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Y3 Biology Of Cancer > Week 4 > Flashcards

Week 4 Flashcards

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1
Q

How common is colorectal cancer in both men and women ?

A
  • 2nd most common cancer in females in 3rd most common in males.
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2
Q

What is an adenocarcinoma?

A

Cancer that grows in the epithelial cells of glands.

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3
Q

Where does colorectal cancer develop?

A

In the GI tract, rectal and colon adenocarcinomas develop in the cells of the lining of the large intestine (crips). They often start in the inner lining and then spread to other layers

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4
Q

Describe the make-up of mucinous adenocarcinomas and how they spread compared with normal adenocarcinomas.

A

60% made up of mucus. This causes cancer cells to spread more quickly and become more aggressive that normal adenocarcinomas.

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5
Q

Why are mucinous adenocarcinomas hard to treat?

A

o Mucous layer surrounds cancer – hard to be treated by chemotherapy
 Use more intense / aggressive therapy

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6
Q

Where do carcinoid tumours develop and what does this make them?

A

develop in nerve cells – neuroendocrine cells that help regulate hormone production…. So are neuroendocrine tumours (NETs).

May also develop in the lungs or GI tract.

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7
Q

Where do primary colorectal lymphomas develop?

A

Develop in the lymphatic system in lymphocytes. Usually in narrow areas such as the lymph nodes, bone marrow, spleen, thymus, and digestive tract.

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8
Q

Where do Gastroinetinal stromal tumours form? And what type of tumour are they classed as and why?

A

o Form in interstitial cells of Cajal (ICCs) in the GI tract.
o Classified as sarcomas
 Cancers that begin in the connective tissues.

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9
Q

What is a Leiomyosarcoma? And Where do they affect?

A

A sarcoma which is a cancer of the smooth muscle.
Leiomyosarcomas can affect three layers of muscle in the colon and rectum. These muscles usually work together to guide waste through the digestive tract.

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10
Q

Why have incidence rates of adenocarcinomas stayed fairly constant over years?

A

Incidents rates have stayed fairly constant due to lifestyle factors, eating processed foods and red meats, drinking alcohol, obesity etc.
- These are increasing in recent years.
However, survival rates are positive for colorectal cancer, especially if it is found early.

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11
Q

What % of cancers are considered fully preventable?

A

55%

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12
Q

What age sees the peak rate of bowel cancer cases and why?

A

85-89 - The older generation have more time to develop mutations which lead to bowel cancer.

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13
Q

Outline some of the symptoms of colorectal cancer.

A

Change in bowel habits.

Bleeding from the anus.

Blood in your stool.

abdominal pain.

Loss of appetite.

Persistent lethargy and looking pale or jaundice.

Weight loss

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14
Q

Explain why patients with colorectal cancer may have altered faeces.

A

o Faces is exceptionally thin due to decrease in the width of the colon.

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15
Q

Why do patients with colorectal cancer experience a loss of appetite and lethargy / jaundice.

A

Intestines are being compacted so makes the patient feel full.

There may also be a lack of vitamins such as B12 which means insufficient erythrocytes are being produced. This leads to jaundice and anaemia.

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16
Q

Name some of the risk factors for developing colorectal cancer.

A

Hereditary factors - positive family history.

Modifiable risk factors - smoking, processed meats, alcohol intake, red meat, low intake of vegetables, body fat and obesity.

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17
Q

Name a couple of diseases which increase risk of colorectal cancer.

A

Long term inflammatory bowel disease.

Diabetes

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18
Q

Explain how eating red meat and processed food increases the risk of getting colorectal cancer.

A

These food contains lots of nitrates. Nitrates are converted to nitric oxides within the mouth. There nitric oxides react with secondary amines within the body to form n-nitroso compounds.
N-nitroso compounds and carcinogenic and so can cause mutations.

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19
Q

Explain how consuming a westernised diet with high processed foods, red meats and low fibre can cause risk of colorectal cancer.

A

A lack of fibre means that n-nitroso compounds (formed due to eating too much red) are not moved out of the bowels very quickly and so are in contact with the intestines for a long time. They are then able to cause damage.

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20
Q

Explain how consuming excessive alcohol levels contributes to colorectal cancer.

A

Oxidative metabolism of alcohol produces acetaldehyde using ADH from the cytosol.
This is couples with the reduction of NAD to NADH.

NADH is then re-oxidised to NAD+ using reactive oxygen species.

CYP2E1 metabolises to acetaldehyde at elevated ethanol (alcohol) concentrations.

Accumulation of reactive oxygen species from alcohol oxidation leads to the formation of lipid peroxides. These cause modifications of proteins and DNA.

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21
Q

Explain how acetaldehyde can cause mutations that can lead to colorectal cancer.

A

Acetaldehyde is a toxic carcinogen and is broken down to produce lots of reactive oxygen species. If these are in the cells lining to colon for too long, due to build-up, DNA damage is caused.

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22
Q

Explain how lack of fibre in the diet may lead to colorectal cancer.

A
  • Usually acts as a fuel source for ‘helpful’ bacteria which make short chain fatty acids. These protect the intestines by producing mucous. They also ‘switch-off’ inflammation when necessary.
    o Fibre also bulks out the faeces to help remove bacteria and toxic material.
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23
Q

In terms of colorectal cancer, explain what happens if inflammation occurs in the GI tract.

A

The ROS barrier becomes damaged and becomes porus allowing n-nitrosocompounds to reach the intestinal cells and cause mutational changes.

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24
Q

What does ‘NSAIDS’ stand for?

A

Nonsteroidal anti-inflammatory drug

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25
What current info do we have proving that NSAIDS reduce risk of colorectal cancer?
- Protective medicine that was not originally designed for patients of colorectal cancer. Initially for people with cardiovascular disease. o Patients on these medicines has a lower incidence of colorectal cancer than those not on the medication.
26
How is the effectiveness of NSAIDS affected by the inhibitor of COX?
Effectiveness of NSAIDS is contributed to by their potent inhibitor of cyclooxygenase (COX) enzymes. This is because COX-2 expression and prostaglandin E2 synthesis are elevated in CRC. COX-1 has a low expression in normal human colorectal tissue. Whereas Cox-2 is elevated in tissue involved in inflammation and cancer.
27
Explain how COX expression is different in cancerous cells compared with normal cells.
COX-1 has a low expression in normal human colorectal tissue. Whereas Cox-2 is elevated in tissue involved in inflammation and cancer.
28
Name the mechanisms by which Aspirin reduces risk of getting colorectal cancer?
- Interrupts nuclear factor kappa B - Interrupts extracellular signal regulated kinases - Induces caspase 8 and 9 - Inhibits beta-caetin signalling
29
Why are patients with cardiovascular disease given aspirin?
This stops COX-2 and prevents thromboxins causing bloodclots via homeostasis.
30
How is aspirin used to TREAT colorectal cancer?
Aspirin stops PGE2 being formed which is supposed to help aid colorectal cancer given PGE2 causes cell proliferation, angiogenesis, invasion and metastasis.
31
How do statins inhibit cell growth?
Ras and G-proteins normally progress the cell cycle. Statins lower activation of these within tumour cells and therefore act as an anti-proliferative medication.
32
How do statins work for treating colorectal cancer in terms of NF Kappa B?
Statins 'switch off' NF Kappa B which means reduced migration of cancer cells, no formation of MMP and reduced communication between cancer and stromal cells. This reduced communication prevents more cancerous tissue being formed given cancer uses stromal cells to increase its tissue mass.
33
From what mechanisms can colorectal cancer arise?
Chromosomal instability. CpG island methylator phenotype (CIMPs). Micro-satellite instability
34
What is chromosomal instability?
Essentially, sister chromatids are not separated evenly within cells. Mis-segregation then leads to a detrimental effect accounting for around 85% of all sporadic CRC cases.
35
Outline how the CIN pathway works to cause colorectal cancer.
The CIN pathway inactivates mutations in tumour suppressor genes which leads to increase clonal expansion of cells. This results in loss of heterozygosity and loss of tumour suppressor TP53. This causes expanding cells to have additional growth advantages which ultimately leads to invasive cancers.
36
What is P53 and what effect would its loss within a genome have?
It is a tumour suppressor gene, so its loss would result in large scale proliferation, de-maturation and inflammation of cancerous cells. Ultimately lack of cellular regulation.
37
Why is colorectal cancer caused by the CIN mechanism hard to treat?
Chromosomal instabilities are hard to treat. Each CIN is different. Drugs with different mechanisms would be needed to target all tumour cells.
38
Describe the CIMP method of causing colorectal cancer.
This is a subset of colorectal cancers that happen through epigenetic instability pathways. These are characterised by hypermethylation of promoter CpG island sites, resulting in the activation of several tumour suppressors and other tumour-related genes. This enables further methylated and tumour progression to occur.
39
Describe the structure of CpG islands.
Contain regions of genomes which are CG rich.
40
Name a factor which contributed to abberant methylation.
Ageing
41
What are microsatellite instabilities ? Explain their mechanisms that lead to colorectal cancer risks.
a. Microsatellites consist of repeated sequences of about 1-6 nucleotides. b. Their mechanism is generally DNA slippage in the process of replication c. The normal mismatch repair DNA system can correct errors in this process. However, the lack of mismatch repair genes in tumour cells or defects in the process of replication repair can lead to a possibility of genomic mutations increasing. d. Loss of DNA mismatch repair functions, due to somatic or germline genetic alterations of MMR genes, leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as microsatellite instability.
42
How does the microsatellite instability pathway work?
- Driven by a loss of the APC gene. - Characterised by inactivation of mismatch repair genes. - Failure of the mismatch repair genes leads to mutations in specific target genes involved in proliferation and cellular differentiation such as transforming growth factor beta receptor II and proteins that are involved in apoptosis regulation This ultimately leads to microsatellite unstable invasive tumours.
43
What drives the microsatellite instability pathway?
Loss of the APC gene.
44
What is the function of APC?
APC is a tumour suppressor which keeps stem cells pluripotent and controls their growth. This stops destruction complexes.
45
How does loss of APC contribute to formation of colorectal tumours.
Colorectal tumours are known to arise through a gradual series of histological changes, the so-called 'adenoma-carcinoma' sequence, each accompanied by a genetic alteration in a specific oncogene or tumour suppressor gene. Loss of APC function triggers this chain of molecular and histological changes
46
What happens to beta-catenin in the absence of Wnt ligands?
The absence of Wnt ligands leads to phosphorylation and unbiquitination of Beta-catenin by the destruction complex. In this state, Beta-catenin is targeted for proteasomal degradation. In the absence of Beta-catenin, a repressive complex is formed to repress target genes.
47
What activates the Beta-catenin pathway and what does this cause?
The beta-catenin pathway is activated when secreted Wnt ligands bind to their receptors. Intracellular signalling then causes stabilization and accumultion of beta-catenin which then translocates to the nucleus. There beta-catenin forms an active complex with binding partners. This allows gene expression.
48
What is the main function of beta-catenin?
Signal transduction towards the nucleus of the cell. It is a transcription factor which switches on genes associated with growth.
49
What happens in terms of beta-catenin if APC is damaged?
Beta catenin can be released and so enter the nucleus and send signals to activate growth and proliferation.
50
Define the term adenoma.
A type of polyp, or a small cluster of cells that forms on the lining of your colon. They are benign but can develop into malignant carcinomas.
51
What type of cells are thought to acquire the colorectal cancer mutations and why?
Normal, epithelia cells, of the intestines do not live for very long (turned over every few days). So, it is thought that stem cells, which survive for a long time, acquire mutations with age. These then survive and are passed on when division into daughter cells occurs. - This creates the heterogenous phenotype. Lots of cancerous cells with different mutations.
52
If mutations happen within epithelial cells, what happens?
Mutations can occur within epithelial cells which cause them to be immortal and have oncogenic traits though.
53
Outline the cancer stem cell theory.
Among all cancerous cells, a few act as stem cells that reproduce themselves and sustain the cancer. These stem cells divide to produce daughter stem cells with mutations. A proposed theory is that the long-lived nature and replicative events defining cancer stem cells allow them to acquire more mutations over time compared to differentiated cells that have finite life spands. This allows carcinogenesis to occur.
54
What is the purpose of Wnt signalling in stem cells.
It maintains crypt progenitor compartments.
55
Outline the process of Wnt signalling in stem cells and the effect this has.
When Wnt binds the receptor complex, the activity of the destruction complex (which contains APC) is inhibited. Therefore, beta catenin accumulates and binds to nuclear binding proteins of the Tcf/Lef family. this enables transcription.
56
Why is Wnt signalling needed within stem cells?
Wnt signalling helps maintain the stem and progenitor cells of the crypts. Most mutations within this pathway inactivate APC, enabling rapid growth and polyp formation. This is typically the initiating event in colorectal cancer formation.
57
Outline the stages of colorectal cancer and what is happening in each.
Stage 1 – The cancer hasn’t spread outside the bowel wall Stage 2 – The cancer has grown into or through the outer layer of the bowel wall Stage 3 – The cancer has spread to nearby lymph nodes Stage 4 – The cancer has spread to other parts of the body
58
Outline the treatment for stage 1 colorectal cancer.
Surgery. | No chemotherapy.
59
Outline the treatment for stage 2 colorectal cancer.
Surgery to remove the cancer. Chemotherapy may be suggested after the surgery if there is a high risk of the cancer coming back.
60
Outline the treatment for stage 3 colorectal cancer.
Surgery to remove cancer. Chemotherapy after surgery.
61
Outline the treatment for stage 4 colorectal cancer.
May be recommended to have: surgery, chemotherapy, radiotherapy, targeted cancer drugs.
62
In general, how does metastatic cancer treatment work?
It mimics the immune system
63
Outline what first line chemotherapy usually is.
This is usually a combination of drugs; folonic acid (leucovorin) and fluorouracils and oxaliplatin. (FOLFOX)
64
How does Folonic acid act as a chemotherapy agent?
Folonic acid is not a chemotherapy agent alone but potentiates 5FU by enhancing inhibition of the key enzyme, thymidylate synthetase, by fluorouracil metabolite.
65
How does oxiplatin act as a chemotherapy agent?
The platinum complex in the drug binds to DNA and forms cross-links. The cross-links inhibit DNA replication, transcription and arrest of the cell cycle, resulting in cell death.
66
What does FOLFOX drug need to be toxic?
5FU
67
How does 5FU work against cancer?
* 5FU mimics both uracil and thymine, interfering with nucleoside metabolism by incorporating into RNA and DNA triggering cytotoxicity and cell death. * This stops RNA and DNA production = cytotoxic and should cause cells to die. * Also inhibits enzymes which enable DNA production. * It irreversibly inhibits thymidylate synthase (TS) leading to a dNTP imbalance resulting in DNA damage and cell death * 5-FU is a pro-drug and the intracellular conversion of 5-FU into 5-fluoro-uridine-monophosphate (FUMP) and 5-fluoro-deoxy-uridine-monophosphate (FdUMP) is essential for its action * Makes 5-FU more potent.
68
What is biological therapy?
A type of treatment that uses substances made from living organisms to treat disease.
69
How do biological therapies work to fight cancer?
. In cancer, some biological therapies stimulate or suppress the immune system to help the body fight cancer. Other biological therapies attack specific cancer cells
70
Name some types of biological therapies used to treat cancer.
Types of biological therapy include immunotherapy (such as cytokines, cancer treatment vaccines, and some antibodies) and some targeted therapies.
71
How do T cells work against cancer?
- T cells are usually cytotoxic to cancerous cells and trigger apoptosis when necessary.
72
What type of cancer is Pembrolizumab used to treat?
Pembrolizumab is recommended as an option for untreated metastatic colorectal cancer with high microsatellite instability or mismatch repair deficiency in adults.
73
Outline the mechanism that Pembrolizumab uses to treat cancer.
- When functioning properly, T cells are activated and can attack tumour cells. - Some tumours can evade the immune system through the PD-1 pathway. The PD-L1 and PD-L2 ligands on tumours can bind with PD-1 receptors on T cells to inactivate the T cells. - KEYTRUDA binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. This helps restore the immune response.
74
What is the disadvantage of Pembrolizumab as a cancer treatment?
Can affect healthy cells as well as tumour cells.
75
What happens to cancer patients with BRAF mutations?
- BRAF normally activates MAP kinases when phosphorylated. - If mutated, BRAF can be constantly signalling, meaning growth factors are no longer needed for cancers to grow, proliferate and evade apoptosis. The BRAFV600E mutation confers Ras-independent stimulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway involved in proliferation, migration, angiogenesis and the suppression of apoptosis.
76
What does treatment do in patients of colorectal cancer with BRAF mutations?
Increases life expectancy by 6-9 months.
77
What is the cancer drug 'Encorafenib' desgined to do?
Switch off BRAF signalling. It inhibits the mitogen-activated protein kinase pathway, specifically BRAF kinase.
78
What does the drug Cetuximab do?
It is an epidermal growth factor receptor inhibitor.
79
Why can colorectal cancer cause weight loss and anaemia?
- Intestine width reduced, causes feeling of fullness, don’t eat as much food. - Lack of B12 intake means fewer erythrocytes will be produced. o A lot of blood can be lost in the faeces. This means level cant be maintained. - Increased bowel movement o Not enough time for nutrients to be taken in whilst they are in the intestines. Material moved out of nutrients very quickly.
80
Why have colorectal cancer levels remained stable in recent years?
- Treatment is good. - If treated early, people usually survive - Incidences stayed the same, if not increased, due to lifestyle factors such as consuming red meat and drinking alcohol in excessive quantities. - Obesity = inflammatory state = risk factor.
81
Why is fibre CRC protective?
- Directly anti-inflammatory. ‘Helpful bacteria’ which it acts as a fuel source for, ‘switch-off’ inflammation when needed. - Usually acts as a fuel source for ‘helpful’ bacteria which make short chain fatty acids o These fatty acids inhibit NF kappa B - Fibre also bulks out the faeces to help remove bacteria and toxic material (e.g., n-nitroso compounds). - Usually helps NF kappa B pass stool quicker, toxic substances then leave the intestines quicker.
82
How do statins protect form CRC?
Statins seem to inhibit cell growth by lowering activation of Ras and G-proteins which usually progress the cell cycle within cancerous cells. Therefore, they are an anti-proliferative medication. They also switch of NF Kappa B which reduces migration of cancer cells and means that MMPs are not formed. This prevents communication between cancer and stromal cells. This prevents more cancerous tissue being formed when cancer uses stromal cells to increase its tissue mass.
83
Why don't we put all CRC patients on NSAIDS?
They target all cells; not necessarily just cancerous cells so can be damaging. Evidence that the treatment is directly effective is not abundant.
84
Describe and explain the causes and effects of chromosomal instability on colorectal cancer.
Week 4 lecture notes
85
Ulcerative colitis is a chronic inflammatory disease of the colon. Suggest and explain why having ulcerative colitis increases the risk of someone developing colorectal cancer.
Week 4 lecture notes
86
Describe and explain some of the risk factors for developing or avoiding colorectal cancer.
Week 4 lecture notes
87
How may aspirin protect from CRC?
COX-2 synthesises large amounts of PGE2. PGE2 inhibits apoptosis, is proinflammatory and immunosuppressive and stimulates tumour angiogenesis and proliferation. In addition, COX-2 causes oxidation (activation) of cocarcinogens. Aspirin and non-aspirin NSAIDs inhibit COX-2 and subsequent PGE2 formation and action Experimental evidence suggests additional COX independent actions of aspirin and non-aspirin NSAIDs on oncogenic signalling. This includes modifications of transcription factors (NFκB), induction of apoptosis and DNA stabilization. Aspirin has the advantage of concomitant antiplatelet effects
88
Briefly explain what chromosomal instability, CpG island methylator phenotype and Microsatellite instability are.
Naked CpG island DNA (top) is unmethylated (yellow) and coated by proteins (green ovals) that protect against DNA methylation establishment and/or spreading. The nature of these proteins is unknown, but probably include transcription factors, co-activators or similar molecules. During repeated rounds of the stem-cell mobilization and replication that accompany ageing, DNA methyltransferases (circles) are recruited to the borders of some CpG islands, depositing methyl groups (red) and creating methylation pressure for these islands. The balance of methylation pressure (circles) and methylation protection (ovals) is disrupted in the CpG island methylator phenotype (CIMP), resulting in the spread of methylation into the transcription start area and the triggering of the silencing cascade. Schematic diagram of microsatellite stability (MSS) and microsatellite instability-high or mismatch repair deficiency (MSI-H/ dMMR). a DNA polymerase initiates replication at microsatellite sequences (cytosine/adenine [CA] 6 repeats). b The CA repeat is wrongly incorporated into the chain of replicated DNA due to DNA polymerase slippage during replication. c When DNA mismatch repair is intact, the replication error is repaired and MSS is maintained. d In mismatch repair deficiency, failure of elimination of the incorrectly incorporated CA repeat leads to the instability of microsatellite lesions (CA 7 repeats
89
What is APC, how can its loss result in CRC development?
APC protein normally builds a "destruction complex" This complex is able to bind β-catenins in the cytoplasm, that have dissociated from adherens contacts between cells. This allows phosphorylation of β-catenin, resulting in it being targeted for ubiquitination and degradation by cellular proteasomes. This prevents it from translocating into the nucleus, where it acts as a transcription factor for proliferation genes If mutated this ‘break’ is lost, meaning Mutations in APC or β-catenin must be followed by other mutations to become cancerous; however, in carriers of an APC inactivating mutations, the
90
What are cancer stem cells and why are they important for CRC progression?
Tumour growth is driven by CSCs, a small subpopulation of cells with embryonic stem cell (ESC) characteristics. These cells divide asymmetrically to produce differentiated cancer cells as well as identical daughter cells, a characteristic shared with normal ESCs. However, CSCs have lost control of replication and differentiation, which leads to tumourigenesis.

Y3 Biology Of Cancer (8 decks)

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