L11 - Development of Neoplasia Flashcards
What is the effect of NSAIDs on mucosal tissue?
NSAIDs (aspirin) deplete mucosal prostaglandins by inhibiting the cyclo-oxygenase (COX) pathway.
Leads to mucosal damage.
Describe intestinal gastric cancer?
Differentiated, well formed glandular structure.
Tumours are polyploid or ulcerating lesions with rolled edges.
- more likely to involve distal stomach and occur in patients with atrophic gastritis
Anal fissure
Tear in vertical axis of the squamous lining of the anal canal between the anal verge and the dentate line.
Symptoms: pain during / after defecation
Define ‘adenocarcinoma sequence’
Step wise pattern of mutational activation of oncogenes (e.g. K-Ras).
And activation of tumour suppressor genes (p53)
Lynch syndrome
Hereditary non polyposis colorectal cancer
Cause of Hereditary non-polyposis colorectal cancer
Inherited mutations in genes that encode proteins responsible for deletion, excision and repair of errors that occur during DNA replication.
What effect may NSAIDs have on polyps in FAP patients ?
FAP - Familial Adenomatous Polyposis
Protective effect - may cause polyp regression.
- Inhibition of cycloxygenase-2 , COX 2.
- COX 2 necessary for production of prostaglandin E2.
- Prostaglandin E2 promotes epithelial proliferation , hence no further proliferation of polyps.
What is the APC gene?
APC - Adenomatous polyposis coli
APC - controls Beta-catenin concentrations and interacts with E-Cadherin (involved in cell adhesion)
Wnt signaling pathways
Group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors.
Describe the classic adenocarcinoma sequence?
- both copies of APC gene must be functionally inactivated
- APC key negative protein regulator of B-catenin, component of Wnt signalling
- APC protein normally binds to and promotes degradation of B-catenin
- loss of APC function, B-catenin accumulates, translocates into nucleus
- forms complex with DNA bind factor TCF
- activates transcription of genes, MYC cyclin that promotes proliferation
- further mutations accumulate, mutations in kras that prevent growth and apoptosis.
State briefly factors contributing to cancer development?
- Inflammatory micro-environment
- Insensitivity to growth inhibitors
- Self-sufficient growth
- Limitless regeneration
- Sustained angiogenesis
- Evasion of apoptosis
- Tissue invasion and metastasis
Describe normal apoptosis
Programmed cell death.
Genetically regulated.
Important for development and tissue homeostasis.
No inflammatory response (unlike necrosis)
Briefly overview the cell cycle
G1 - Duplication of cellular contents S1 - chromosome duplication G2 - cell double checks duplicated chromosomes for errors Mitosis Cytokinesis
Describe G0 phase?
Cell is neither dividing or preparing to divide.
Cells exist in a quiescent stage.
Quiescent - state or period of inactivity or dormancy
Describe the correlation between altered differentiation and prognosis of tumours?
Well differentiated tumours - better prognosis
Poorly differentiated tumours - poorer prognosis
Describe invasion and metastasis of a tumour?
- Proliferation and angiogenesis of tumour
- Detachment / invasion into lymphatics, venules or capillaries
- Transport
- Arrest in organs
- Adherence to vessel wall
- Establishment of microenvironment
- Proliferatory angiogenesis
- Metastasis
Describe tumour angiogenesis
VEGF - vascular endothelial growth factor, regulator of tumour angiogenesis.
- Small tumour releases angiogenic factors (VEGF)
- Nearby capillaries stimulated to divide and sprout.
State briefly the colorectal cancer pathway
- Normal mucosa
- Early adenoma
- Late adenoma
- Carcinoma
Describe development of colorectal cancers?
- usually develop from benign polyps
Describe familial adenomatous polyposis?
- 100 to 1000 polyps throughout colon
- Autosomal dominant
- mutation in APC gene
Describe HNPCC?
Hereditary non polyposis colorectal cancer
- tumour more likely RHS
- autosomal dominant
- mutations in DNA mismatch repair genes, MSH2 & MLH1
Describe mismatch repair?
- Error in newly synthesised strand
- Binding of mismatch proofreading proteins
- MSH2, MLH1 - DNA scanning detects abnormalities in new DNA strand
- Strand removed
- Repairs DNA synthesis
Briefly describe the colorectal cancer pathway?
Normal mucosa to Early adenoma - APC - MLH1, MSH2 Early adenoma to late adenoma - k-ras Late adenoma to carcinoma - p53
Describe the function of K-ras gene?
Provides instructions for making a protein called k-ras.
Protein relays signals from outside the cell to the cell’s nucleus.
Signals instruct cell to grow and divide, differentiate.
K-ras = GTPase, hence will be turned on and off by GTP & GDP molecules.
Turned on: attaching to GTP
Turned off: bound to GDP
How may diet influence risk of developing colorectal cancer?
- leafy green vegetables are protective
- processed red meat increases risk
- obesity increases risk
Colorectal cancer environmental factors
Diet Chronic inflammation - ulcerative colitis Hormones - acromegaly
Acromegaly
Hormonal disorder. Pituitary gland produces too much GH.
Why do some people infected with H. Pylori develop stomach cancer?
H.Pylori: Gram -, urease, catalise, oxidase, spiral shaped.
- express virulence factors affecting host signalling pathway.
Superficial gastritis - atrophic gastritis - intestinal metaplasia - dysplasia - gastroadeno carcinoma
How has H.Pylori evolved the ability to colonize the highly acidic environment found within the stomach?
H.Pylori metabolises urea to ammonia via urease.
Generates neutral environment enveloping the bacterium.
Barret oesophagus
Healthy oesophageal epithelium replaced with metaplastic columnar cells.
Can occur as result of damage from prolonged exposure of oesophagus to refluxate of gastroesophageal reflux disease GERD.
How does GERD lead to Barret oesophagus?
Erosion of oesphageal mucosa.
Inflammatory cells infiltrate.
Epithelial necrosis.
Damage believed to promote replacement of healthy oesophageal epithelium with metaplastic columnar cells.
