaphase pulling apart dicentric choromsome.
This create new double stranded breaks. (this is known as the brdige-fusion breakage cycle)
Is telomerase is expressed cancer develops
If telomerase is not expressed mitotic catastrophe occurs.

Question 7

What is the bridge-fusion-breakage cycle?

Answer 7

Occurs in cells with shortened telomeres still undergoing replication - sign of replicative disfunction
Inactive p53 gene expression
Non-homologous end joining and salvage pathway results in dicentric chromosomes (joining of parts of choromsomes so two centromeres per chromosome)
Then undergoes metaphase and anaphase resulting in dsDNA breakage.
Process repeats, resulting in high genomic instability.

Question 8

What is mitotic catastrophe?

Answer 8

A mode of cell death due to abnormal initiation or progression of the cell cycle.
Helps prevent the formation of cancerous cells.

Question 9

What is the function of hTERT telomerase?

Answer 9

Elongates telomeric DNA by extending it in hexanucleotide sequences.
May be activated during bridge-fusion-breakdage cycle
Leads to replicative immortality and avoidance of mitotic catastrophe.

Question 10

What signalling helps regulate cancer metastasis?

Answer 10

Intrinsic cell singalling and mutations
Signals from the tissue environment.

Question 11

What is the multi-step hypothesis model of carcinogenesis?

Answer 11

Carcinogenesis requires the accumulation of multiple mutations.
Mutations arise independently in different clonal cells resulting in subclones with varying abilities to grow, invade, metastases and respond to therapy.
Over time as tumours grow in size more mutations are acquired, tumours become more aggressive and acquire greater malignant potential - this is known as tumour progression.

Question 12

What is meant by tumour progression?

Answer 12

Over time as the tumour grows it acquire new mutations, becomes more aggressive and has higher malignant potential.

Question 13

What is the clonal selection process in cancer cells?

Answer 13

First mutation - gives slight growth advantage
Second mutation - progeny cell, more uncontrollable growth and form benign tumour
Third mutation - in progeny cells, overcome TME constrainsa nd outgrowth other masses with same genetic changes
Fourth mutation - progency metastasis via blood stream and stable daughter colonies at other sites.

Some cells in a given tumour will share genetic mutations, acquire early in their evolutionary history.
Can take decades for required mutation to occur, hence cancer risk increases with age.

Question 14

How does the multip-step hypothesis of cancer development apply to colorectal cancer?

Answer 14

APC (TSG) mutation in single epithelial cells - cell divided to form a localised polyp - benign tumour
Genetic instability increases over daughter generations, progressive mutation of Ras (becomes oncogene as constitutively active) and mutation of p53 (loss of function), generates a malignant cell - this gain of malignant potential is known as cancer progression.
Cell porgency invade the basement membrane that surrounds tissues, eventually some tumour cells invade blood vessels which will distribute them to other sites in the body.
Additional mutations enable the tumour cells to exit from the blood vessels and proliferate at distant sites.

Question 15

What are the stages of progression in the developer of cancer in the uterine cervix epithelium?

Answer 15

Normal epitheliul - stratified sqaoumous division only in basal layer
Low grade intra-epithelial neoplasia - dividing cells in lower 1/3, superficial cells are still flattened and show sign of differentiation but this is incomplete.
High grade IEN - all epithelial layers of prolferating cells and have defective differentiations
invasive carcinoma - cells destroy and move through basal lamina, invade underlying connective tissue.

Question 16

What are some key bank terms to use when describing benign tumours gross features?

Answer 16

Localised
Organised
Slow and expansive growth
Non-metastatic
Non-invaisve
Encaspulated
Clear, smooth borders.

Question 17

What are some key term to use when describing the histology of benign tumours?

Answer 17

Encapsulated
Unfirm cell shape and size
Cell orientation - resembles normal - somewhat well differentiated
Nuclear to cytoplasm ratio is normal 1:4 to 1:6
Low mitotic count - normal mitossis
Normal amount of chromatin

Question 18

What are some key features to use when describing the histological features of malignant tumours?

Answer 18

Anaplastic
Non differentiated
Non capsulated
Pleomoprhic in shape and size
Diasorganised and haphazard cell orientation
Nuclear to cytoplasm ratio is increased and disproportionately large.
Abnormal apoptosis
Increased mitotic count
Hyperchromatic - abundant DNA stains darker

Question 19

What are some key terms to use when describing the gross features of malignant tumours?

Answer 19

Fast and invasive growth
Metastasis
Destructive
Crab like - non capsulated
No clear border

Question 20

What are some key malignant cancer names to know?

Answer 20

Sarcoma - form in solid mesenchymal tissue (bones, fat, muscle)
Leukemia and lymphoma - blood cell cancers
Carcinoma - from epithelial cells (skin or internal lining of organs)
Sqaoumous cell carcinoma - tumours look like stratified squamous epithelium
Adenocarcinoma - in glandular pattern
Mesothelioma - of pleura.
Melanoma - skin cancer

Question 21

What are the different mechanisms for cancer cells to spread?

Answer 21

Direct spread
Lympathic spread
Haematogenous spread
Transcoelomic spread
Perineural spread

Question 22

What is meant by direct spread of a cancer?

Answer 22

Progressive infiltration, invasion and destruction of the surrounding tissue

Question 23

What is meany by lymphatic spread of a cancer?

Answer 23

Mainly seen in carcinomas
Follow natural lymph drainage pattern.
Regional nodes can act as a temporarily barrier for spread due to high immune function - cell may be destroyed after arrested growth or gains new mutations and continues to grow.

Question 24

How pattern of lymphatic drainage is often shown in breast cancer?

Answer 24

Upper outer quadrant breast cancer tends to spread to axillary lymph nodes
Inner quadrant drain through the lymph nodes along the internal mammary artery.

Question 25

What are the features of haematogenous spread of a cancer?

Answer 25

Normally seen in sarcomas - also carcinomas Norm in veins as thinner walls Arterial speed less likely as thicker walls are less readily penetrated. Tends to follow route of venous drainage.

Question 26

What are some examples of route of haemoatogenous spread of cancer?

Answer 26

Portal drainage to liver Caval drainage to lungs Close proximity to vertebral column - tne do tdrain through paravertebral plexus e,g thyroid and prostate Lung cancers commonly metastasis to the skeletal system including the spine.

Question 27

What is meant by transcoelomic spread of cancers?

Answer 27

Metastasis across a body cavity aka peritoneal cavity, subarachnoid cavity, pleural cavity. Diagnosis requies parancentesis of ascitis/pleural fluid.

Question 28

What are some examples of common patterns of transcoelomic spread of cancers?

Answer 28

Breast and lungs - pleural effusion Ovarian and gastric - peritoneal involvement, malignant ascites.

Question 29

What is perineural spread? What are some common examples?

Answer 29

Spread along nerve bundles Common in prostate carcinoma and some basal cell carcinomas.

Question 30

In detail describe the process of invasion-metastasis cascade of cancer cells?

Answer 30

1. Primary tumour formation 2. Localixed invasiveness enables in situ carcinomas cell to break through the basement membrane 3. Intravasation - either lymphatic of blood microvessels 4. Transporation via general circulation to distant anatomical sites 5. Tumour may become trapped, subsequently extravasate, and form dormant micrometastais 6. May eventually acquire the ability to colonize the tissue in which they have landed, enabling them to form a macroscopic metastasis 7. Colonisation

Question 31

Explain the process by which tumour cells invade the epithelial basement mebrane.

Answer 31

1. Acquire mutations to give more metastasis potential. 2. Downregulated E-cadherin expression - loosening of intracellular junctions, able to detaches from primary tumour and advance into surrounding tissues. 3. Secrete proteolytic enzymes to degrade the ECM, or secrete signalling messengers to cause stromal cells like fibroblasts and inflammatory cells to secrete proteases 4. Attach to novel EM components - use of fibrinogen receptor, lamin receptor etc, 5. degrade the basement membrane, followed by tumour migration often by autocrine motility factor.

Question 32

Describe the process of intravasation of caner cells.

Answer 32

Often requires help from stromal cells aka macrophages. Forms tumour microenvironment of metastasis (TMEM) or triads/ovals - from carcinoma cells, macrophages and endothelial cells in close proximity. Carcinoma cells express significant levels of Mena actin cytoskeleton regulating protein - associated with cell motility. Counting of TEMS can be used as a good prognostic marker.

Question 33

Describe the process of extravasation of tumour cells>

Answer 33

A metastasizing cell is trapped physically in a capillary. Large number of plates attach to cancer cell forming a microthrombus Cancer cell pushes aside endothelial cell on one side of capillary wall - direct contact with underlying basement merane Within a day the microthrombus is dissolved by prroteases. Cancer begin to proliferate in the lumen of the capillary Several days - the cancer cell break through the capillary basement membrane and invade the surrounding tissue parenchyma.

Question 34

What is the process of colonisation of a tumour cell in a secondary location?

Answer 34

Survival within foreign tissue. Initial growth of cells in foreign tissue. Persistence of growth.

Question 35

Why is it easy for tumour cells to survive as they travel through circulation?

Answer 35

Aggregate in clumps Homotypic adhesions among tumour cells Heterotypic adhesions between tumour cells and platelets. Platelet-tumour aggregates enhance survival and implantability.

Question 36

What is meant by organ tropism of cancer?

Answer 36

Certain cancer prefer to metastasise to certain locations 1. Tumout cells may have adhesion ligands expressed preferntiall on endothelial cell of the target organ 2. Target tissue may be a non permissive environmental aka skeltal muscle are well vascularised and rare site of metastasis.

Question 37

Give some examples of cancer metastasis organotropism

Answer 37

Breast - bone, lung, liber brain Thyroid - bone, liver, lung Colon - liver, lymph node Uterine - lung, lymph nodes Kidney - lung Prostate - bone.

Question 38

What is the epithelial-mesenchymal transition of cancer cells?

Answer 38

EMT - cancer cell disaggregate and exhibit dramatic shape changes Acquire a de-differenitaed phentypeoe Loose polarity and intracellular contacts, gain mesenchymal properties: Increased migratory capacity Increased contractility Increased production of ECM

Question 39

What are the key phenotypic differences between epithelial and mesenchymal cells?

Answer 39

Epithelial - cuboidal in shep, presence of cell junction, apicobasal polarity. Mesenchymal - spindle-lile shape, increased contractility, increase matrix deposition

Question 40

Contrast the proteome between epithelial and mesnechymal cells

Answer 40

Epithelial - E-cadherin, occlusins, cytokeratins Mesenchymal - N-cadherin, collagen 1, fibroncetin, FSP-1.

Question 41

How does the epithelial-mesenchymal transition relate to the metastasis of cancer?

Answer 41

Must undergo EMT in order to invade through BM, invasate and spread One in target tissue must undergo a MET in order to form new clinically detectable tumour, note cell retain some gained malignancy.