Carcinogenesis

Question 1

List the 8 cancer hallmarks

Answer 1

1. Sustaining proliferative signalling.
2. Evading growth suppressors - insensitivity to growth inhibitory signals.
3. Resistance to cell death (by evasion of apoptosis).
4. Replicative immortality (limitless replicative potential).
5. Angiogenesis (new blood vessel formation).
6. Reprogramming of energy metabolism.
7. Evasion of immune surveillance.
8. Activation of invasion/metastasis.

Question 2

List a known bacterial carcinogen and list 2 tumours associated with this infection.

Answer 2

Helicobacter pylori infection of the stomach is associated with gastric adenocarcinoma and marginal zone B-cell lymphoma.

Question 3

List 7 viruses which are known carcinogens and one tumour type associated with each virus.

Answer 3

1. Epstein-Barr virus (Burkitt’s lymphoma and nasopharyngeal carcinoma).
2. Hepatitis B virus (Hepatocellular carcinoma).
3. Hepatitis C virus (Hepatocellular carcinoma and some lymphomas).
4. Human T-lymphotropic virus (Adult T-cell leukaemia).
5. Human papilloma virus 16 + 18. (Squamous cell carcinoma of cervix, penis, anus, head and neck).
6. Human herpesvirus 8. (Kaposi’s sarcoma. Primary effusion lymphoma).
7. Merkel cell polyomavirus. (Merkel cell carcinoma of the skin).

Question 4

List 3 trematodes (flukes) which are known carcinogens and their associated tumours.

Answer 4

1. Clonorchis sinensis (Biliary cancer. Pancreatic cancer. Gallbladder cancer).
2. Opistorchis viverrini (Biliary cancer. Pancreatic cancer. Gallbladder cancer).
3. Shistosoma haematobium (Squamous cell carcinoma of the bladder).

Question 5

Which two tumour types are associated with exposure to ionising radiation?

Answer 5

Myeloid leukaemia (acute and chronic).
Papillary carcinoma of the thyroid.

Question 6

List 3 skin tumours which are associated with non-ionising radiation (UVB from sunlight).

Answer 6

1. Squamous cell carcinoma.
2. Basal cell carcinoma.
3. Malignant melanoma.

Question 7

What is an oncogene?

Answer 7

Proto-oncogenes are essential for cell growth and differentiation. Mutations of proto-oncogenes form oncogenes that lead to unregulated cell growth.

Question 8

List 5 oncogene types.

Answer 8

1. Growth factors eg. platelet-derived growth factor which is mutated in some astrocytomas (brain tumours).
2. Growth factor receptors eg. Her 2 which is amplified in some breast cancers.
3. Signal transducers eg. RAS which is the most commonly mutated human oncogene.
4. Nuclear regulators.
5. Cell cycle regulators eg cyclins and cyclin-dependent kinases.

Question 9

Which component of the mitogen activated protein pathway activates BRAF?

Answer 9

RAS

Question 10

What is Knudsons two-hit hypothesis?

Answer 10

Knudsons two hit hypothesis applies to tumour suppressor genes and states that both copies of the gene must be affected to cause disease.

Question 11

Two important tumour suppressor genes are p53 and Retinoblastoma. Describe the normal function of p53.

Answer 11

DNA damage triggers expression of the p53 gene which prevents the cell from entering the S-phase of the cell cycle. This means that there is arrest of the cell cycle at the G1 phase which allows DNA repair to take place by up-regulation of DNA repair enzymes. p53 stops the cell cycle by causing transcription of a cyclin dependent kinase inhibitor (p21) which blocks the CDK4/Cyclin D complex. If the DNA damage is so severe that it cannot be repaired, p53 can cause permanent cycle arrest/senescence or it can trigger apoptosis by up-regulating BAX which disrupts BCL2. This causes cytochrome c to leak from mitochondria triggering apoptosis. BCL2 normally stabilises the mitochondrial membrane blocking release of cytochrome c. As the p53 gene conserves stability of the genome, it is known as the guardian of the genome.

Question 12

What is the function of the retinoblastoma gene in the cell cycle?

Answer 12

Retinoblastoma regulates the progression from the G1 to the S phase of the cell cycle. The E2F transcription factor is released when retinoblastoma is phosphorylated by the cyclin D/cyclin-dependent kinase 4 complex. Retinoblastoma mutation results in constitutively free E2F allowing progression through the cell cycle and uncontrolled growth of cells.

Question 13

BCL2 regulates apoptosis. How do apoptosis regulators work?

Answer 13

Apoptosis regulators stop normal cells from dying but promote cell death in mutated cells whose DNA cannot be repaired. BCL2 prevents apoptosis by stabilising the mitochondrial membrane and blocking the release of cytochrome c. If BCL2 is disrupted, cytochrome c is released triggering apoptosis. BCL2 is overexpressed in a form of lymphoma called follicular lymphoma. Remember that lymphoma is a malignant tumour of lymphocytes. Follicular lymphoma shows a translocation between chromosomes 14 and 18 (t(14;18)) which moves the BCL2 gene from chromosome 18 to the Ig heavy chain locus on chromosome 14 causing increased BCL2. This causes enhanced stabilisation of the mitochondrial membrane preventing apoptosis and allowing the malignant lymphocytes to become immortal.

Question 14

What is the role of telomerase in carcinogenesis?

Answer 14

Telomeres normally shorten with serial cell divisions eventually causing cell senescence. Cancers often show upregulation of telomerase.

Question 15

How do cancers create a new blood supply to support their growth?

Answer 15

Cancers commonly produce fibroblast growth factor and vascular endothelial growth factor which are both angiogenic factors responsible for blood vessel creation.

Question 16

List the hallmarks of cancer and drug classes which are being developed to target these.

Answer 16

1. Sustaining proliferative signalling. EGFR inhibitors.
2. Evading growth suppressors. Cyclin-dependent kinase inhibitors.
3. Avoiding immune destruction. Immune-activating anti-CTLA4 mAb.
4. Enabling replicative immortality. Telomerase inhibitors.
5. Tumour-promoting inflammation. Anti-inflammatory drugs.
6. Activation of invasion and metastasis. Inhibitors of HGF/c-Met.
7. Angiogenesis. Inhibitors of VEGF signalling.
8. Genome instability and mutation. PARP inhibitors.
9. Resisting cell death. Pro-apoptotic BH3 mimetics.
10. Reprogramming of energy metabolism. Aerobic glycolysis inhibitors.

Question 17

What is dysplasia?

Answer 17

Dysplasia is disordered cell growth, which most often refers to a proliferation of pre-cancerous cells. It is also called intraepithelial neoplasia. Dysplasia often arises from longstanding hyperplasia (endometrium) or metaplasia (oesophagus and bronchus). Dysplasia is theoretically reversible with alleviation of the inciting stress. If the stressor persists dysplasia can progress to carcinoma which is irreversible.

Question 18

What is a neoplasm?

Answer 18

Neoplasm means new growth. This growth is unregulated, clonal and irreversible. Neoplastic tumours can be benign or malignant.

Question 19

Describe the differences between benign and malignant tumours.

Answer 19

Benign tumours remain localised, have a slow growth rate and closely resemble the tissue from which they arise. They are often circumscribed or encapsulated.

Malignant tumours are by definition invasive and are capable of directly invading the surrounding tissue and many have the capacity to metastasise. They are often rapidly growing with an irregular margin. Well-differentiated malignant tumours may closely resemble the tissue from which they arise whereas poorly differentiated malignant tumours may not look anything like their tissue of origin.

Question 20

What is the difference between carcinoma in situ and invasive carcinoma?

Answer 20

The term carcinoma in-situ refers to an epithelial neoplasm showing all of the cellular features associated with malignancy but which has not yet invaded through the epithelial basement membrane, separating it from potential routes of metastasis (blood vessels and lymphatics).

Question 21

How do you distinguish a benign cell from a malignant cell?

Answer 21

Malignant cells have increased nuclear to cytoplasmic ratios, show nuclear pleomorphism and hyperchromasia, have an irregular chromatin distribution pattern within their nuclei, with irregular nuclear membranes +/- prominent nucleoli.

Benign cells have low nuclear to cytoplasmic ratios. All benign nuclei show a similar nuclear size and are not hyperchromatic. They have vesicular, evenly distributed chromatin with smooth nuclear membranes.

Question 22

What is the term used to describe a malignant tumour of epithelial origin?

Answer 22

Carcinoma

Question 23

What is the term used to describe a malignant tumour of glandular epithelium or a tumour showing glandular differentiation?

Answer 23

Adenocarcinoma

Question 24

What is the term used to describe a keratin-producing malignant tumour of squamous epithelium?

Answer 24

Squamous cell carcinoma

Question 25

What is the term used to describe a malignant tumour of soft tissue?

Answer 25

Sarcoma

Question 26

What is the term used to describe a malignant tumour of lymphocytes?

Answer 26

Lymphoma. If malignant lymphocytes or malignant myeloid cells involve the bone marrow and appear in the peripheral blood, this is leukaemia.

Question 27

What is the term used to describe a malignant melanocytic tumour?

Answer 27

Malignant melanoma

Question 28

What is the term used to describe a benign tumour of blood vessels?

Answer 28

Haemangioma

Question 29

What is the term used to describe a malignant tumour of blood vessels?

Answer 29

Angiosarcoma

Question 30

What is the term used to describe a benign tumour of fat?

Answer 30

Lipoma

Question 31

What is the term used to describe a malignant tumour of fat?

Answer 31

Liposarcoma

Question 32

What is a benign skeletal muscle tumour called?

Answer 32

Rhabdomyoma

Question 33

What is a malignant skeletal muscle tumour called?

Answer 33

Rhabdomyosarcoma

Question 34

What is a benign tumour of smooth muscle called?

Answer 34

Leiomyoma

Question 35

What is a malignant smooth muscle tumour called?

Answer 35

Leiomyosarcoma

Question 36

What is a benign peripheral nerve sheath tumour called?

Answer 36

Schwannoma

Question 37

What is a malignant peripheral nerve sheath tumour called?

Answer 37

A malignant peripheral nerve sheath tumour!

Question 38

What is a benign tumour of fibroblasts called?

Answer 38

Fibroma

Question 39

What is a malignant tumour of fibroblasts called?

Answer 39

Fibrosarcoma

Question 40

What is tumour grade?

Answer 40

The grade of a tumour is defined as the extent to which the tumour histologically resembles the cell or tissue of origin. Grade is synonymous with differentiation and is a measure of how aggressive the tumour is likely to be. Low grade tumours grow slowly while high grade tumours grow rapidly and metastasize quickly.

Question 41

List 3 factors which allow tumours to invade.

Answer 41

1. Decreased cell adhesion - reduced expression of e-cadherin and expression of integrin receptors.
2. Secretion of proteolytic enzymes – collagenases, gelatinases and stromeolysins.
3. Increased cell motility - loss of contact inhibition.

Question 42

Describe the 3 steps in the pathogenesis of invasion.

Answer 42

Step 1: Loosening of intercellular junctions. Inactivation of e-cadherin. Inappropriate expression of SNAIL and TWIST, which suppress e-cadherin expression. Activation of beta-catenin.

Step 2: Degradation of the extracellular matrix. Protease secretion by tumour or stroma dissolves proteins. Matrix metalloproteinases (MMPs) dissolve basement membranes and matrix and release growth factors from stroma.

Step 3: Migration and invasion. MMPs 2 and 9 cleave the basement membrane. Tumour cells produce autocrine motility factors and insulin-like growth factor 1 has chemotactic activity for malignant cells. Stromal cells produce hepatocyte growth factor/scatter factor which promotes malignant cell movement.

Question 43

Describe the steps which are involved in tumour metastasis.

Answer 43

1. Detachment of tumour cells.
2. Invasion of connective tissue to reach lymphatics and blood vessels.
3. Intravasation into the lumen of the vessels.
4. Evasion of host defence by natural killer cells and T-cells.
5. Adherence to endothelium at the remote location eg. liver, lung, bone.
6. Extravasation of cells from the vessel into the tissue at the new location.
7. Survival and growth at the new location.

Question 44

List the three possible routes of metastasis

Answer 44

1. Lymphatic - to draining lymph nodes. Usually the first site of metastasis for carcinomas.
2. Haematogenous - to liver, lung, bone and brain. Favoured by sarcomas, which do not tend to use the lymphatic route of metastasis.
3. Trancoelomic - seen with malignant ovarian tumours and tumours of the GIT in the peritoneal cavity and pleural/pericardial cavity spread is usually from lung or breast.

Question 45

What else can cause lymph nodes which drain tumour sites to become enlarged?

Answer 45

Sinus histiocytosis (macrophages collecting in the node sinuses) or lymphoid hyperplasia.

Question 46

List the 5 carcinoma primary sites which most commonly metastasise to bone.

Answer 46

1. Lung.
2. Breast.
3. Kidney.
4. Thyroid.
5. Prostate.

Question 47

Which virus causes patients who are immunosuppressed to develop multiple squamous cell carcinomas of the skin? Think here of any virus you know of which can infect squamous epithelium.

Answer 47

Human papilloma virus.

Question 48

List four mechanisms by which tumour cells can evade immune surveillance.

Answer 48

1. Selection of antigen-negative clones.
2. Loss of MHC molecules.
3. Expression of transforming growth factor beta.
4. Expression of PD1 ligand which can switch of T-cells.

Question 49

How do immune checkpoint inhibitors work?

Answer 49

PD-L1 (programmed cell death ligand 1) is often expressed on the surface of tumour cells. When PD-L1 engages its receptor (PD-1) on cytotoxic T lymphocytes, the cytotoxic T cells become unresponsive and lose their ability to kill tumour cells. CTLA-4 is another receptor expressed on T cells which can inhibit T cell function. The discovery of checkpoints that shut off anti-tumour immunity has led to the development of antibodies that block these checkpoints and enhance the immune response. These are called checkpoint inhibitors.

Question 50

What is the tumour stage and what system is currently used for staging tumours?

Answer 50

The stage of a tumour refers to how large it is and how far it has spread. We currently use the TNM system for staging cancers. T refers to the tumour size or extent of local invasion. N refers to lymph node metastases and M refers to distant metastases.

Question 51

What is Horner’s syndrome?

Answer 51

A right upper lobe tumour of the lung can spread around the brachial plexus, compressing the nerves causing wasting, pain, weakness and paraesthesia in the arm. This tumour can also compress the sympathetic chain causing the eyelid to droop (ptosis), a constricted pupil (miosis), and absence of sweating of the face (anhidrosis). This is known as Horner’s syndrome.

Question 52

Why do tumours cause profound weight loss (cachexia)?

Answer 52

Disseminated malignant tumours are commonly associated with profound weight loss despite adequate nutrition. The catabolic state of a cancer patient with severe weight loss and debility is called cachexia and is thought to be mediated by tumour-derived humoral factors that interfere with protein metabolism causing muscle loss (sarcopenia). Weight loss can also be associated with nutrition interference eg. due to oesophageal obstruction severe pain or depressive illness.

Question 53

What is the Warburg effect?

Answer 53

Most cancers produce energy by a high rate of glycolysis with formation of lactic acid whereas normal cells have a low rate of glycolysis with oxidation of pyruvate in mitochondria. This effect is called the Warburg effect and is the reason why positron emission tomography (PET) scans work. The patient is given 2-18F-2-deoxyglucose (FDG), which is taken up by tumours and causes them to light up.

Question 54

List five other metabolic effects of tumours.

Answer 54

1. Tumours of endocrine glands can produce hormones eg. an adrenocortical adenoma can secrete cortisol causing Cushings syndrome.
2. Tumours of tissues which do not normally produce hormones can produce hormones causing paraneoplastic syndromes. A small cell carcinoma of the lung (an aggressive form of lung cancer) can produce ACTH or ADH.
3. Neuropathy and myopathy can be associated with lung carcinomas.
4. Venous thrombosis is seen with mucin-producing carcinomas eg. pancreatic adenocarcinoma.
5. Glomerular injury can be caused by immune complex deposition related to an immune reaction to the tumour antigens.

Question 55

How do tumours cause death?

Answer 55

Lung: If tumour obstructs a bronchus it may not be possible for secretions to get past and this predisposes to pneumonia. Acute bronchopneumonia is a common cause of death in patients with terminal cancer.

Bone: Metastatic carcinoma to the bones may cause hypercalcaemia which may be difficult to control leading to renal failure and cardiac arrhythmias. Cancer cells in the bone marrow impair haematopoiesis leading to anaemia, an increased risk of infection and increased risk of bleeding. Pathological fractures can also cause spinal cord compression.

Liver: Metastatic tumour in the liver can cause electrolyte abnormalities leading to death.

Blood vessels: Tumour invasion of blood vessels can cause haemorrhage and tumours can obstruct major veins such as the superior vena cava causing heart failure.

Brain: Metastatic tumours within the brain can be associated with raised intracranial pressure or they may develop intratumoral haemorrhage. The brain swelling can eventually cause the cerebellar tonsils to be pushed into the foramen magnum compressing the respiratory centre in the brainstem resulting in death.

GIT: Carcinomas which involve the gastrointestinal tract can cause obstruction. This can impair nutrition, cause ulceration or perforation. Impaired nutrition predisposes to developing infection.