Neoplasia 3

Question 1

What is carcinogenesis?

Answer 1

The causes of cancer

Question 2

What factors make you more suseptible to cancer?

Answer 2

A combination of intrinsic host factors such as heredity (mediliam trait or subtle genetic risk factors), age, gender (especially hormonal) and extrinsic factors related to the environment and behavior account fir cancer risk. Much of the increased cancer incidence over the last century is due to prolonged life span.

Question 3

What are 30% of cancer deaths due to?

Answer 3

About 30% of cancer deaths are due to the five leading behavioral and dietary risks:

• High BMI
• Low fruit and vegtable intake
• Lack of physical activity
• Tobacco use (associated with 25% of cancer deaths)
• Alcohol (carcinogenic - oropharangeal cancer)

Question 4

Where does most of the evidence for cancer risk come from?

Answer 4

Epidemiological and animal studies

Question 5

What percentage of a populations cancer risk comes from extrinsic factors?

Answer 5

Extrinsic factors account for approximately 85% of a population’s cancer risk. Extrinsic carcinogens fall into 3 main categories:

• Chemicals
• Radiation
• Infection

Question 6

2 Napthylamine is an industrial carcinogen used in the dye manafacturing industry. What does the malignant neoplasms caused by this chemical teach us?

Answer 6

• There is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset
• The risk of cancer depends on total carcinogen dose
• There is cometimes organ spcificy for particular carcinogens e.g. 2-napthylamine causes bladder carcinoma.

The dependance on dosage is why industrial carcinogens e.g. asbestos, coal tars, vinyl chloride have an effect primarily on the relevent workers and tobacco smoke’s effect is largely limited to smokers.

Question 7

What seqeuence must carcinogens be administered in?

Answer 7

Some chemical carcinogens called initiators must be given first followed by a second class of carcinogens called promoters. This was shown by experimenrs on animals.

Question 8

What is the Ames test?

Answer 8

The ames test shows that initiators are mutagens while promoters cause prolonged proliferation in target tissue.

This culminates in a monoclonal expantion of mutant cells. Mutant monoclonal antibodies eventually become fully malignant through a furthr process called progression.

Question 9

What is the nature of chemical carcinogens?

Answer 9

Mutagenic chemical carcinogens (i.e initiators) can be classified as polycyclic aromatic hydrocarbons, aromatic amines, N-nitroso compounds, alkylating agents and diverse natural products e.g aflatoxin, asbestos

Question 10

Why need to use rat liver?

Answer 10

Because some of these chemicals are pro-carcinogens and are only converted to carcinogens by cytochrome P450 enzymes in the liver.

Question 11

What are complete carcinogens?

Answer 11

Carcinogens that act as both initiators and promoters.

Question 12

What are some different types of radiation?

Answer 12

Radiation is any type of energy travelling through space and some forms are mutagenic.

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 comprmises alpha particles, beta particles and gamma rays.

Question 13

How does radiation damage DNA?

Answer 13

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 stand DNA breaks.

Question 14

How can infection cause cancer?

Answer 14

Thet act directly or indirectly.

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 promotor for any pre-existing mutations or else causes new mutations from DNA replication errors.

Question 15

How does HPV cause cancer?

Answer 15

Human papilloma virus which is storgly linked to cervical carcinoma is a direct carcinogen because it expresses the E6 and E7 proteins that inhibit p53 and pRB protein function retrospecctively, both of which are important in cell proliferation.

Question 16

What things pathogens can indirectly lead to cancer?

Answer 16

Hep B and Hep C are indirect carcinogens that cause chronic liver cell injury and regeneration. Bacteria and parasites can also indirectly lead to neoplasms. Helicobacter pylori causes cronic gastric inflammation and parasitic flukes cause inflammation in bile ducts and bladder mucosa, increasing the risk for gastric, cholangio- and bladder carcinoma respoectively.

Question 17

How does HIV cause cancer?

Answer 17

HIV acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur

Question 18

How do germ line mutations cause cancer?

Answer 18

Inherited predisposition to neoplasia can occur through germ line mutations.

In the 1800s a type of malignant retinal tumour called retinoblastoma was reported in multiple members of the same family. A dominent pattern of inherience was seen. As well as running in families, this tumour occured sporadically.

Question 19

What is the difference between inherited and sporadic retinoblastoma?

Answer 19

In the 1970s Knudson postulated a two hit hypothesis to explain the differences between tumours occurring in families and those occurring in the general population.

For familial cancers, the first hit was delivered through the germline and affected all cells in the body. The second hit was a somatic mutation. In the case of retinoblastoma this was in one of the 10 million+ retinal cells already carrying the first hit.

In contrast, sporadic retinoblastoma has no germline mutation and so requires both hits to be somatic mutations and to occur in the same cell.

In 1986 the actual gene, RB, was identified. Several other malignant neoplasms are now recognised that have both familial and sporadic counterparts and that follow the same two hit genetic basis as retinoblastoma

The timing of the two hits differs between familial and sporadic retinal blastoma.

Question 20

How can initiation and promotion lead to neoplasms?

Answer 20

Initiations and promotions lead to neoplasms when they affect proto-oncogenes and tumour suppressor gene.

Tumour suppressor geen = inhibit neoplasm growth (same genes as Knudson described)

They act like breaks on tumour growth, both alleles much be inactivatd which explains why they need two hits, ie one for each allele.

Oncogenes = genes that enhance neoplastic growth.

Proto-oncogenes = Mutated oncogene (abnormally activated).

Only one allele of each proto-oncogene needs to be activated to favour neoplastic growth.

Question 21

What is the RAS gene?

Answer 21

The first oncogene to be discovered was RAS and this is mutated in approximately a third of all malignant neoplasms.

The RAS proto-oncogene encodes a small G protein that relays signals into the cell that eventually pushes the cell past the cell cycle restriction point. Mutant RAS encodes a protein that is always active, ultimately producing a constant signal to pass through the cell cycle’s restriction point.

Question 22

What is the RB gene?

Answer 22

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

Question 23

Give examples of proto-oncogenes.

Answer 23

Proto-oncogenes can encode:

• Growth factors (e.g. PDGF),
• Growth factor receptors (e.g. HER2),
• Plasma membrane signal transducers (e.g. RAS),
• Intracellular kinases (e.g. BRAF),
• Transcription factors (e.g. MYC),
• Cell cycle regulators (e.g. CYCLIN D1),
• Apoptosis regulators (e.g. BCL2).

Tumour suppressor genes encode proteins in the same pathways but with anti-growth effects (e.g. TP53).

Question 24

How do mutations in DNA repair genes lead to malignant neoplasms?

Answer 24

Some inherited cancer syndromes have germline mutations that cause malignant neoplasms indirectly by affecting DNA. There are three ways it can be damaged:

• Mismatch repair
• Nucleotide excision repair
• Double strand breaks

Question 25

What disease is caused by a nucleotide excision replair defect?

Answer 25

Xeroderma pigmentosum (XP), which is an autosomal recessive disease, is due to mutations in one of 7 genes that affect DNA nucleotide excision repair (NER). These patients are very sensitive to UV damage and develop skin cancer at a young age.

Question 26

Which disease is caused by a defect in one of several DNA mismatch repair genes?

Answer 26

Hereditary non-polyposis colon cancer (HNPCC) syndrome, which is autosomal dominant, is associated with colon carcinoma and the germline mutation affects one of several DNA mismatch repair genes.

Question 27

What disease is associated with double standed breaks?

Answer 27

Familial breast carcinoma is associated with either BRCA1 or BRCA2 genes that are important for repairing double stranded breaks. These various mutations can also be found in sporadic malignant neoplasms.

Question 28

How do they lead to genetic instability?

Answer 28

Chromosome segregation during mitosis can also be abnormal in malignant cells.

Together, these alterations account for the accelerated mutation rate found in malignant neoplasms that is known as genetic instability.

Genes that maintain genetic stability belong to a class of tumour suppressor genes called CARETAKER GENES.

Question 29

Why are multiple mutations required to make a malignant neoplasm?

Answer 29

Most malignant tumours require alterations affecting a combination of mutiple tumour suppressor and proto-oncogenes.

Cancer evolves by initiation and promotion and finally porgression.

The exact number of mutations needed for a fully evolved malignant neoplasm is unknown but is thought to be approximately 10 or less.

Question 30

How does a colon carcinoma develop?

Answer 30

Starts as a colonic adenoma from which as a carcinoma. This is knwon as the adenoma-carcinoma sequence.

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. This illustrates a general principle of step-wise accumulation of mutations in malignant neoplasms. This steady accumulation of multiple mutations is called cancer progression.

Question 31

What are the six hallmark cellular behaviours that cancer mutations affect?

Answer 31

It is not believes that fully evolves malignant neoplasm exhibits sox hallmarks of cancer plus one enabling features:

1. Self-sufficiency in growth signals
2. Resistance to growth stop signals
3. No limit on the number of times a cell can divide (immortilisation)
4. Sustained ability to induce now blood vessels (angiogenesis)
5. Resistance to apoptosis
6. The ability to induce and produce metastases. (malignant only whereas other hallmarks can also be attributed to benign tumours)

Genetic instability is the enabling characteristic.

Question 32

Describe the model of cancer pathogenesis

Answer 32

• First, somatic cells are exposed to environmental carcinogens or pormoters, culmonating 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 afectig a proto-oncogene or tumour suppressor gene whose protein transcripts play a crutial role in cell signalling pathwyas affecting “hallmark” changes.
• During progression the cells aquire further activated oncogenes or inactivated tumour suppressor genes incuding ones that cause genetic instability.
• This eventually results, after many years or evem decades, in a population of cells that have aquired a set of mutations that produce all of the “hallmarks of cancer”