Neoplasia 4 Flashcards
Tumor organization:
1. Tumor parenchyma
2. Tumor Stroma:
a. non-neoplastic support structure.
- extracellular connective tissue proteins and glycoproteins embedded in a proteoglycans matrix.
- provides Blood vessels for nutrition
fibroblasts- collagen for support matrix
inflammatory and immune cells.
Mesenchymal Tumors organization:
Epithelial Tumor organization:
- **Mesenchymal tumor: **
- produce the ECM in their stroma
- produce their own stroma.
- ex: Osteosarcoma produces bone
- spindle shaped tumors i.e. fibrosarcomas (stroma is collagen) -
Epithelial tumors:
- surrounding mesenchymal non neoplastic cells produce ECM
- epithelial cells trigger non neoplastic fibroblasts to produce collagen.
- may also produce a capsule (prevents metastasis)
* *- induce surrounding stroma to produce ECM vs. mesenchymal tumors whose own stroma produces ECM. (KEY PHRASING TO UNDERSTAND BOTH ECM) **
Tumor- Stromal Interactions:
This is a 2 way communication system involving:
a. cytokines
b. hormones.
c. inflmmatory mediators
d. growth factors
–> Modulate the growth rate, differentiation state, behavoir of both cell groups.
a. **tumor cells release PDGF (platelet dervided growth factor) **
b. tumor derived TGF-alpha ( transforming growth factor- alpha) tells fibroblasts to differentiate into myofibroblasts which recruits pericytes at edge of vessels allowing angiogenesis to occur.
Describe an example of the tumor stromal interactions involving neoplastic epithelial cells.
- Neoplastic epithelial cells (parenchyma) secrete:
- Platelet derived growth factor from the tumor cells which:
- activates the fibroblasts in the surrounding mesenchymal non neoplastic cells to:
- Increase collagen production
- Causing Scirrhous/ desmoplastic response: **(dense collagenous stroma) **
Tumor Stromal Interactions con’t:
TUMOR PRODUCTION PRODUCES:
a. growth factors
b. cytokines
c. inflammtory mediators
d. proteases.
e. tumor antigens
* *AND INITIATES A STROMAL RESPONSE:**
STROMAL RESPONSE:
a. inflammatory/ immune cells
b. ECM
c. Stromal fibroblasts
d. Vascular endothelium
THE STROMAL RESPONSE INITIATES A TUMOR RESPONSE: (remember this is 2 way communication system modulating growth rate, differentiation state, and behavior of both cells)
TUMOR RESPONSE:
a. proliferation rate
b. differentiation rate
c. local invasiveness
d. metastatic capacity.
Inflammatory response from the Stroma response:
Heavy infiltrations of neutrophils, eosinophils, mast cells, lymphocytes, histocytes recruited by chemokines and cytokines.
Tumor antigens:
Tumor antigens:
Surface expressed proteins/ glycoproteins/ glycolipids or carbohydrates.
Can be tumor specific +/- tumor associated.
Tumor specific antigens can help us localize tumors and find metastasis using anitbodies against the tumor restricted antigens.
Tumor Specific antigens:
- Often newly expressed i.e. oncogenes, mutated genes, embryonic or oncofetal antigens
Tumor Specific Shared antigens:
expressed by many tumors and only a limited number of normal adult tissues (proves less useful because less specific since its shared)
Tissue Specific antigens:
Shared by tumors and normal tissues
Ex: Differentiation antigens
- expressed at a specific differentiation stage.
If these tissue specific antigens are expressed at higher levels on tumor cells than normal cells then they function like tumor specific antigens.
Immunosurveillance:
- Acts to suppress tumor development:
- recognizes self antigens on tumor cells as foreign.
- attacks as if infected by microbes
- Failure–> Tumor emerges
- Tumor susceptibillity of immune suppressed transplants recipients increases suggesting that without immunosurveillance that is a problem.
Canine Cutaneous Histiocytoma
Histiocytes- resident skin macrophages.
Histiocytoma:
Neoplastic population: bean shaped histiocytes
Macrophages, big pale nucleus with lots of cytoplasm.
Mature lymphocytes will come in and infiltrate.
**In young dogs: histiocytomas regress and this is assisted by lymphocytes. **
Will get areas of coagulative necrosis.
Immunohistochemistry:
- Direct Method: Enzyme labelled primary antibody reacts with tissue antigen.
- Indirect Method: Enzyme labelled secondary antibody reacts with primary antibody bound to the tissue antigen.
Positve Test: Brown with Blue Background
Canine Cutaneous Histiocytoma: Effects of Immunosurveillance…..
Early in tumor cell production will see lots of round cells (many histiocytes but little lymphocytes)
Later in tumor cell will see many lymphocytes and little histiocytes.
Therefore immunosurveillance is working.
Anti tumor effector mechanisms:
Dependent on:
a. immune responsiveness of the host.
b. characteristics of tumor antigen.
**Innate Immune Response: **
a. first line of non specific attack.
b. NK cells and macrophages
c. no dendritic cell priming required in the innate immune response.
Adaptive/ acquired Immune System:
a. cell mediated and humoral
b. antigens must be presented in a reconizable form.
- Central role of the dendritic cells is to present the antigen in a recognizable form. Thererfore dendritic cells are key in the adaptive immune response.
Innate Immune system: (NK cells)
Lymphocytes:
a. bone marrow derived
b. lack usual B and T cell markers.
c. kill neoplastic and virally infected cells.
d. specifically target MHC- free cells.
NK cell + tumor –> lytic granules released –> APOPTOSIS of TARGET CELLS (cytolysis)
Innate Immune System: Macrophages
NK cells + T cells activate IFN-gamma which stimulates circulating macrophages.
Circulating macrophages then release:
a. reactive Oxygen intermediates
b. lysosomal enzymes
c. nitric oxide
d. TNF alpha
These will then kill the tumor cells. (cytolysis)
Direct contact **with the macrophage and the tumor cell is ESSENTIAL. **
Cytotoxic T lymphocytes (CD8):
Primary effectors of adaptive anti tumor immune response.
- primed by dendritic cells to reconize tumor antigens on cell surface.
- stimulate apoptosis.
Dendritic cells are antigen presenting cells (APC’s) which contain either MHC-1 or MHC-2 molecules. Dendritic cells capture and process antigens from the tumor cells and present the antigens using their MHC molecule to the CD8+ (cytotoxic T lymphocytes) which will active the T cell and cause apoptosis of the tumor cell. They present the antigen to Naive T lymphocytes (lymphocytes which have not yet experienced an antigen). Because dendritic cells contain MHC1 and MHC2 molecules they can present antigens proteins to naive CD4+ (naive T helper cells) as well as CD8+ (naive cytotoxic t Cells).
What do the cytotoxic T cells do once they are presented with the antigen?
Attach to target cell.
Immunologic synapse forms.
Lytic granules release.
Of these lytic granules, PERFORINS (pore forming proteins) mediate entry into target cell.
GRANZYMES (serine proteases) (also apart of the lytic granules) enter the cell through the pores produced by the perforins and initiate apoptosis.
Central role of dendritic cells in the Adaptive Immune Response:
Ag released from dying tumor cells or Ag secretion from live tumor cells are both ANTIGENS.
ANTIGENS are ingested by dendritic cells which fragments the antigens to antigenic proteins and presents the antigenic proteins on its cell surface.
These antigens are presented to either T lymphocytes or B lymphocytes.
- Antigen activated T lymphocytes can be CD8+ cytotoxic t cells. In this case the dendritic cell uses and MHC 1 molecule to present to the T cell.
- Antigen activated T lymphocytes can also be CD4+ t helper cells. In this case dendritic cells use the MHC 2 molecule to present to the naive t cell.
- Antigen activated B cells cause immunoglublin secreting plasma cells. (antibody secreting plasma cells.
B lymphocytes:
Antibody- producing B lymphocytes mediate the humoral immune response to tumors.
- Antibodies recognize tumor antigens
- activate local complement cascade
- generate a membrance attack complex
- tumor cell membrane damage
- rapid cell death by necrosis
Helper T4 Lymphocytes
Function: Enhance CD8+ and B cell function
- action mediated through cytokine secretion
- IL-2 drives CD8+ proliferation
- IFN- gamma stiumlated CD8+ T cell differentation
Immune evasion by tumors:
- Failure to produce tumor antigen. This is an antigen loss variant of tumor cells. Favored in clonal expansion or antigen hidden by fibrin or antibodies. Thefore not recognized by the Immune System.
- Mutations in MHC genes or genes needed for antigen processing therefore T- cell won’t recognize.
- Production of immuno suppressive proteins.
- Immunosuppression: tumor cells or products many be immuno suppressive
- Fas ligand: binds to Fas receptors on T-lymphocytes and triggers their apoptosis.
- Tumor cells release antigen into circulation. - Tolerance
- Tolerant to self antigens
