Neoplasia II

Question 1

Causes of cancer?

Answer 1

Inherited predisposition - more rare cancers often have a single genetic cause, e.g: retinoblastoma, FAP (Familial Adenomatous Polyposis)
Another example is BRCA mutations for breast cancer

Chemicals
Radiation
Infections
Inflammation
Lifestyle factors - obesity
Unknown cause

Question 2

Meaning of autosomal dominant and examples in cancer?

Answer 2

Only need one copy of the faulty gene for it to have an effect
E.g: retinoblastoma - children with RB (retinoblastoma protein, which is a tumour suppressor, mutation have a greatly increased risk
FAP - Family Adenomatous Polyposis. Involves APC gene, with a 100% chance of bowel cancer before age 50

Question 3

What is the double hit hypothesis?

Answer 3

One working gene is enough
Two faulty copies to have a functional problem
Those who have inherited one faulty copy have increased risk and only need one more “hit”

Question 4

Examples of gene mutations and what they lead to?

Answer 4

p53 - Li Fraumeni (p53 mutations can cause many cancers)
APC - FAP/Gardener’s
PTCH - Gorlin’s syndrome (increases risk of developing various cancerous and noncancerous tumors and affects many areas of body)
PTEN - Cowden’s syndrome (multiple tumor-like growths called hamartomas and an increased risk of certain forms of cancer)
RET - MEN1 (Multiple Endocrine Neoplasia type 1)
MLH1 etc - HNPCC (Hereditary Non-Polyposis Colorectal Cancer and Muir Torres - subtype of HNPCC)

Question 5

Chemicals that increase risk of cancer?

Answer 5

Smoking - increases risk of almost all types of cancer

Aflatoxin (fungus on peanuts) - association with liver cancers

Beta-naphthylamine (chemical dyes - now heavily regulated) - strong association with bladder cancer

Nitosamines (food preservatives)

Arsenic - skin cancer

Question 6

Cancers associated with smoking?

Answer 6

Lung cancer - very strong association with small cell lung cancer
Head and neck cancers
Bladder cancers
Cervical cancer - with HPV (Human Papilloma Virus - microbial carcinogenesis)

Question 7

Example of how radiation can cause cancer formation?

Answer 7

UV radiation (UV: 280-320nm)
UV can cause formation of pyrimidine dimers in DNA
Initially cells can repair the DNA damage but, with repeated exposure, repair mechanisms are overwhelmed

Question 8

Sources of radiation exposure?

Answer 8

UV
X-rays
CT scan (huge amount of radiation - most are susceptible to leukaemias and thyroid cancers)

Question 9

Cyclins in the cell cycle?

Answer 9

Cyclins - family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (Cdk) enzymes, e.g: cyclin A, B, D, E are a cascade reaction that drive the cell cycle

Question 10

Action of cyclase inhibitors?

Answer 10

No transcription - E2F binds to RB (tumour supressor) and so E2F (codes for transcription factors) is not free to bind to DNA and begin transcription

Transcription - Ps bind to Rb and E2F is thus free, can bind to DNA and can promote transcription of DNA polymerase

Question 11

Cell cycle in HPV?

Answer 11

E7 (an oncogene product of HPV) binds to Rb and this leaves E2F (which normally binds to Rb) free. E2F can bind to DNA and promote transcription of DNA polymerase

Question 12

Functions of E6 and E7?

Answer 12

E6 - increases destruction of p53

E7 - prevents retinoblastoma (RB) protein from acting

Question 13

What is EBV?

Answer 13

Epstein-Barr virus - implicated in several tumours, part. lymphomas, e.g: Burkitt-lymphoma, B-cell lymphomas, Hodgkin lymphomas, and with nasopharyngeal carcinoma

Question 14

Role of chronic inflammation in cancer formation?

Answer 14

Causes many lymphomas - constant lymphocyte reproduction may lead to error in production
Often, tumours are caused because the tissue is replicating so often that it becomes unstable

Question 15

Risk factors for chronic inflammation and cancers?

Answer 15

Paraplegic patients with permanent catheters - uroepithelium changes to squamous (copes better with inflammation) due to catheters

Stomach - chronic gastritis predisposes to malignant changes

Often in the context of METAPLASTIC CHANGE

Question 16

What is Schistosomiasis?

Answer 16

Disease caused by parasitic flat worms of the Schistosoma type

May infect the urinary tract or the intestines and, if left for a long time, may lead to bladder cancer

Question 17

Obesity as a cancer risk factor?

Answer 17

Hyperplasia in the endometrium
Steroid hormone oestrogen is similar in structure to cholesterol
Increases risk of renal cell carcinoma

Question 18

How can obesity cause cancer?

Answer 18

Associated with growth factors (IGF-1)

Effects on mTOR pathway and others

Question 19

Distribution of weight in obesity?

Answer 19

Centripetal obesity - those with abnormal distribution around the belly are at higher risk of cancer

Question 20

Common link between all cancer risk factors?

Answer 20

All interfere with 4 molecular groups of cancer development, via mutation or otherwise, e.g: microbial like HPV

Progrowth - oncogenes
Avoid inhibition of growth - tumour suppressors
Apoptosis - BCL2 switches off apoptosis
Spell checkers, e.g: p53

Question 21

What is dysplasia?

Answer 21

Pre-malignant change in the EPITHELIUM - literally translated to DISORDERED GROTH

Cells have accumulated mutations in sufficient quantity to be identifiably abnormal down the microscope

Question 22

Describe neoplastic to cancer

Answer 22

Now invasive as the neoplasm has achieved some level of immortality (4 categories)

To invade tissues, must be able to produce substances that can help digest connective tissue, e.g: MMP (Matrix MetalloProteinases)

Question 23

What is metastasis?

Answer 23

Transition/displacement - used to describe a tumour that has spread to a site distant from its origin
Once tumour enters a vessel, it forms an aggregate with platelets and adheres to vessels at distant before invading - different tumours will express different receptors for vessel wall adherence

Question 24

Route of metastasis?

Answer 24

Lymphatic spread - often spread to local lymph nodes first

Often predictable, e.g: a lot of venous circulation enters the liver and hepatic metastases are thus quite common

Occasionally, less predictable, e.g: prostate to bone

Question 25

Cancer cell need for oxygen?

Answer 25

Tumours need a blood supply - for oxygen; dividing cells are very metabolically active and so require lots of oxygen and thus blood

Question 26

Angiogenesis in terms of cancer?

Answer 26

Tumours need oxygen, thus blood and thus blood vessels

Successful tumours develop the ability to create their own blood supply - angiogenesis
Often have mutations that allow production of proteins encouraging new vessel growth, e.g:
Vascular Endothelial Growth Factor (VEGF)
Platelet Derived Growth Factor (PDGF)

Question 27

Medicines used in cancer treatment?

Answer 27

Bevacizumab - blocks VEGF receptor and is used to treat cancers reliant on VEGF pathway, e.g: advanced bowel cancer and some lung cancers

Imatinib – PDGFR inihibtor used to treat tumours of connective tissues (gastrointestinal stromal tumours) and some tumours of the blood (lymphomas and leukaemias)