Tumors

Question 1

Tumors/Cancers/Neoplasms

Answer 1

uncontrolled division of abnormal cells in a part of the body

Question 2

Benign

Answer 2

• remain in single location, not highly invasive

Question 3

Malignant

Answer 3

spread by the blood or lymph to distant sites and/or aggressive local invasion

Question 4

Carcinoma

Answer 4

arises from epithelial cells

Question 5

Sarcoma

Answer 5

arises from mesenchymal cells

Question 6

Leukemia

Answer 6

tumor cells int he blood (haemopoietic cells)

Question 7

Hallmarks of cancer

Answer 7

• evading growth suppressors
• sustained proliferative signaling
• deregulating cell energetics
• avoiding immune destruction
  -tumor promoting inflammation
• genome instability and mutation
• enabling replicative immortality
• resisting cell death
• activating invasion and metastasis
• inducing angiogenesis

Question 8

What causes DNA mutations?

Answer 8

• can be spontaneous
• Reactive oxygen species
• viral infections
• carcinogens

Question 9

Cancer cell cycle control

Answer 9

• more than 50% of cancers have acquired mutations at p53 (tumour suppressing protein)
  **Gene usually prevents uncontrolled division or growth
• p53 checkpoints- when these aren’t working, too much division occurs

Question 10

Tumour progression

Answer 10

1. Avascular phase
   - small lesions
   -steady state between apoptosis and proliferation (dormant tumors)
2. Vascular phase
   - exponential tumor growth in association with “angiogenic switch”

Question 11

Tumour microenvironment

Answer 11

• tumours need amino acids, oxygen, lipids etc. to make it
• includes a collection of immune cells, endothelial cells, and fibroblasts that have unique metabolic features which allow them to manipulate their external environment to promote survival, proliferation, and immune evasion

Question 12

Cancer cell secreting cytokines

Answer 12

TGFbeta
IL-1beta, IL-6, TNFalpha
VEGF
IL-10, TGFbeta, M-CSF, IL-35

Question 13

TGFbeta

Answer 13

makes cancer-associated fibroblasts

Question 14

IL-1beta, IL-6, TNFalpha

Answer 14

Creates migratory cancer cells (mesenchymal)

Question 15

VEGF

Answer 15

Causes abnormal vessel growth

Question 16

IL-10 or TGFbeta, (or M-CSF, IL-35)

Answer 16

1. Turns off monocyte maturation (macrophages)
2. Turns on Treg cells

Question 17

Angiogenic Switch

Answer 17

• dormant tumor cells are in steady state of proliferation and apoptosis
• Secretion of angiogenic growth factors by the tumour facilitate recruitment of endothelial cell precursors from bone marrow
• Angiogenic sprouting results in highly abnormal blood vessels (irregular shapes, have dead ends, labyrinth of vessels)
• unorganized collection of vessels sharing features of arterioles, venules, and capillaries

Question 18

Tumour site recruitment

Answer 18

• Each tumour will have unique properties linked to different gene expression of individuals
• inflammation within the tumor results in WBC recruitment, but the metabolic environment at the tumor alters the behaviour of those cells

Question 19

Suppressed state in Tumour

Answer 19

• Release of Il-10 or TGF beta
• PDL1 present on tumors inhibit T effector cells

Question 20

Tumour associated antigens

Answer 20

• difficult for immune system to overcome the immunosuppressive environment
  -BUT tumor associated antigens provide diagnostic markers as well as targets for therapy

Question 21

4 types of tumor associated antigens

Answer 21

1. tissue-specific antigens- normal proteins found in cells
2. reactivated gene products- normal proteins that are not normally expressed after fetal development
3. viral antigens- present on cancer cells as a result of viral infection (eg. FeLV)
4. mutated gene products (eg. loss of MHC, glycoprotein changes)

Question 22

Tumour surveillance

Answer 22

1. Early- apoptotic tumor cells can be phagocytosed
2. If tumor expressed antigen with high immunogenicity, DC’s can present antigen to CD8 to have it killed

Question 23

What does the destroying of tumor cells depend on?

Answer 23

largely dependent on immunogenicity of the tumor associated antigen

Question 24

Effector cells of tumors

Answer 24

1. Natural Killer Cells (main effector)= antigen independent
2. cytotoxic T cells= antigen dependent
3. Activated macrophages
4. Antibodies

Question 25

Natural killer cells attacking tumor cells

Answer 25

• recognition of cells expressing stress molecules on their surface
• recognition of cells no longer expressing MHCI
• kill virus infected and tumor cells without previous sensitization (no memory)
• antibody dependent cellular cytotoxicity
• serial killers

Question 26

Cytotoxic T cells killing tumors

Answer 26

• destroy tumor cells that display novel antigen on MHCI
• probably most imporant in virus-induced tumors that express viral antigens

Question 27

Activated macrophages role in destroying tumors

Answer 27

• activated by IFN gamma
• kill through release of cytotoxic factors

Question 28

Antibody role in destroying tumors

Answer 28

may have some effects through complement-mediated lysis and natural killer cell mediated killing

Question 29

Lack of nutrients problem

Answer 29

Lymphocytes struggle to proliferate or synthesize proteins associated with effector mechanisms due to lack of nutrients

Question 30

Tumor therapy

Answer 30

Main methods until recently:
- Chemotherapy (harsh, target quickly dividing cells)
- Radiation (harsh, target quickly dividing cells)

New potential targets:
- angiogenesis
- target tumor-associated metabolic enzymes
- immunotherapy

Question 31

Immunotherapy

Answer 31

Manipulate immune cells to acquire an effector state
- overcome suppression of tumor microenvironment
OR immunize against a specific antigen (passive immunization, vaccines, adoptive T cell therapy)

Question 32

Most effective tumor treatment

Answer 32

• combination of chemotherapy/radiation and immunotherapy

**everyone will respond differently though

Question 33

Chemotherapy and immunotherapy

Answer 33

Chemo- takes away tumors ability to grow fast

Immunotherapy- ways to induce immune cells to destroy tumor

Question 34

NK cell Immunotherapy

Answer 34

1. chemokines to activate NK cells
2. Inhibit checkpoint
3. antibody mediated intervention for tumor ligand shedding
4. adoptive transfer of modified cells
5. cytokines released to recruit more NK cells
6. Tri-specific NK engagers

Question 35

Vaccines

Answer 35

• major issue is the antigenic heterogeneity of most tumor populations
• used only for viral induced tumors (FeLV, Mareks disease, Canine Melanoma)

Question 36

Dendritic cell vaccines

Answer 36

• patient specific treatments. Isolate dendritic cells from a patient and expose them to the antigen of interest in vitro
• dendritic cells are injected back into patient
• hopefully cells elicit a strong cell-mediated immune response

**have shown promise against: melanoma, prostate cancer, lymphoma

Question 37

Passive administration of monoclonal antibodies

Answer 37

• Magic bullets

Have many mechanisms:
- antibody and complement dependent cytotoxicity
- coupled to a toxin or cytokine
- coupled to a radioisotope
- coupled to an enzyme which specifically activated a cytotoxic drug
- antibody triggers apoptosis

Question 38

genetic engineering of monoclonal antibodies

Answer 38

• generated in mice
• then engineered “species-ization” of Fc fragments which basically switches the mouse Fc to the target host Fc
• Fc can also be engineered to elicit a specific effector mechanism

Question 39

Immunotherapy in vet med

Answer 39

immunotherapy for cancers and treatments
- Cytopoint
- Bedinvetmab
- Frunevetmab

Question 40

Cytokine tumor immunotherapy

Answer 40

• IFN gamma treatment
• cytokines are toxic, so capillary leak syndrome, severe rash, endotoxin-like effects (fever/chills), nausea, depression
• not ideal because they are hard to control, not specific and can act systemically
• local application directly into papilomas or carcinomas of the vulva in cattle have seen good results (80% remissions)