GI Cancer Flashcards
what are the characteristics of cancer?
Tissue invasion and metastases
Insensitivity to anti-growth signals
Limitless replicative potential
Evasion of apoptosis:
This leads to mutation being passed on when the cell proliferates.
Self-sufficiency in growth signals
Cells are able to synthesise their own growth signals.
Sustained angiogenesis:
Development of new blood vessels which are used to obtain nutrients to sustain cancer growth
You can develop cancer anywhere along the GIT…
what are the 2 types of oesophageal cancer?
2 types:
Adenocarcinoma:
Derived from an intestinal lineage which appear in the oesophagus due to BM as a result of GORD
Occurs at/close to Gastro-oesophageal junction
Squamous cell carcinoma:
Derived from the native squamous epithelium of oesophagus
Develop in the proximal 1/3 and middle 1/3 predominantly.
The 5 year survival rate for oesophageal cancer = 8%
Incidence of adenocarcinoma is rising
Risk factors for oesophageal adenocarcinoma are?
GORD
Barrett’s metaplasia:
Stratified squamous epithelium becomes simple intestinal columnar epithelium
There is a strong link with reflux 🡪 10% of GORD patients have BM
The Conversion rate of BM to adenocarcinoma is 0.5-1%
Lower oesophageal sphincter relaxing drugs (more reflux)
Obesity
Gender: Males > females
Increased Age
what are the protective factors of oesophageal adenocarcinoma?
H-pylori
You make less stomach acid –> less reflux
Fruit + vegetables
Anti-oxidants
How does H pylori survive stomach acid?
- has an enzyme called urease → which converts stomach acid into urea and bicarb
- it attaches to mucosa, and it releases urease and mucin which helps break down mucosa allowing it to go muscus layer where its more neutral
- urease makes alakli to make
- produces exotoxins which can cause inflammation
what are gastric cancers?
HP is responsible for ulcer formation:
Hp infection of the corpus –> hypochlorhydria –> largely associated with Gastric ulcers
Hp infection in the antrum –> hypergastrinemia –> Large volume of acid which then overwhelms the buffering capacity of SI –> Duodenal ulcers
Helicobacter pylori (Hp) infection is the most important risk factor for gastric cancers
what is the cancer mechanism for gastric cancer development?
- HP infection in the corpus
- HP produced an inflammatory response via IL-8
- Neutrophils and monocytes then release IL-1β –> down regulation of gastrin
- This means parietal cells produce less acid (↑ pH of stomach)
- This results in hypochloridria and atrophic gastritis which is then a precursor for developing gastric cancer.
Treatment of Hp infection?
triple therapy:
Antibiotics (amoxicillin + clarithromycin), + PPI
what is Hereditary diffuse gastric cancer?
Another type of gastric cancer (not influenced by HP)
Caused by germline mutations in the CDH1 gene (produces E -cadherin)
E-cadherin is important in ensuring that epithelial cells are adhered to each other (found in Adherens Junctions)
CDH1 mutation cause E-cadherin deficiency so cells can’t bind tightly together.
Therefore, cells become disorganised🡪 tumour 🡪 invade other tissue.
Cancer cells also break away from initial tumour (as no cell-cell adhesion), travel via blood stream and metastasise in another area.
I.e. due to mutation the cells become more invasive, more motile and more likely to metastasise 🡪 cancer
what can E-cadherin also be supressed by ?
E-cadherin can also be supressed by other mechanisms:
Epithelial mesenchymal transition (EMT) regulators
Epigenetic events
Promoter hypermethylation 🡪 silences expression of the gene
These can then all then result in gastric cancers occurring
how do you suppress E-cadherin through EMT regulators?
Snail + slug are both EMT regulators
EMT regulators supress e-cadherin expression
The lack of e-cadherin means again the cells adhere less.
Therefore, the cells undergo epithelial mesenchymal transition (EMT)
These cells are then associated with tumorigenesis as cells are much more invasive.
Left image: Cells are tightly adhered to each other is the absence of snail
Right image: Cells have been induced to produce snail which means they are no longer tightly adhered to each other.
what is Colorectal Cancer?
53% survival at 10 years
Higher incidence rate in western world
40% of bowel cancers could be prevented by changing lifestyle
Risk factors of colorectal cancer?
Increased age
Men > Women
Eating lots of processed + red meat
NB: Fish is protective
A Very low fibre diet will significantly ↑ risk
Fibre speeds up transit time so digesta (which may contain carcinogens) does not stay in GIT for as long so won’t interact with mucosal epithelium for as long.
Obesity
NB: High level of physical activity reduces risk
High Alcohol intake
Individuals who report long-term (10 years) regular use of aspirin have 50% reduced risk and this is similar for other NSAIDs.
what are the 2 types of colorectal cancer?
There are 2 types of colorectal cancer:
Sporadic (80-90%)
Due to sporadic mutation in APC gene (see below)
Lifestyle related
Tends to affect elderly
Familial (10%) (Examples FAP + HNPCC)
Already have genetic Mutation in one allele of APC gene
Affects younger individuals
what is Familial adenomatous polyposis coli (FAP)?
FAP: Multiple benign adenomatous polyps in the intestine at an early age
These polyps (adenomas) are causes by germline mutation of APC gene (tumour suppressor gene) on chromosome 5q21
These polyps can then develop into cancer
Patients are therefore offered a prophylactic surgery to remove the segment of the bowel that has excessive polyps so reduce risk of cancer.
what happens in normal colonic epithelial cells vs colon cancer cells?
Normal Colonic Epithelial Cells
In the absence of a mutation APC would bind to some other protein partners forming a destruction complex.
One of the proteins in this destruction complex is GSK-3B which is a kinase.
This kinase phosphorylates beta-catenin.
Phosphorylated beta-catenin is marked for degradation by ubiquitin/proteasome pathway.
Therefore, levels do not get too high and we get controlled cell growth.
Colon Cancer Cells
In FAP you get mutation in APC.
You can therefore no longer form a functional destruction complex.
Therefore beta-catenin won’t be phosphorylated so it will accumulate and go into nucleus of cells.
Here it bind to transcription factors and induces oncogenes so you get uncontrolled cell growth.
This is how Wnt signalling is deregulated in the colorectal cancer
explain the Adenoma Carcinoma Sequence ?
This is the progressing of polyps to adenoma carcinoma.
In patients with FAP they have one mutated APC allele
However, you need two mutated alleles to cause a cancer.
As the patient with FAP ages they may get a mutation in second allele (somatic mutation) and then develop the cancer.
So patients with FAP develop disease much younger
Sporadic occurs much later in individuals as it requires the mutation of both APC alleles.
what are ways to Improve 5-year survival of Colorectal cancer?
National bowel cancer screening program:
This programme aims to identify asymptomatic individuals (60-69 years) with a potentially curable disease
Screening of individuals is performed every 2 years by a stool smear test.
This is done to look for signs of blood in faeces (faecal occult blood test (FOBT))
Around 2% of individuals will have blood is present 🡪 they will then require a colonoscopy
Colonoscopy results
35% of patients will have adenomas 🡪 perform a polypectomy (remove adenomas)
If patient had a few adenomas you then ask them to do another FOBT 2 years later
If patient had lots you then ask them come back for colonoscopy 1 year later after removal of polyps
11% of patients will have cancer 🡪 surgery is offered.
This is in addition to symptomatic patients
Drug repurposing in the future?
example?
Drug repurposing is using drugs already approved for treatment of one condition to treat another disease.
Example: Metformin (diabetic drug) lowers the risk of developing colorectal cancer.
You can then Couple repurposing of drugs with tumour genetic signatures.
This involves personalising therapies by sequencing genome of individual and the tumour so we can see what drugs people are best likely to respond to
Best example: cetuximab
Cetuximab is an inhibitor for EGF R receptor.
What normally happens is EGF binds to receptor and induce intracellular signalling cascade which involves Ras, Raf and MEK.
This then drives tumour cell proliferation.
If you use cetuximab it can stop binding of EGF and then stops intracellular signalling.
In patients with colorectal cancers however you see mutations in RAS (activating mutations) which means RAS remains constitutively active irrespective of EGF so giving cetuximab will have little relevance.
