What is the difference between invasion and metastasis?
Invasion if of local tissues and destroys normal tissue, at this point the cancer is still a local disease
Metastasis is the spreading from the site of origin to distant sites and forming new tumours in these areas
At this point the cancer has become a systemic disease
How many cancer patients are killed by metastatic disease?
Half
What proportion of breast cancer patients are killed by metastatic disease?
1/3
What proportion of lung cancer patients are killed by metastatic disease?
Majority
What proportion of patients with basal cell carcinoma are killed by metastatic disease?
Essentially none
By what basic mechanisms do tumour cells start to invade local tissues?
1) Increased motility
2) Decreased adhesion
3) Mechanical pressure
4) Production of proteolytic enzymes
What are the 2 classes of adhesion molecule which are lost in malignant cells?
Cell to cell adhesion molecules - cadherins
Cell to matrix adhesion molecules - integrins
What changes occur leading to a reduction in adhesion of malignant cells?
Mutation of E-cadherin in malignant cells leads to loss of cell-cell adhesion and contact inhibition
Changes in integrin expression in malignant cells lead to decreased cell-matrix adhesion
What is meant by the epithelial-mesenchymal transition?
Occurs in malignancy epithelial cells gain mesenchymal properties and can invade and migrate. Eg. epithelial cells are tightly connected polarised and tethered whereas mesenchymal cells are loosely connected and able to migrate
What is the role or proteolytic enzymes in invasion?
They are matrix metalloproteinases produced by the malignant cells which degrade the extracellular matrix
Interstitial collagenases are produced by malignant cells, what do they degrade?
Collagen types I, II, III
Gelatinases are produced by malignant cells, what do they degrade?
Collagen type IV, gelatin
Stomolysins are produced by malignant cells, what do they degrade?
Collagen type IV, proteoglycans
What is the main constituent of extracellular space?
Collagen
Are metalloproteinases produced by healthy cells?
Yes, they play a role in normal tissue regulation and are balanced by tissue inhibitors of metalloproteinases
How does the balance between metalloproteinases and inhibitors change in malignancy?
Increase in metalloproteinases and decrease in tissue inhibitors of metalloproteinases so they are no longer balanced, this favours tissue breakdown
What is the role of metalloproteinases in normal tissue regulation?
Needed to mop up collagen and remodel tissues etc.
How does mechanical pressure contribute to invasion?
Uncontrolled proliferation forms a mass
Pressure occludes vessels
Get pressure atrophy
Tumour spreads along the line of least resistance
Name the 4 routes of metastasis?
1) Lymphatic
2) Blood
3) Transcoloemic
4) Implantation - spillage of tumour during biopsy/surgery etc.
Give 4 cancers which commonly metastasize by the blood route?
1) Liver
2) Lungs
3) Bone
4) Brain
What is meant by the transcoloemic route of metastasis?
Across peritoneal, pleural, pericardial cavities or in CSF
Name the 5 stages of metastasis?
1) Detachment invasion
2) Intravasation (invasion of cancer cells through the basement membrane into blood vessels or lymphatics)
3) Survival against host defences
4) Adherence extravasation (from the lymph or blood vessels into surrounding tissues)
5) Growth (involving angiogenesis)
Carcinomas commonly spread by which route?
Lymphatic
Sarcomas commonly spread by which route?
Blood
Bone metastases are common in what 5 cancers?
1) Breast
2) Prostate
3) Lung
4) Kidney
5) Thyroid
Ovarian cancer commonly spreads by which route?
Transcoloemic
Brain and adrenal metastases commonly come from which cancer?
lung cancer
What 2 types of bone metastases can occur?
Bone metastases can by:
Lytic (lung)
Sclerotic (prostate)
What are the 2 different theories about patterns of metastasis?
1) Mechanical hypothesis - pattern in dictated by anatomy eg. lymphatic drainage
2) Seed and soil hypothesis - malignant cells can travel anywhere, but ‘seeds’ are more likely to grow on good soil - ie organs with a good tissue environment for malignant cells
Why can people recover from a cancer and then present years later with metastases?
Metastatic cells can remain dormant for years
How is organ selectivity for metastasis explained?
Tissue environment is important in the development of metastases
What role does angiogenesis have in metastasis?
Essential if metastases are to grow larger than 1-2 mm
Factors promoting angiogenesis are produced by what 3 types of cells?
Tumour cells, stromal cells and inflammatory cells
Name 3 factors which promote angiogenesis?
VEGF
PDGF
TGF-beta
Name 4 inhibitors of angiogenesis?
ECM proteins
Thrombospondin
Canstatin
Endostatin
How does the balance between promotors and inhibitors of angiogenesis change in metastasis and why?
Promotor expression increases and outnumber inhibitor expression, not only are promotors produced by tumour cells, the tumour cells illicit an inflammatory response which leads to the stromal and inflammatory cells produced these promotors which further contributes to the formation of new blood vessels
Give 3 reasons to stage and grade a tumour?
1) Determine prognosis - survival time, quality of life
2) Decide how to treat a tumour
3) Research - compare therapies or prognostic factors
What is meant by stage of a tumour?
How advanced the tumour is. Has the cancer spread and if so what is the extent of the spread.
If you had an arrow depicting cancer disease course from pre-invasive to death stage would tell you how far along the arrow the tumour is
What is meant by the grade of a tumour?
How aggressive is the tumour and how different does it look from the tissue of origin
If you had an arrow depicting cancer disease course from pre-invasive to death grade would tell you how fast the tumour is moving along the arrow
Tumours are staged using TMN what does this stand for?
T=tumour
M=metastases
N=nodes
Each organ has an individual TMN system, stage can be clinical, pathological or radiological
How does TMN staging basically work?
T = size and extend of primary tumour
M = presence and extent of distant metastases
N = presence and number of lymph node metastases
TMN can be combined to give and overall stage for the tumour from 1-4
How does the stage of a breast cancer affect the treatment?
1 - surgery only
2 - surgery and radiotherapy
3 - surgery and chemo
4 - chemo
What is Duke’s staging for colorectal cancer?
A = invades into, but not through bowel wall B = invades through the bowel wall but with no lymph node metastases C = local lymph nodes involved D = distant metastases
How does Duke’s staging for colorectal cancer correlate with survival?
A = >90% 5 year survival B = 70% 5 year survival C = 30% 5 year survival D = 5-10% 5 year survival
Grading is performed by which specialists?
Histopathologists
What is grading based on?
Differentiation - how much does the tumour resemble the tissue it originates from
Nuclear pleomorphism and size
Mitotic activity
Necrosis
How do grade and stage correlate with outcome?
Both correlate well with outcome
What 3 things lead to systemic malignant disease?
1) Invasion
2) Metastasis
3) Angiogenesis
