Cellular and molecular events in carcinogenesis

Question 1

Initiation

Answer 1

Carcinogen induces the genetic alteration that gives the transformed cell its neoplastic potential.

Question 2

Promotion

Answer 2

Stimulation of clonal proliferation of the initiated transformed cell.

Question 3

Progression

Answer 3

Culminating in malignant behaviour characterised by invasion and its consequences.

Question 4

Chromosomal abnormalities

Answer 4

Translocation or additional chromosome.

Philadelphia chromosome. Translocation t(9;22) bcr-abl in CML.

Question 5

Burkitt’s lymphoma

Answer 5

Translocation of c-myc oncogene (Cr 8) to Ig gene locus (Cr 14).

Question 6

Follicle centre cell lymphoma

Answer 6

Translocation between Cr 14 (Ig locus) and 18 (bcl-2)

Question 7

Ewing’s tumour and peripheral neuroectodermal tumour

Answer 7

Chromosom 11 (fli-1) and 22 (ews)

Question 8

What is needed to transform tumour cells into neoplastic cells?

Answer 8

Expression of telomerase.

Loss/inactivation of tumour suppressor genes.

Activation/abnormal expression of oncogens.

Question 9

Genetic instability can be inherited by which two major patterns?

Answer 9

Chromosomal instability - causing breaks

Microsatellite instability - defective DNA mismatch repair.

Question 10

Tumour suppressor genes

Answer 10

Caretaker genes - repair DNA damage
Gatekeeper - promotes cell death with damaged DNA

Examples: RB1 and p53

Question 11

Function of p53

Answer 11

Repair DNA damage before S phase (arresting cell in G1 until damage is repaired)

Apoptotic cell death in extensive DNA damage.

Question 12

Examples of gatekeepers

Answer 12

p53, RB1, APC

Question 13

Examples of caretakers

Answer 13

BRCA1, BRCA2, MSH2, MLH1, FANC genes, XP genes

Question 14

How can p53 lose its normal function?

Answer 14

Mutation (non-sense, missense)

Complexes of normal and mutant p53 proteins inactivating or subverting the normal protein.

Binding to proteins encoded by oncogenic DNA viruses.

Question 15

Transfection

Answer 15

Partially transformed cell cultures can be fully transformed by the addition of DNA bearing oncogenes.

Question 16

Transduction

Answer 16

Oncogenic retroviruses can transform cells by transferring oncogenes from another cell.

Question 17

Classification of oncogenes

Answer 17

GFs: sis - coding for PDGF

Receptors for GFs: erbB coding for EGFR

Signalling mediator with tyrosine kinase activity: src

Signalling mediator with nucleotide binding activity: ras

Nuclear-binding TF oncoproteins: myc

Question 18

Oncogenes can be activated by

Answer 18

mutation: protein molecule is altered = excessively active

excessive production of a normal oncoprotein due to gene amplification, reduced degradation.

Question 19

Epigenetic contribution to tumour growth:

Answer 19

Gene silencing by hypermethylation of promoter DNA sequence.

Histone modifications (methylation, acetylation).

Interference by microRNA.

Copy number changes to enhancer and silencer DNA sequences.

Question 20

What is the most important criteria for metastasis?

Answer 20

Invasion

Question 21

Invasion is due to…

Answer 21

Reduced cellular cohesion.

Production of proteolytic enzymes.

Abnormal cell motility.

Question 22

What are the common routes of metastasis?

Answer 22

Lymphatic vessels, blood vessels, and through body cavities.

Question 23

In epithelial neoplasms cells need to acquire motile and migratory properties…what is this process known as?

Answer 23

Epithelial-mesenchymal transition

Question 24

Invasion

Answer 24

Influenced by decreased cellular adhesion (E cadherin, dispersed integrins, loss of contact inhibition).

Secretion of proteolytic enzymes MMPs: interstitial collagenases, (I,II,III) gelatinases (IV, gelatin) stromelysins (IV, proteoglycans)

Abnormal or increased cellular motility.

Question 25

What are MMPs counteracted by?

Answer 25

TIMPs tissue inhibitors of metallopreoteinases.

Question 26

Invasion within epithelium is known as

Answer 26

Pagetoid infiltration

Question 27

Metastasis

Answer 27

Original tumour (primary tumour) spreads to form another tumour (secondary tumour).

Question 28

The metastatic sequence

Answer 28

Detachment: of tumour cells from their neighbours Invasion: of the surrounding CT to reach conduits Intravasation: into the lumen of vessels Evasion: of host defence mechanisms such as NK cells Adherence: to endothelium at remote locations. Extravasation: of cells from the vessel lumen into surrounding tissue.

Question 29

Tumour cells proliferate in the new environment...what do they need to grow and why?

Answer 29

Blood vessels (angiogenesis) because nutrients and oxygen need to be delivered to all cells.

Question 30

Routes of metastasis

Answer 30

Haematogenous - by blood stream. Secondary tumours in organs that drains blood from primary site. Lymphatic - regional lymph nodes Transcoelomic - pleural, pericardial, and peritoneal cavities.

Question 31

What type of cancer prefers lymphatic spread...

Answer 31

Carcinomas

Question 32

What type of cancer prefers haematogenous spread...

Answer 32

Sarcomas

Question 33

What organs are commonly involved in haematogenous metastasis?

Answer 33

Liver Lung Bone Brain

Question 34

What are the five carcinomas that favour bone metastasis?

Answer 34

Lung Breast Kidney Thyroid Prostate

Question 35

Lymph node metastases cause what?

Answer 35

Oedema - interrupt the flow.

Question 36

Transcoelomic tumours

Answer 36

Effusion of fluid into cavity - rich in protein and may contain fibrin. Also contains neoplastic cells (aspiration of fluid as Dx). Tumours often grow as nodules on mesothelial surfaces.

Question 37

What are the clinical effects of tumours?

Answer 37

Local effects (compression, invasion, ulceration{=blood loss and anaemia} or destruction of adjacent structures). Metabolic effects. Effects due to metastases, if tumour is malignant.

Question 38

Metabolic effects can be subdivided into:

Answer 38

Tumour type-specific effects and non-specific metabolic effects.

Question 39

Tumour type-specific effects

Answer 39

Endocrine tumours. Thyroid adenoma - thyrotoxicosis Adrenocortical adenoma - Cushing's Parathyroid adenoma - hyperparathyroidism

Question 40

Non-specific metabolic effects

Answer 40

Malignant tumours - weight loss.

Question 41

Cachexia

Answer 41

Catabolic clinical state of a CA PT. Due to tumour-derived humoral factors that interfere with protein metabolism.

Question 42

Warburg Effect

Answer 42

Producing energy by a high rate of glycolysis with fermentation of lactic acid (in normal cells low rate with oxidation of pyruvate in mitochondria). PET uses FDG - FDG uptake is increased in tumours.

Question 43

Treatment is guided by

Answer 43

Tumour type Grade or degree of differentiation Stage or extent of spread

Question 44

Tumour grade it identified by

Answer 44

Mitotic activity Nuclear size, hyperchromasia and pleomorphism Degree of resemblance to normal tissue.

Question 45

Tumour stage

Answer 45

Extent of spread.

Question 46

Cuthbert Dukes staging system

Answer 46

For colorectal CA Dukes' A: invasion into, but not through the bowel muscular wall Dukes' B: invasion through the bowel muscular wall but without lymph node metastases Dukes' C: involvement of the local lymph nodes Dukes' D: hepatic metastases present.

Question 47

TNM system

Answer 47

T - tumour size N - degree of lymph node involvement M - extent of metastases

Question 48

Dormancy

Answer 48

Cancer patients are never fully cured - prognosis is given the probability of survival or the length of disease-free interval.

Question 49

Non-invasive carcinomas of the breast

Answer 49

Ductal carcinoma in situ and lobular (acini) carcinom in situ.

Question 50

Invasive carcinomas of the breast

Answer 50

Infiltrating ductal of no special type Infiltrating lobular Mucinous Tubular Medullary Papillary Others

Question 51

Paget's disease of the nipple

Answer 51

Erosion of the nipple - looks similar to eczema. Associated with underlying ductal carcinoma in situ or invasive carcinoma. Roughening, reddening and slight ulceration of the nipple. Within the epidermis of the nipple, large, pale-staining malignant cells histologically.