Cancer Biology

Question 1

Hallmarks of Cancer

Answer 1

1. Self sufficiency in growth signals
2. Insensitivity to anti-growth signals
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angigogenesis
6. Tissue invasion and metastasis

Question 2

5 mechanisms of angiogenesis

Answer 2

1. Increased VEGF and other endothelial growth stimulator production
2. vascular co-option (tumour cells grow along existing blood supply)
3. Vascular intusussception
4. Vascular mimicry (tumour cells create blood vessel like channels)
5. Vascuologenesis (uses bone marrow derived stem cells)

Question 3

New Cancer Hallmarks

Answer 3

1. Immune evasion
2. Deregulated metabolism
   Cancer Enabling:
3. genome instability
4. Tumour promoting inflammation

Question 4

Mechanisms of cancer immune evasion (6)

Answer 4

• Immunosuppressive microenvironment (GF, IL-10; TGF-B)
• Myeloid derived stem cells and tumour associated macrophages
• Recruitment of Treg cells through IL-10
• Defective antigen processing/MHC I presentation
• reduced costimulatory molecule production
• Expression o f T cell inhibitors

Question 5

PARR
- Test principles
- Indications

Answer 5

• PCR amplifies variable region of TCR and B cell Ig. If a clonal population of cells this can be detected
• use for lymphoid malignancy differntation from inflammation populations of lymphocytes in tissues

Question 6

PARR Limitations

Answer 6

• pseudoclonality if low cell numbers
• Cross-lineage rearrangements prevent B/T cell differentiation
• Mutation to variable region may result in inability to amplify population of interest
• small population of clonal expansion may be lost in background of polyclonal inflammation
• Some infectious and inflammatory diseases can have clonal expansion of lymphocytes
• Low specificity (30-50%); highly sensitive(90%)

Question 7

C-kit test principles
Clinical importance

Answer 7

An oncogene commonly mutated in canine MCT
It is a growth factor promotant
Constituitive activation is associated with poor prognosis in some MCTs.

Question 8

CKIT - VCO 2019 review Findings

Answer 8

• Presence of mutation was not predictive of survival
• While previous reports suggested aberrant suppression associated with death it may just be due to association with other predictive factors.
• Presence of the mutation is not predictive of TKI responsiveness

Question 9

Ki67 - Test meaning and indications

Answer 9

A marker of cellular proliferation more sensitive and objective than traditional histological markers in some cancers.
Used in cancers such as melanoma where there are borderline features of malignancy histologically but this helps to determine if adjunctive therapy is necessary.

Question 10

Liquid Biopsy - Test principles

Answer 10

Blood based test that measures cell free DNA in plasma. The cfDNA undergoes next generation sequencing to look for genomic alterations that give a ‘cancer signal’

Question 11

Liquid Biopsy - Indications

Answer 11

PetDX recommendations include
- screening patients >7y and serial monitoring
- screening patientsd with breed predisposition to cancers
- Aid-in diagnosis of cancer if suspected from clinical illness
- Detection of recurrence of cancer/assessment of complete removal

Question 12

Liquid Biopsy - current knowledge

Answer 12

JVIM 2023 - PetDx funded study, 350 dogs. Positive result in 54.7%
Positive for 32% with early disease and 85% with late disease
JAVMA 2023 - PetDx funded
Large scale study 1500 private patients
- PPV of 75%
- Sensitivity of 67.5%
- Specificity of 97.5%

Not 100% sensitive even in late stage disease so is not a rule-out test. False positives may result in unnecessary investigations (but seem rare in current studies)
Variable performance depending on cancer type - further studies still needed

Question 13

Cancer Immunosuppressive Microenvironment

Answer 13

Tumour associated macrophages and myeloid derived stem cells create an immunosuppressive environment by:
- Production of IL10; TGF-B,
- Direct CD8 T cell inhibition by MDSC
- Stimulate angiogenesis
- Recruit Tregs which also suppress the antitumour immune function
- Synthesis PGE2 and ROS to modify/remodel the ECM

Question 14

What are check point molecules

Answer 14

Cell surface molecules that may be counter-regulatory (inhibitory) of T cell proliferation and effector function

They may be negative (coinhibitory)
or positive (costimulatory)

VCO 2018n showed upregulation of some checkpoint molecules in lymphoma

Question 15

Paraneoplastic HYpercalcaemia: Caused, CS, Tx

Answer 15

• PTHrP production
• Activation of Vit D by some lymphomas
• Expression of other facotrs: GF-B, IL-1
• PUPD, arrhythmia, constipation, urolithiasis, azotaemia, weakness
• frusemide, steroids, removal of cancer, bisphosphonates

Question 16

Paraneoplastic Hypoglycaemia causes (4)

Answer 16

• Insulinoma producing insulin
• IGF-1 production in hepatocellular carcinoma, melanom, HSA
• Increased tumour glucose utilisation
• Impaired hepatic function in advanced liver disease

Question 17

Paraneoplastic hypertrophic osteopathy - pathophys and symptoms

Answer 17

Nerve stimulation of the periosteum causing excessive proliferation and increased blood supply resulting in bone growth progressing from distal limbs proximally. Patients have swollen and painful limbs. This may be caused by increased tumour expression of VEGF/PDGF or increased circulating GH.
Associated with pulmonary tumours or other intrathoracic tumours. Though signs of respiratory disease are often absent.
- may also have concurrent ocular signs

Question 18

Paraneoplastic Cachexia:
Cause, symptoms

Answer 18

• Reduced intake from GI upset or increased ghrlin production. Stimulation of CRTZ
• Inflammatory cancer cytokine suppression of appetite
• TNF-a induced proteolysis and skeletal muscle catabolism
• Increased tumour glucose utilisation through increased channels and inefficient energy conversion.
  All result in muscle wastage and weight loss