molecular basis of neoplasia

Question 1

tumour origin

Answer 1

• Tumours arise from normal tissue
• Any tissue type can develop into a cancer
• Tissue type dictates the type of cancer
Colon ► glandular epithelium ► adenocarcinoma
Stomach ► glandular epithelium ► adenocarcinoma
Skin/Cervix ► squamous epithelium ► squamous cell carcinoma
Lymph node ► lymphocytes ► lymphoma

most tumours recapitulate their original tissue

Question 2

multistep carcinogenesis

Answer 2

• Colon dysplasia varies in severity and progressive degrees, precedes cancer and might reverse
• Phenotypic changes: nucleus/cytoplasm ratio, nuclei polarization alterations, increased mitosis, reduced function (i.e. secretory)
• Caused by genetic changes

Question 3

tumour origin

Answer 3

• As a general rule:
- benign tumours have the suffix -oma (adenoma, leiomyoma)
- malignant epithelial tumours are usually regarded as carcinomas (adenocarcinoma)
- malignant mesenchymal tumours are usually regarded as sarcomas (leiomyosarcoma)
• Many malignant tumours have benign precursors

Question 4

tumour characteristics

Answer 4

• Many normal tissues undergo continuous turnover
• New cells are produced by cell division from stem cells and old cells die by apoptosis
• An imbalance between the rates of cell division and cell death will cause tumour development
• Growth control mechanisms ensure that cell division = apoptosis
• For a tumour to develop, growth control mechanisms need to be subverted
• For a tumour to survive and become malignant, it needs to acquire further features:
- limitless replication / immortality
- angiogenesis
- invasion and metastasis

Question 5

growth control

Answer 5

growth control can be mediated via a number of different mechanisms:
• Levels of secreted growth factors
• Environmental growth inhibitory factors
• Levels of secreted growth inhibitors
• Intrinsic program of differentiation & apoptosis
• Anti-tumour immune response

Question 6

cell-growth control: colonic mucosa

Answer 6

• The colonic mucosa is a well organised and dynamic structure
• Gradients of morphogens/ matrix components/ signalling activity have been described

Question 7

hallmarks of cancer

Answer 7

• self sufficiency in growth signals
• insensitivity to anti-growth signals
• evading apoptosis
• evading immune surveillance
• tissue invasion and metastasis
• sustained angiogenesis
• limitless replicative potential

Question 8

mechanisms of tumorigenesis

Answer 8

• Tumours arise when normal cells acquire new features (such as escape from growth control)
• This can occur by disrupting gene function at a germline and/or somatic level

Question 9

gene mutations

Answer 9

• disrupting gene function occurs by mutation
• gene mutation may occur through:
• > sequence change
• > gene amplification
• > gene deletion
• > gene silencing (epigenetic)
• gene mutation is permanent

Question 10

effects of mutations

Answer 10

• Gene mutation results in either change in protein structure or levels (or both)
• This causes either gain-of-function (i.e. more of the same, or a new function) or loss-of-function

• In terms of cancer:

• genes with gain-of-function mutations are usually oncogenes
• genes with loss-of-function mutations are usually tumour suppressor or DNA repair genes

Question 11

growth factor receptors

Answer 11

• Gain-of-function mutations to growth factors promote uncontrolled cell growth
• e.g. EGFR (epidermal growth factor receptor) mutations are observed in about 15% of lung cancers

Question 12

tumour drug-resistance

Answer 12

• There are various drivers of tumour drug-resistance

* Possible solutions include genotyping to identify tumour mutations and monitoring of tumour changes during therapy

Question 13

self-sufficiency of growth signals

Answer 13

• Self sufficiency of growth signals may occur through mutations that cause:

• increased secretion of growth factors
• upregulation of growth factor receptors
• activation of growth factor receptors (ligand no longer required)

Question 14

growth hormones are receptors

Answer 14

• Binding of ligand to receptor activates the tyrosine kinase (TK) domain
• Tyrosine kinase activation leads to signalling cascade
- growth factor receptor signalling cascades promote changes in gene expression

Question 15

evasion of apoptosis

Answer 15

evasion of apoptosis may occur through:
• Up-regulation of anti-apoptotic factors
- Bcl2 is upregulated in follicular lymphomas due to the t(14;18) translocation
• Down-regulation of pro-apoptotic factors
- caspase 3 is down-regulated in colorectal tumours
• Loss of function of pro-apoptotic factors
- TP53 is mutated in colorectal tumours

Question 16

sustained angiogenesis

Answer 16

can occur through:
•	Increased secretion of growth factors
e.g. hypoxia induces VEGF release by renal cancer cells
•	Upregulation of growth factor receptor
•	Activation of growth factor receptors

Question 17

neuroblastoma

Answer 17

prognostic markers:
•	Loss of material from 1p
•	n-myc amplification 
-	copy number >10 poor prognosis 
-	gene located at 2p24
-	karyotypic correlate DMs and HSRs
•	Overexpression of Bcl-2 associated with poor prognosis.