22. Behaviour of Tumours Flashcards
In what ways do tumours behave in local disease?
Invasion
- invades adjacent normal tissue
- destroys normal tissue
In what way do tumours behave in systemic disease?
Metastasis
- spreads from site of origin to distant sites and forms new tumours in these new areas
What is invasion associated with?
- increased motility
- decreased adhesion
- production of proteolytic enzymes
- mechanical pressure
What are the cell to cell adhesion molecules?
Cadherins
What are the cell to matrix adhesion molecules?
Integrins
What does mutation of E-cadherin lead to?
Loss of cell-cell adhesion and contact inhibition
What do changes in integrin expression?
Decreased cell-matrix adhesion
What 3 things are involved in less adhesion/more motility?
- cadherins changes
- integrins changes
- epithelial-mesenchymal transition
What is the difference between epithelial cells and mesenchymal cells?
Epithelial cells - tightly connected, polarised and tethered
Mesenchymal cells - loosely connected, able to migrate
What happens to the epithelial cells in cancer?
Epithelial cells gain mesenchymal properties allowing them to invade and migrate
What are matrix metalloproteinases?
Enzymes responsible for the degradation of most extracellular matrix proteins
What do interstitial collagenases degrade?
Collagen types I, II and III
What degrades collagen type IV and gelatin?
Gelatinases
What degrades collagen type IV and proteoglycans?
Stomolysins
Name 3 matrix metalloproteinases
- interstitial collagenases
- gelatinases
- stomolysins
What do stomolysins degrade?
Collage type IV, proteoglycans
What is in balance in normal tissue regulation? (concerning proteolytic enzymes)
Matrix metalloproteinases and tissue inhibitors of metalloproteinases are in balance
In cancer, what is out of balance concerning proteolytic enzymes?
More matrix metalloproteinases than tissue inhibitors of metalloproteinases - favours ECM breakdown
What causes increased mechanical pressure in cancer?
Uncontrolled proliferation forms mass = increased pressure
What is the consequence of increased mechanical pressure in cancer?
- pressure from mass occludes vessels
- pressure atrophy
- spread along lines of least resistance
Secondary tumour burden is often what?
Secondary tumour burden is often greater than that of the primary site
Give some features of metastasis
- metastasis is often the presenting tumour
- primary site might be unknown
- occurs at different stages in natural history in different tumours
- may be early or more commonly, a late relapse
Give 4 potential metastasis routes
- lymphatic
- blood
- transcoelomic
- implantation
What does the transcoelomic route of metastasis mean?
Across peritoneal, pleural, pericardial cavities or in CSF
What does implantation route of metastasis mean?
Spillage of tumour during biopsy/surgery
Metastasis by blood occurs in which cancers?
- liver
- lungs
- bone
- brain
What are the stages in metastasis?
- detachment
- invasion
- intravasation
- survival against host defences
- adherence
- extravasation
- growth
- angiogenesis
What is intravasation?
The invasion of cancer cells through the basal membrane into a blood or lymphatic vessel
What is extravasation?
Cancer cells exiting the capillaries and entering organs
What is the typical pattern of metastasis in carcinomas?
Lymphatic spread first
What is the typical pattern of metastasis in sarcomas?
Blood spread first
What are the 2 types of bone metastases?
- lytic (bone)
- sclerotic (prostate)
What are the 2 hypotheses concerning patterns of metastasis?
- mechanical hypothesis (dictated by anatomy)
- seed and soil hypothesis (“seeds carried in all directions but can only live and grow if they fall on congenial soil”)
Why is tissue environment important in patterns of metastasis?
Influences organ selectivity for metastases
Are metastatic cells always active?
Metastatic cell can remain dormant for years
What is angiogenesis?
New vessel formation (derives from existing vessels)
What is the role of angiogenesis?
- role in development and healing
- role of bone marrow derived endothelial stem cells uncertain
- essential if metastases are to grow larger than 1-2mm
What are the promoters of angiogenesis?
- VGEF
- PDGF
- TGFb
What are inhibitors of angiogenesis?
- ECM proteins
- thrombospondin
- canstatin
- endostatin
Why is staging and grading of cancer important?
- determine prognosis (survival time and quality of life)
- decide how to treat the tumour
- research (compare therapies or prognostic factors)
What is the stage of cancer?
How advanced is the tumour? Has the cancer spread and if so, what is the extent of spread?
What is the grade of cancer?
How aggressive is the tumour? How different does it look from tissue of origin?
What are stage and grade in terms of the arrow from pre-inavsive to metastasis and death?
Stage = how far along the arrow the tumour is
Grade = how quickly the tumour progresses 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 and stage can be clinical, pathological or radiological
What is T in TMN staging?
Size and extent of primary tumour
What is M in TMN staging?
Presence and extent of distant metastases
What is N in TMN staging?
Presence and number of lymph nodes metastases
TMN can be combined to give what?
An overall stage for the tumour (I to IV)
What are the different T stages in breast cancer staging?
Tis = in situ disease T1 = less than 2cm T2 = 2-5cm T3 = over 5cm T4 = involving skin or chest wall
What are the different N stages in breast cancer staging?
N0 = no nodes N1 = ipsilateral nodes N2 = more node involvement
What are the different M stages in breast cancer staging?
M0 = no distant mets M1 = distant mets
What do the overall stages mean?
0 = Tis I = T1, N0, M0 II = T1/2, N1 or T3 III = T(any), N2 or T4 IV = T(any), N(any), M1
How does stage of breast cancer indicate treatment?
Surgery, surgery and radiotherapy, surgery can chemotherapy, just chemotherapy… as stage progresses
How does stage correlate with outcome?
Decreased survival at all years with increased stage
Describe Dukes staging for colorectal cancer
A = invades into, but not through bowel wall
B = invades through bowel wall but with no lymph node metastases
C = local lymph nodes involved
D = distant metastases
How does Dukes staging correlate with survival?
A = over 90% 5yr survival
B = 70% 5yr survival
C = 30% 5yr survival
D = 5-10% 5yr survival
What is grading based on?
- differentiation (how much tumour resembles tissue it originates from)
- nuclear polymorphism and size
- mitotic activity
- necrosis
Describe basic grading
G1 = near normal (well differentiated) G2 = moderately differentiated G3 = poorly differentiated G4 = undifferentiated
How does marked nuclear atypia affect grade?
Increases grade by one
