Neoplasia 4 Flashcards
-Tumour organisation- parenchyma vs stroma -Host defences- Inflammation -Tumour immunity
PARENCHYMA
Neoplastic population of cells in a tumour
STROMA
Non-neoplastic support structure. Comprises extracellular connective tissue proteins and glycoproteins embedded in a proteoglycans matrix. Blood vessels provide nutrition Fibroblasts Inflammatory and immune cells.
MESENCHYMAL TUMOURS
eg. sarcomas.
These produce THEIR OWN ECM, from the stroma of the tumour.
eg. an osteosarcoma produces bone.
EPITHELIAL TUMOURS
eg. carcinomas.
The SURROUNDING MESENCHYMAL NON-NEOPLASTIC CELLS PRODUCE ECM.
They may also produce a capsule, giving a better prognosis (clear margin for excision)
Tumours can also produce ‘bizarre things’- eg. plasmacytomas can produce amyloid.
TUMOUR-STROMAL INTERACTIONS
Interactions are complex- 2 way between tumour and stroma.
They become interdependent on one another.
A wide variety of signalling molecules are involved- cytokines, growth factors, hormones (in endocrine tumours), inflammatory mediators.
-These modulate growth rate, differentiation state and behavious of BOTH cell groups.
eg. Tumour release of PDGF
eg, Tumour derived TGFa (Transdforming Growth Factor a) causes fibroblasts to differentiate to myofibroblasts and pericytes to move to edges of vessels, allowing angiogenesis to occur.
eg. ADENOCARCINOMA IN THE EYE
Tumour cells release Platelet Derived Growth Factor.
This activates tumour associated fibroblasts.
There is increased collagen production- scirrhous/dermoplastic response from non-neoplastic mesenchymal cells.
INFLAMMATION
Often heavy infiltrates of neutrophils, eosinophils, Mast cells, lymphocytes and histiocytes.
Attracted by chemokines and cytokines.
eg. Lymphocyte infiltration often seen in FISS (Feline Injection Site Sarcoma)
INFLAMMATION IS NOT NECESSARILY PROTECTIVE.
eg. Studies suggest that NSAIDs reduce tumour incidence (NSAID = reduced inflammation = reduced tumours?)
TUMOUR IMMUNITY
- Tumour antigens
- Immunosurveillance
- Antitumour effector mechanisms- NK cells, macrophages, T cells, B cells.
- Evasion of immune response.
- Tumour immunotherapy.
TUMOUR ANTIGENS
Surface expressed proteins/glycoproteins/glycolipids or carbohydrates.
Can be tumour specific (most useful) or tumour associated.
CLINICAL APPLICATIONS:
- Diagnostic tool
- Therapeutic tool- Monitoring response to therapy
- Complex imaging using antibodies against tumour restricted antigens- can be used to localise tumours and find metastases.
TUMOUR SPECIFIC ANTIGENS
Often newly expressed:
- Oncogenic viruses
- Altered cellular products (mutated genes)
- Embryonic or oncofoetal antigens can be produced by reexpression of embryonic/oncofoetal genes.
eg. Carcinoembryonic antigen, a-fetoprotein.
TUMOUR SPECIFIC SHARED ANTIGENS
Expressed by MANY tumours, seen in limited numbers of normal adult tissues.
eg. MAGE family of proteins
- Promising possibility for antitumour immunotherapy.
TISSUE SPECIFIC ANTIGENS
Shared by tumours and normal tissues.
eg. Differentiation antigens (expressed at a SPECIFIC differentiation stage in normal tissues)
These antigens are useful if they are expressed at a higher level on tumour cells than normal cells.
This makes them function like tumour specific antigens.
IMMUNOSURVEILLANCE
-Suppresses tumour development by recognising self antigens on tumour cells as ‘foreign’.
Immune system then attacks as if infected with microbes.
Failure of immunosurveillance causes tumours to emerge.
The strongest evidence for this is the susceptibility of immunocompromised transplant patients to tumours.
IMMUNOHISTOCHEMISTRY
Used after H&E and special stains to DETECT SPECIFIC ANTIGENS.
DIRECT: Enzyme labelled primary antibody reacts with tissue antigen.
INDIRECT: Enzyme labelled secondary antibody reacts with primary antibody bound to tissue antigen.
Positive = BROWN.
eg. CD3 marker is used to detect T cells.
ANTITUMOUR EFFECTOR MECHANISMS
Dependent on immune responsiveness of host and on characteristics of tumour antigen.
INNATE IMMUNE SYSTEM- First line of non specific attack.
NK cells, macrophages.
NO dendritic cell priming is required.
ADAPTIVE IMMUNE SYSTEM- Cell mediated and humoral branches.
Antigens must be presented in a recognisable form- dendritic cells play a CENTRAL role.
NATURAL KILLER CELLS
NK cells. Part of innate immune system. LYMPHOCYTES- bone marrow derived -Lack usual B and T cell markers -Kill neoplastic and virally infected cells. -Specifically target MHC FREE cells.
When the NK cell contacts tumour, it releases lytic granules, causing apoptosis (cytolysis) of target cells.
MACROPHAGES
No priming required, but do require direct contact.
T cells and NK cells release IFNy (interferon gamma), which STIMULATES circulating macrophages to release:
-ROIs
-LYSOSYMAL ENZYMES
-NITRIC OXIDE
-TNFa
-> cytolysis and death of tumour cells.
Direct contact!!!
CYTOTOXIC T LYMPHOCYTES
Adaptive immune system.
CD8.
Primary effectors of adaptive anti tumour immune response.
-Primed by dendritic cells to recognise TUMOUR ANTIGENS on cells surface.
-Stimulate apoptosis.
Do not react to normal host cells displaying MHC associated self antigens.
DO react to their specific tumour antigen, displayed specifically on the tumour cell.
This activates the T cell.
MAIN 4 TUMOUR ANTIGENS
- Oncogene/mutated suppressor gene
- Mutated self protein
- Over or aberrantly expressed self protein
- Oncogenic virus.
CYTOTOXIC T CELLS contd.
Attach to target cell
-> Immunologic synapse forms
-> Lytic granules released:
PERFORINS- Pore forming, mediate entry in to target cell.
GRANZYMES- Serine proteases, initiate apoptosis.
DENDRITIC CELLS
Fragment antigens and present them on their surface in such a fashion that allows activation of T and B cells.
Dendritic cells play a central role in the ADAPTIVE immune response.
T cells and B cells can then go on to lyse cells or produce antibodies respectively.
B LYMPHOCYTES
Adaptive immune system.
Produce antibodies and mediate the HUMORAL response to tumours:
ANTIBODIES recognise tumour antigens
- > activate local complement cascade
- > generate a Membrane Attack Complex
- > tumour cell membrane damaged
- > rapid cell death by NECROSIS.
HELPER T LYMPHOCYTES
Part of adaptive immune system.
CD4.
Enhance CD8 (cytotoxic T cells) and B cell function.
IMMUNE EVASION BY TUMOURS
- Failure to produce tumour antigen.
An antigen loss variant of tumour cells is favoured by clonal expansion, or antigen is hidden by fibrin or antibodies. - Mutations in MHC genes or antigen processing genes.
eg. Class I MHC-deficient tumour cell. - Production of immunosuppressive T cells (eg. cytokines- damage T cells)
- Tolerance- Tolerant to self antigens (eg. those shared with normal tissue)
- Presentation of non-self antigens without co stimulatory molecules. - Immunosuppression- Tumour cells or products may be immunosuppressive.
eg. Fas ligand- binds to Fas receptors on T lymphocytes and triggers their apoptosis.
- Tumour cells release antigens into circulation, where they form immune complexes which may be immunosuppressive.
TUMOUR IMMUNOTHERAPY
Effective immunotherapy is preferable to cytotoxic chemotherapy, which is indiscriminate and targets dividing cells.
STRATEGIES:
Provide mature effector cells to recognise and destroy tumours. This is PASSIVE immunotherapy.
ACTIVE immunotherapy- stimulates host immune response against tumour.
Coupling toxins to monoclonal antibodies may allow targeted delivery of therapeutic agents to tumour cells.
TUMOURS: DIRECT SYSTEMIC EFFECTS ON HOST
Replace normal tissue, so affect function.
- Space occupying effect
- Erosion of vessels can cause acute haemorrhage
- Emboli passing in to vessels may cause infarcts at a distant site (common in kidneys and spleen, less so in lungs due to collateral circulation)
- Blockage of vessels eg. Lipoma strangulation colic in horses.
eg. Choroid plexus hyperplasia- can be benign, but this still has space occupying effects.
This has direct effects:
-Astrocytes cause scarring.
-Gitter cells remove myelin.
