7 Molecular Basis of Neoplasia in practice Flashcards
Describe tumor origin
Tumours arise from normal tissue
- Any tissue type can develop into a cancer
How does tissue type play a role in cancer?
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
Which type of cells is more likely to develop into cancers?
Frequently diving cells such as epithelial cells are more likely to develop into cancers
Describe the phenotypic changes seen in multistep carcinogenesis (and the cause)
Phenotypic changes:
- Nucleus: cytoplasm ratio
- Nuclei polarisation alterations
- Increased mitosis
- Reduces function (i.e. secretory)
It is caused by genetic changes
Describe carcinogenesis in colon cancer
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
Describe carcinogenesis in cervical cancer
- 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
Describe tumour grade
and indicate its relationship with prognosis
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)
What is the suffix used for benign tumours?
- oma
e. g. Adenoma, leiomyoma
What is the term used for malignant epithelial tumors?
Carcinomas
e.g. adenocarcinoma
What is the term used for malignant mesenchymal tumors?
Sarcoma
e.g. Leiomyosarcoma
Describe the characteristics of tumors
- 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
Describe the different mechanisms by which growth control can be mediated
- Levels of secreted growth factor
- Environmental growth inhibitory factors
- Levels of secreted growth inhibitors
- Intrinsic program of differentiation and apoptosis
- Anti-tumor immune response
Using colonic mucosa as an example, show how varying levels of different growth control mechanisms can impact growth
- Colonic mucosa is a well organized and dynamic structure
- Gradients of morphogens/matrix components/ signalling activity have been described
Describe the conditions needed for tumours to develop
For a tumour to develop, growth control mechanisms need to be subverted
Describe the conditions needed for tumors to survive + become malignant
For a tumor to survive and become malignant, it needs to acquire further features:
- limitless replication/immortality
- angiogenesis
- invasion and metastasis
List the 6 ‘hallmarks’ of cancer
[and the 7th emerging one]
- 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
Describe the mechanisms of tumorigenesis
- 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
How does dene function disruption occur?
Mutation
How does gene mutation occur?
- Sequence change
- Gene amplification
- Gene deletion
- Gene silencing (epigenetic)
Gene mutation is permanent
Describe the effects of mutations
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
Describe gain/loss-of-function mutations in terms of the genes involved
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
Explain the process of acquired resistance by cancerous cells
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
Describe the self-sufficiency of growth signals
- (hallmarks of cancer)
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
Give examples of sustained proliferation (through self-sufficiency of growth signals)
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
Describe evasion of apoptosis (by tumours, hallmarks of cancer)
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
Describe sustained angiogenesis
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
Explain how knowledge of the genetic changes in a tumour may refine diagnosis
- 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)
Describe the use of precision medicine in oncology
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
Describe how identifying mutations is refining prevention
- 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
