Why And How Neoplasms Occur

Question 1

What is the cause of neoplasia?

Answer 1

• Multifactorial
• Intrinsic host factures (age, sex, heredity)
• Extrinsic (environment and behavioural) = 85%

Question 2

What are the five major risks for cancer deaths?

Answer 2

About 30% of cancer deaths are due to the five leading behavioural and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol use. Tobacco smoke alone is associated with approximately a quarter of all cancer deaths.

Question 3

What are the three main categories of extrinsic carcinogens?

Answer 3

Chemicals, radiation and infections.

Question 4

Why do industrial carcinogens primarily effect relevant workers?

Answer 4

The risk of cancer depends on total carcinogen dosage

Question 5

Describe the role of initiators and promotors within chemical carcinogenesis

Answer 5

Initiators (mutagens) must be given first followed by a second class of carcinogen, promoters. Promoters cause prolonged proliferation in target tissues.

Question 6

What does the Ames test show?

Answer 6

The Ames test shows that initiators are mutagens, while promoters cause prolonged proliferation in target tissues.

Question 7

How do mutant monoclonal collections of cells become fully malignant?

Answer 7

Process of progression

Question 8

What are pro-carcinogens?

Answer 8

Only converted to carcinogens by cytochrome P450 enzymes in the liver.

Question 9

What are complete carcinogens?

Answer 9

Carcinogens that act as both initiators and promoters

Question 10

What is radiation?

Answer 10

Any type of energy travelling through space, some forms are mutagenic.

Question 11

Describe the different types of radiation

Answer 11

Ultraviolet (UV) light does not penetrate deeper than skin. Ionising radiation strips electrons from atoms and includes X-rays and nuclear radiation arising from radioactive elements. Nuclear radiation comprises alpha particles, beta particles and gamma rays.

Question 12

How does radiation damage DNA?

Answer 12

• Radiation can damage DNA directly and also indirectly by generating free radicals.
• The most important type of radiation is UV because we are exposed daily from sunlight leading to increased skin cancer risk.
• For most people the main exposure to ionising radiation is natural background radiation from radon, which seeps from the earth’s crust.
• Ionising radiation damages DNA bases and causes single and double strand DNA breaks.

Question 13

How do infections act as carcinogens?

Answer 13

Some infections directly affect genes that control cell growth. Others affect growth indirectly by causing chronic tissue injury where the resulting regeneration acts either as a promoter for any pre- existing mutations or else causes new mutations from DNA replication errors.

Question 14

What type of carcinogen is HPV?

Answer 14

A direct carcinogen because it expresses the E6 and E7 proteins that inhibit p53 and pRB protein function respectively, both of which are important in cell proliferation.

Question 15

What type of carcinogens are Hepatitis B and C?

Answer 15

Hepatitis B and C viruses are indirect carcinogens that cause chronic liver cell injury and regeneration.

Question 16

How do bacteria and parasites lead to neaoplasms?

Answer 16

Bacteria and parasites can indirectly lead to neoplasms. Helicobacter pylori causes chronic gastric inflammation and parasitic flukes cause inflammation in bile ducts and bladder mucosa, increasing the risk for gastric, cholangio- and bladder carcinomas respectively.

Question 17

How does HIV lead to neoplasms?

Answer 17

Human Immunodeficiency virus (HIV) acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur.

Question 18

What is a retinoblastoma?

Answer 18

Malignant retinal tumour

Question 19

What are tumour suppressor genes?

Answer 19

Genes that inhibit neoplastic growth. Both alleles must be inactivated to favour neoplastic growth.

Question 20

What are oncogenes?

Answer 20

Genes that enhance neoplastic growth. They are abnormally activated versions of normal genes. Only one allele of each proto-oncogene needs to be activated to favour neoplastic growth.

Question 21

What does the ‘two hit hypothesis’ seek to explain?

Answer 21

Theory to explain the differences between tumours occurring in families and those occurring in the general population.

Question 22

How does the ‘two hit hypothesis’ apply to familial cancers?

Answer 22

For familial cancers, the first hit is delivered through the germ line and affects all cells in the body. The second his is a somatic mutation.

Question 23

How does the ‘two hit hypothesis’ apply to sporadic cancers?

Answer 23

No germ line mutation therefore both hits are required to be somatic mutations within the same gene.

Question 24

What is the RAS gene?

Answer 24

• Mutated in approximately ⅓ of all malignant neoplasms
• RAS proto-oncogene encodes for a small G protein that relays signals into the cell that eternally pushes the cell past the cell cycle restriction point.

Question 25

What does a mutant RAS gene do?

Answer 25

Encodes a protein that is always active, ultimately producing a constant signal to pass through the cell cycle’s restriction point.

Question 26

What is the function of the RB gene?

Answer 26

Restrains cell proliferation by inhibiting passage through the restriction point. Inactivation of both RB alleles therefore allows unrestrained passage through the restriction point.

Question 27

How can the restriction point be deregulated?

Answer 27

By an activated oncogene or an inactivated TS gene.

Question 28

What do proto-oncogenes encode for?

Answer 28

Growth factors, growth factor receptors, plasma membrane signal transducers, intracellular kinases, transcription factors, cell cycle regulators or apoptosis regulators.

Question 29

What causes xeroderma pigmentosum?

Answer 29

Germ line mutations that cause malignant neoplasms indirectly due to mutations in DNA repair genes. XP is autosomal recessive and is due to mutations in one of the 7 genes that affect DNA nucleotide excision repair (NER). Patients are very sensitive to UV damage and develop skin cancer at a young age.

Question 30

What is HNPCC?

Answer 30

Hereditary non-polyposis colon cancer syndrome is an autosomal dominant disease associated with colon carcinoma and the germ line mutation affects one of several DNA mismatch repair genes.

Question 31

What is the importance of the BRCA 1/BRCA 2 genes?

Answer 31

Genes that are important in repairing double strand DNA breaks. These various mutations are found in familial breast carcinoma and sporadic malignant neoplasms.

Question 32

What is genetic instability?

Answer 32

The accelerated mutation rate found in malignant neoplasms due to abnormal chromosome segregation during mitosis, micro satellite instability and nucleotide instability.

Question 33

What are caretaker genes?

Answer 33

Tumour suppressor genes that maintain genetic stability

Question 34

How many mutations are required to make a malignant neoplasm?

Answer 34

Multiple mutations are required to make a malignant neoplasm. Most require alterations affecting a combination of multiple TS genes and photo-oncogenes.

Question 35

What is the adenoma-carcinoma sequence?

Answer 35

Carcinomas arise from adenomas. Analysis of early adenomas, later adenomas, primary carcinomas and metastatic carcinomas showed that mutations accumulate during this sequence and the time frame is typically decades.

Question 36

What is progression?

Answer 36

The steady, step-wise accumulation of mutations in malignant neoplasms.

Question 37

How do cancers evolve?

Answer 37

Initiation and promotion. Followed by progression.

Question 38

What are the six hallmarks of cancer exhibited by malignant neoplasms?

Answer 38

(1) self-sufficiency in growth signals;
(2) resistance to growth stop signals;
(3) no limit on the number of times a cell can divide (cell immortalisation);
(4) sustained ability to induce new blood vessels (angiogenesis);
(5) resistance to apoptosis;
(6) the ability to invade and produce metastases.

Question 39

Describe the cancer pathogenesis model

Answer 39

First, somatic cells are exposed to environmental carcinogens (chemicals, radiation, infections) that are either initiators (that cause mutation) or promoters (that cause sustained proliferation) culminating in a monoclonal population of mutant cells . In about 5% of cancers inherited mutations in the germline can be present.

By chance, some of these clones harbour mutations affecting a proto-oncogene or a tumour suppressor gene, whose protein transcripts play crucial roles in cell signalling pathways affecting “hallmark” changes.

During progression the cells acquire further activated oncogenes or inactivated tumour suppressor genes, including ones that cause genetic instability.

This is eventually results, after many years or even decades, in a population of cells that have acquired a set of mutations that produce all of the “hallmarks of cancer”