Case 4- cancer

Question 1

Geographical incidences of cancer- ionising radiation

Answer 1

Due to the fallout from the Chernobyl nuclear accident levels of ionizing radiation are high in parts of Ukraine and other areas of Europe. Incidence of Thyroid cancer is higher there. Free radicals can cause DNA damage which may cause a tumour.

Question 2

Geographical incidences of cancer- Radon

Answer 2

Comes from the radioactive decay of radon present in some types of rocks. Some areas have larger amounts of these rocks and more radon in the environment.

Question 3

Geographical incidences of cancer- Smoking

Answer 3

Higher incidences of lung cancer in areas where smoking is more common- russia

Question 4

Geographical incidences of cancer- viruses

Answer 4

HIV virus increases the risk of developing a number of cancers, prevalent in areas of Africa. Human herpes virus 8 is associated with an increased risk of Kaposi sarcoma. Some virus’s increase the risk of cancer, in the areas where there are more of these viruses, there is more cancer.

Question 5

Geographical incidences of cancer- UV radiation

Answer 5

Causes DNA damage. There are higher instances of skin cancer in some countries e.g. Australia. In Australia the levels of UV light are high due to the amount of sunlight and also due to a hole in the ozone layer

Question 6

Carcinogenesis

Answer 6

The process in which a normal cell transforms into a cancer cell

Question 7

Multi-step hypothesis of carcinogenesis

Answer 7

In initiation a normal cell undergoes its first mutation (initiation mutation) this may make it immortal. The mutation may be due to a carcinogen. It is initially PRE-CANCEROUS, as the number of cells grow it becomes a PRE-NEOPLASTIC lesion. As the cell divides and experiences pressures from the environment or just has spontaneous mutations, it will pick up further mutations making it more genetically unstable, meaning it is likely to pick up more mutations. As the cell picks up more mutations the cell becomes abnormal until it’s a transformed cell which is cancerous. As the cell becomes malignant it goes from a pre-neoplastic lesion (polyp) to a NEOPLASTIC lesion. Cells can break off from this and travel elsewhere, they are metastatic and can form secondary cancer growths

Question 8

Tumour heterogenity

Answer 8

In tumour heterogeneity, the different cells within the tumour may develop different mutations and have destinct morphology and phenotypes. They have different selective pressures causing them to acquire different mutations.

Question 9

Types of mutations

Answer 9

• Mutations during cell division that were not fixed.
• Point mutations or deletion of bases
• Chromosomal abnormalities can be known as translocations when one part of the chromosome breaks off and sticks to another chromosome. Dependent on which genes break off and where they locate. May cause genes controlling cell division to be constantly expressed
• Epigenetic changes doesn’t change gene sequence but their expression. May stimulate the cell cycle and division.

Question 10

Changes associated with cell transformation- Self stimulus to growth

Answer 10

Growth normally stimulated by growth factors. Cancer cells don’t require extracellular growth factors. Cancer – produces own growth factors, excess growth factor and activated pathways

Question 11

Changes associated with cell transformation- Evading growth suppressors

Answer 11

Normal cells have checkpoints, in cancer these checkpoints don’t worl

Question 12

Changes associated with cell transformation- resisting cell death

Answer 12

Normally cells undergo apoptosis, cancer cells don’t

Question 13

Changes associated with cell transformation- replicative immortality

Answer 13

Normal cells undergo finite number of divisions and enter senescence due to progressive telomere loss. Cancer cells extend telomeres (e.g. express telomerase enzyme) and avoid senescence

Question 14

Changes associated with cell transformation- angiogenesis

Answer 14

Cancer cells promote growth of blood vessels ‒ via increased VEGF or preventing inhibition of angiogenesis. To help provide substances to the tumour.

Question 15

Changes associated with cell transformation- invasion and metastasis

Answer 15

Cancer cells have abnormal cell-cell interactions with decreases cellular adhesion. Due to the secretion of proteolytic enzymes e.g. matrix metalloproteinases (MMPs) that help to break down the basement membrane. They have abnormal motility.

Question 16

Two emerging hallmarks of cancer

Answer 16

Avoiding immune destruction and deregulating cellular energetics

Question 17

Two enabling characteristics of cancer

Answer 17

Genomic instability (more likely to develop tumours) and tumour promoting inflammation (some cells produce pro-growth signals).

Question 18

Where do the mutations need to occur for cancer to form

Answer 18

Most likely in an oncogene (proto-oncogene) or tumour suppresor gene

Question 19

When can the mutations occur

Answer 19

1. Germ line mutations- inherited like BRDA1
2. Somatic DNA mutations -acquired after conception. Can be the result of carcinogens or oncogenic viruses which encode viral oncogenes, which stimulate the cell cycle.

Question 20

How can carcinogens lead to direct DNA damage

Answer 20

Could be due to a DNA break, such as a single or double stranded break. Or crosslinking, either from DNA to DNA or from DNA to protein. The DNA may not be repaired perfectly and bases can be deleted by accident, as the base on both strands are deleted the DNA has no way of knowing what the right DNA sequence is. Carcinogens can also lead to epigenetic regulation as a result of methylation and acetylation. This will alter gene expression and lead to uncontrolled cell division. Ultimately carcinogens will lead to the activation of oncogenes and the inactivation of tumour suppressors.

Question 21

How can radiation lead to carcinogenesis

Answer 21

The UV can directly damage the DNA causing DNA/DNA crosslinking or can cause Thymidine dimer when the thymidine bases are mutated. The UV can also indirectly damage DNA when free radicals mediate oxidative DNA damage.

Question 22

How viral oncogenes lead to carcinogenesis

Answer 22

Viruses can encode proteins which inhibit tumour suppressor genes or checkpoint regulators. This enables mutations to build up.

Question 23

Mutations in B-raf kinase

Answer 23

When the cell detects a growth signal the B-raf kinase becomes active and phosphorylate transcription factors allowing the production of the genes which are needed to go through the checkpoint. In cancer the oncogenic B-raf kinase has a mutation which allows it to be active all the time independent of growth factor signalling.

Question 24

Oncogene mutations

Answer 24

• Deletion or point mutation in coding sequence- hyperactive protein made in normal amounts
• Regulatory mutation- normal protein greatly over produced, DNA produces more RNA
• Gene amplification- the normal protein is greatly overproduced as there are more copies of the gene
• Chromosome rearrangement- nearby regulatory DNA sequence causes the normal protein to be overproduces, the DNA may also be fused to an actively transcribed gene which produces hyperactive fusion protein.

Question 25

Mutation in p21

Answer 25

It is a tumour suppressor gene so when p21 is not produced the cyclin/CDK complexes are not made. he cell cycle can not be inhibited, and you do not get Apoptosis. So if you inactivate the negative regulators of the cell cycle you will get increased cell division.

Question 26

Tumour/ neoplasm /new growth

Answer 26

When cell divide at a faster rate then the surrounding epithelial cells and this division is not coordinated by surrounding tissue. Due to the presence or multi step acquisition of new DNA mutations.

Question 27

Neoplasia

Answer 27

The presence of an abnormal growth of tissues. Uncontrolled cellular proliferation with abnormal cell structure and function, irreversible.

Question 28

Hyperplasia

Answer 28

Increased cell division but cells look and act normal, this is reversible and is after only a small amount of mutations in the cell

Question 29

Dysplasia

Answer 29

Pre-cancer, it is atypical hyperplasia. Increased cell division but the cells look abnormal, it is reversible

Question 30

Papiloma

Answer 30

Benign epithelial tumour

Question 31

Adenoma

Answer 31

Benign tumour of epithelial tissue with glandular origin

Question 32

Carcinoma

Answer 32

A tumour which develops in the skin or tissue lining organs

Question 33

Sarcoma

Answer 33

Type of cancer that grow in connective tissue like bones, nerves, muscles, tendons, cartilage and blood vessels of the arms and legs

Question 34

Carcinoma in situ

Answer 34

A group of abnormal cells, disagreement over whether it should be classified as cancer

Question 35

Intraepithelial neoplasia

Answer 35

Development of a benign neoplasia in the epithelium

Question 36

Metastasis

Answer 36

Spread of cancer to a secondary site

Question 37

Cancer invasion

Answer 37

When the cancer spreads to other tissues and goes through the basement membrane

Question 38

Classification of cancer

Answer 38

Histogenic- Classification based on the tissue type the cancer originates from i.e. intraepithelial neoplasia
Anatomical position- i.e. prostate, lung or breast
Can be named after the person who discovered it like Burkitt’s Lymphoma

Question 39

Blastomas

Answer 39

Tumours of blast cells (type of stem cell). More common in young children. You have retinoblastoma which affects the eye

Question 40

Harmatomas

Answer 40

Cells in the connective tissue grow larger as the patient grow. Not a true neoplasm as no new tissue is being created, the cells aren’t dividing they are just getting bigger. Don’t tend to cause any symptoms but are often detected on scans. They can cause a lot of anxiety when detected, and the patient may undergo further investigations and treatment before it is determined that the growth is a harmatoma rather than a neoplasm.

Question 41

Endocrine/neuroendocrine tumours

Answer 41

Originate from tissues that produce a hormone. Causes excessive production of hormones.

Question 42

Cysts

Answer 42

A fluid filled space that is lined by the epithelium. Can be caused by parasites or trauma. Some malignant tumours may also present as cysts. An example is a tetroma which is a tumour of an egg or sperm cell, it causes differentiation and growth to lose control and results in a tumour that can grow body parts like teeth or hair.

Question 43

Big difference between benign and malignant tumours

Answer 43

Malignant tumours invade through the basement membrane

Question 44

Characteristics of benign tumours

Answer 44

Resemblance to normal tissue- well differentiated and closely resemble normal tissue
Direction of growth- exophytic growth, they grow outwards as they are unable to invade and spread through surrounding tissue
Nuclear size- tends to be small.
They grow slower and have a low level of necrosis. They have well defined, circumscribed borders as they are confined to the space they grow into.

Question 45

Characteristics of malignant tumours

Answer 45

Resemblance to normal tissue- poorly differentiated and resemble normal tissue less, there is evidence of destruction. The amount of destruction varies between malignant tumours. If there is a lot of destruction it may be known an anaplastic tissue meaning you are unable to tell which tissue type it has come from
Direction of growth- endophytic growth, they grow inwards as they grow through surrounding tissue when they invade it.
Nuclear size- an enlarged nucleus due to more DNA replication. The larger the nucleus, the more aggressive the tumour.
Grow quicker and have a high level of necrosis as more cell replication and turnover. Malignant tumours have poorly defined, irregular borders as they are not confined by a space and invade surrounding tissue.

Question 46

How do malignant tumour cells detach and invade local structures

Answer 46

1) Decreased cellular adhesion
2) Secretion of proteolytic enzymes (metalloproteinases)
3) Abnormally increased motility

Question 47

Cancer- decreased cellular adhesion

Answer 47

In normal tissue, cells are bound together by adhesion molecules. Malignant cells loose expression of adhesion molecules so they are able to separate from surrounding cells more easily.

Question 48

Cancer- secretion of proteolytic enzymes (metalloproteinases)

Answer 48

Malignant cells secrete proteolytic enzymes e.g. metalloproteinases which break down connective tissue, so the malignant cells can move through the tissue. Normal tissues naturally express inhibitors to metalloproteinases, different amounts depending on the tissue. The more inhibitor the tissue expresses, the harder it is for malignant cells to spread through it. Cartilage

Question 49

Cancer- abnormally increased motility

Answer 49

Normally epithelial cells so not move much and mesenchymal cells (connective tissue) move a bit more. But in epithelial-mesenchymal transition, the malignant epithelial cells express proteins usually produced by mesenchymal cells, becoming more mobile. Normally when a cell bumps into another cell, this contact stops it from moving more but malignant cells lose this contact inhibition.

Question 50

Primary tumours

Answer 50

Tumours located in the site the cancer originated from

Question 51

Secondary tumours (metastases)

Answer 51

Located in different organs or tissues from where the cancer originated from

Question 52

Carcinomatosis

Answer 52

When there are multiple metastases in different sites, hard to find the primary tissue because its so small

Question 53

What is needed for metastases

Answer 53

• Invasion= the cells needs to enter the blood vessel without destroying itself or the vessel.
• Evasion of host defence- it needs to evade the immune system
• Adherence- it needs to stick to the side of the blood vessel at the site of metastasis
• Evacuation- it needs to be able to leave the blood vessel without destroying itself or the vessel.

Question 54

Routes malignant cells can take to spread through the body

Answer 54

• Haematogenous- spreads via the blood stream, normally occurs in the brain, liver, lungs and bone.
• Lymphatics- malignant cells move through the lymphatics system and tend to congregate in lymph nodes leading to their enlargement.
• Transcoelomic- through the pleural, pericardial or peritoneal cavities. Malignant cells spread through the lubricating fluid to different parts of the cavity. If malignant cells have also spread through the lymphatic system and congregated in lymph nodes, this can cause a blockage which can cause fluid to leak out into these cavities. The fluid is called an effusion and helps malignant cells to spread further through the cavities.