7 Molecular Basis of Neoplasia in practice

Question 1

Describe tumor origin

Answer 1

Tumours arise from normal tissue

- Any tissue type can develop into a cancer

Question 2

How does tissue type play a role in cancer?

Answer 2

Tissue type dictates the type of cancer

e. g. Colon, Stomach - Glandular epithelium - adenocarcinoma
e. g. Skin/Cervix - squamous epithelium - squamous cell carcinoma
e. g. Lymph node - lymphocytes - lymphoma

Question 3

Which type of cells is more likely to develop into cancers?

Answer 3

Frequently diving cells such as epithelial cells are more likely to develop into cancers

Question 4

Describe the phenotypic changes seen in multistep carcinogenesis (and the cause)

Answer 4

Phenotypic changes:

• Nucleus: cytoplasm ratio
• Nuclei polarisation alterations
• Increased mitosis
• Reduces function (i.e. secretory)

It is caused by genetic changes

Question 5

Describe carcinogenesis in colon cancer

Answer 5

Colon dysplasia varies in severity and progression, precedes cancer, and might reverse

Histologically, the change from normal to cancerous cells can be seen, explained by dysplasia:
- Blue is bad (hematoxylin stain nuclei dark purple, so more purple = more DNA, larger nuclei, and signifies more mitosis)

The cancer is metastatic; the cancer cells are below the mucosa having grown through the lamina propria

Question 6

Describe carcinogenesis in cervical cancer

Answer 6

• In this example, the epithelium is squamous, (not keratinizing)
• Cells in the basal layer divide and mature as they move up
• Dysplastic region displays limited differentiation and variable nuclei size

Question 7

Describe tumour grade

and indicate its relationship with prognosis

Answer 7

Tumour grade refers to how well a tumour recapitulates its region of origin

• Prognosis is better with well-differentiated tumour cells (they have undergone fewer changes and are less focussed on growth than anything else)

Question 8

What is the suffix used for benign tumours?

Answer 8

• oma

e. g. Adenoma, leiomyoma

Question 9

What is the term used for malignant epithelial tumors?

Answer 9

Carcinomas

e.g. adenocarcinoma

Question 10

What is the term used for malignant mesenchymal tumors?

Answer 10

Sarcoma

e.g. Leiomyosarcoma

Question 11

Describe the characteristics of tumors

Answer 11

• Many normal tissues undergo continuous turnover
• New cells are produced by cell division from stem cells and old cells die from apoptosis
• An imbalance between the rates of cell division and cell death will cause tumor development
• Growth control mechanisms ensure cell division = apoptosis

Question 12

Describe the different mechanisms by which growth control can be mediated

Answer 12

• Levels of secreted growth factor
• Environmental growth inhibitory factors
• Levels of secreted growth inhibitors
• Intrinsic program of differentiation and apoptosis
• Anti-tumor immune response

Question 13

Using colonic mucosa as an example, show how varying levels of different growth control mechanisms can impact growth

Answer 13

• Colonic mucosa is a well organized and dynamic structure

- Gradients of morphogens/matrix components/ signalling activity have been described

Question 14

Describe the conditions needed for tumours to develop

Answer 14

For a tumour to develop, growth control mechanisms need to be subverted

Question 15

Describe the conditions needed for tumors to survive + become malignant

Answer 15

For a tumor to survive and become malignant, it needs to acquire further features:

• limitless replication/immortality
• angiogenesis
• invasion and metastasis

Question 16

List the 6 ‘hallmarks’ of cancer

[and the 7th emerging one]

Answer 16

• Self-sufficiency in growth signals
• Insensitivity to anti-growth signals
• Evading apoptosis
• Limitless replicative potential
• Sustained angiogenesis
• Tissue invasion and metastasis
  AND
  > Evading immune surveillance

Question 17

Describe the mechanisms of tumorigenesis

Answer 17

• Tumours arise when normal cells acquire new features (escape from growth control)
• This can occur by disrupting gene function at a germline and/or somatic level
• The good news: the options for a tumour are (mostly) limited to the genes in the host genome
• Bad news: the limit is over 20,000 genes

Question 18

How does dene function disruption occur?

Answer 18

Mutation

Question 19

How does gene mutation occur?

Answer 19

• Sequence change
• Gene amplification
• Gene deletion
• Gene silencing (epigenetic)

Gene mutation is permanent

Question 20

Describe the effects of mutations

Answer 20

Gene mutation results in either change in protein structures or levels (or both)
- This causes either gain-of-function (new function, or more same) or loss-of-function

Question 21

Describe gain/loss-of-function mutations in terms of the genes involved

Answer 21

Genes with gain-of-function mutations are usually oncogenes
- mutations like this to growth receptors promote uncontrolled cell growth e.g. EGFR mutations are observed in 15% of lung cancers

Genes with loss-of-function mutations are usually tumour suppressor or DNA repair genes

Question 22

Explain the process of acquired resistance by cancerous cells

Answer 22

Treatment of cancers will depend on their varied effects + taking into account differing mutations

Evolution = cells that survive therapy will change; the changes can affect:

• target of the drug (receptor, cell, etc)
• Upstream + downstream pathway activation
• Bypass mechanism

Question 23

Describe the self-sufficiency of growth signals

- (hallmarks of cancer)

Answer 23

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

• an increased secretion of growth factors
• upregulation of growth factor receptors
• activation of growth factor receptors (ligand not needed)

e. g. Binding of ligand to the receptor activates the tyrosine kinase (TK) domain
- tyrosine kinase activation leads to a signalling cascade

Question 24

Give examples of sustained proliferation (through self-sufficiency of growth signals)

Answer 24

Increased secretion of growth signals
- IGF2 (insulin-like growth factor) is upregulated in Wilm’s tumor (a nephroblastoma)

Upregulation of growth factor receptor
- cErbB2 (Her2, a member of the EGFR family) is upregulated in breast cancer

Activation of growth factor receptors
- mutation in the TK domain of c-Kit (receptor for stem cell factor) is GISTs

Question 25

Describe evasion of apoptosis (by tumours, hallmarks of cancer)

Answer 25

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 tumors

Question 26

Describe sustained angiogenesis

Answer 26

It can occur through:

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

Question 27

Explain how knowledge of the genetic changes in a tumour may refine diagnosis

Answer 27

• Identifying mutations characteristic of a tumour type which can be used as a diagnostic test (c-Kit mutations in GIST tumours)
• Identifying genetic subgroups within a morphologically uniform group of tumours
  (e. g. Diffusing large B cell lymphomas are histologically homogenous but expression profiling reveals two subclasses with different prognoses)
• Identifying new prognostic factors
  (e. g. poor prognosis for 18q loss in colorectal cancers)
• Identifying mutations which predict treatment response
  (c-Kit mutations in GIST activate the tyrosine kinase domain and are inhibited by imatinib)
• Identifying new therapeutic targets
  (30% of breast cancers have amplification of the c-Erb2 gene (encodes Her2, and EGFR), this can be targeted by trastuzumab
  (most renal cancers overexpress VEGF; this can be targeted by antiangiogenic inhibitors)

Question 28

Describe the use of precision medicine in oncology

Answer 28

Cancer treatment has moved on from:

• Organ-based (lung, breast, etc.)
• Morphology-based (e.g. Adenocarcinoma vs. squamous cell carcinoma)

and there is now an increasing focus on:
- Targeted treatment based on tumor genotype

Question 29

Describe how identifying mutations is refining prevention

Answer 29

• Identifying mutations which predict the risk of tumour in healthy people and offering preventative strategies

big example:
> 5-10% of breast cancer are familiar and related to BRCA1 and BRCA2 mutations