Neoplasia - Carcinogenesis

Question 1

What is carcinogenesis and what is/are the causes of neoplasia?

Answer 1

Carcinogenesis is the cause of cancer. The cause of neoplasia is multifactorial - a combination of extrinsic factors related to the environment and lifestyle/behaviour, as well as intrinsic host factors (heredity, age, gender etc).

Question 2

Why is there an increased cancer incidence?

Answer 2

Prolonged lifespan.

Question 3

An estimated 30% of cancer deaths are due to 5 behavioural and dietary risks, what are they? Which is particularly linked?

Answer 3

A high BMI, alcohol use, tobacco use, a low fruit and vegetable intake and a lack of physical activity.
Tobacco is associated with a quarter of all cancer deaths.

Question 4

Where does evidence about the risks involved in Carcinogenesis come from?

Answer 4

Epidemiological and animal studies, such as the Immigration act of 1924 providing samples of Japanese migrants and their relatives in the USA.

Question 5

85% of the population’s cancer risk comes from extrinsic factors, which 3 groups can these be split into?

Answer 5

Chemicals, infections and radiation.

Question 6

Give an example of a carcinogenic chemical and its repercussions.

Answer 6

2-napthylamine, a chemical in the dye manufacturing industry, is associated strongly with bladder carcinoma, which became prevalent in industry workers.

Question 7

Malignant neoplasms caused by chemicals can show a long ______ (sometimes _______) from carcinogen exposure to cancer ______. The risk can depend on total carcinogen _________ (why tobacco smoke primarily affects smokers). Sometimes certain carcinogens show _______ specificity.

Answer 7

Delay
Decades
Onset
Dosage
Organ

Question 8

What are the 2 main classes of chemical carcinogen and what order must things happen in to result in neoplasia?

Answer 8

Some carcinogens are initiators and must be given first, followed by promoters, for a longer time. This culminates in monoclonal expansion of mutant cells, which later become fully malignant through progression.

Question 9

What does the Ames test, working out the different properties of carcinogens, show that initiators and promoters do?

Answer 9

Initiators are mutagens, causing mutations in cells, whereas promoters cause prolonged proliferation in target tissues.

Question 10

What are the different classes that mutagenic chemical carcinogens (initiators), can be classified into? (5)

Answer 10

Polycyclic aromatic hydrocarbons, aromatic amines, N-nitroso compounds, alkylating agents and diverse natural products.

Question 11

What are pro-carcinogens and what about complete carcinogens?

Answer 11

Pro-carcinogens are chemicals only converted to carcinogens, once in the body by cytochrome P450 enzymes in the liver.
Complete carcinogens act as both initiators and promoters.

Question 12

What is radiation and what are the different types?

Answer 12

Radiation is any type of energy travelling through space; some types are mutagenic. UV light doesn’t penetrate deeper than the skin. Ionising radiation strips atoms of their electrons and includes X-rays and nuclear radiation, arising from radioactive elements: alpha and beta particles and gamma rays.

Question 13

What is the most important type of radiation as a cause of cancer and what type of iodising radiation are people most exposed to?

Answer 13

Ultra violet is the most important, with daily sunlight exposure, leading to an increased risk of skin cancer. Natural background exposure from radon (which seeps through the Earth’s crust) is people’s main exposure to iodising radiation.

Question 14

How does radiation act to cause cancer?

Answer 14

Like infections, radiation causes cancer by direst and indirect methods. It may damage the DNA directly, with ionising radiation leading to altered bases and double/single strand breaks or indirectly, by creating free radicals.

Question 15

Some infections cause cancer by directly affecting genes controlling gene growth, give an example.

Answer 15

Human Papilloma Virus (HPV) has a strong like with cervical carcinoma. It is a direct carcinogen as it expresses E6 and E7 proteins, which inhibit p53 and pRB(retinoblastoma) genes, which are important in cell proliferation (triggering apoptosis/gateway to the cell cycle).

Question 16

Some infections act indirectly to cause cancer, by causing chronic tissue injury, with resulting regeneration a promoter for pre-existing mutations or making new mutations, from DNA replication errors, give an example.

Answer 16

Hepatitis B and C are indirect carcinogens as they cause chronic liver cell injury and regeneration. Bacteria and parasites can also indirectly lead to neoplasms.

Question 17

How does HIV act as an indirect carcinogen?

Answer 17

The virus lowers immunity, allowing other possibly carcinogenic infections to occur.

Question 18

How do some people have inherited predisposition to neoplasia?

Answer 18

Through germ line mutations.

Question 19

Retinoblastoma was observed to run in families (with a dominant trait), but also occur sporadically. Which hypothesis explains this and how?

Answer 19

The two-hit hypothesis explains that in familial cancers, the 1st hit affecting all cells is from the germ line mutations and the 2nd hit must be a sporadic mutation (to any of the 1/10 million+ retinal cells), whereas the sporadic cancer requires both hits to be somatic and occur in the same same. The Rb gene has been identified (2 alleles, 1 hit to inactivate each).

Question 20

Which genes must be affected for initiation and promotion to lead to neoplasia and how?

Answer 20

Porto-oncogenes and tumour suppressor genes.
TSGs inhibit neoplastic growth - acting like breaks, both must be inactivated, hence the 2 hit hypothesis.
Oncogenes, which enhance neoplastic growth are abnormally activated proto-oncogenes. Only 1 allele needs to be activated to enhance neoplastic growth.

Question 21

Proto-oncogenes and tumour suppressor genes play opposing roles in cell signalling pathways. How is this the case in the regulation of the restriction point in the cell cycle? Include a description of how 1 component of growth control can be deregulated in 2 ways.

Answer 21

RAS is an oncogene activated in 1/3 of malignant neoplasms. The proto-oncogene encodes a G protein relaying signals to push the cell cycle past the R point - the mutant protein is always active, providing a constant signal to go through the cell cycle.
In contrast, the Rb gene restrains proliferation, by inhibiting passage through the R point, so inactivation of both TSG alleles leads to unrestrained passage.

Question 22

What type of proteins can proto-oncogenes and tumour suppressor genes encode?

Answer 22

POGs can encode growth factors, growth factor receptors, intracellular kinases, plasma membrane signal transducers, transcription factors, cell cycle or apoptosis regulators.
TSGs encode proteins on the same pathways, but with an anti-growth effect.

Question 23

Some inherited cancers have germlone mutations that do not affect TSGs or POGs, but caretaker genes, how do these work? Use the example of Xeroderma Pigmentosa.

Answer 23

They act indirectly by affecting DNA repair. Xeroderma Pigmentosa is an autosomal recessive condition from a mutation affecting 1/7 genes for nucleotide excision repair (NER). Patients are sensitive to UV damage and develop skin cancer at a young age.

Question 24

Hereditary non-polyposis colon cancer (HNNCC syndrome), is an autosomal dominant condition associated with colon carcinoma, how does this happen?

Answer 24

A germ line mutation affects one of several DNA mismatch repair genes.

Question 25

How are the BRCA1 and BRCA2 genes associated with familial breast carcinoma?

Answer 25

They are genes that repair double strand breaks, which can otherwise lead to inappropriate chromosomal segregation in mitosis. Various mutations are also found in sporadic malignant neoplasms.

Question 26

The phenotype of genetic instability comes with increased mutation rate (often resulting in neoplasia). Which 3 things can lead to this and how are caretaker genes involved?

Answer 26

Nucleotide, microsatellite and chromosomal instability account for genetic instability. Genes for maintaining genetic instability are called caretaker genes; they are a type of tumour suppressor genes.

Question 27

Most malignant tumours require alterations affecting a combination of TSGs and POGs. What is the adenoma-carcinoma sequence?

Answer 27

Such as in the example of colon cancer, when a colon carcinoma can arise from an adenoma. Analysis of early and later adenomas, primary carcinomas and metastatic carcinomas show mutations accumulating during the sequence. The typical time frame is decades.

Question 28

What is cancer Progression?

Answer 28

The steady accumulation of multiple mutations?

So for cancer: initiation + promotion + progression

Question 29

The number of mutations required for a fully evolved malignant neoplasm is estimated as 10 or fewer. How do promoters help?

Answer 29

They provide a growth advantage for further mutations (progression).

Question 30

It is said that fully evolved malignant neoplasms exhibit 6 hallmarks of cancer, what are they?

Answer 30

1. Self sufficiency in growth signals
2. Resistance to growth stop signals
3. Cell immortalisation - no limit of number of cell divisions
4. Angiogenesis - sustained ability to produce new blood vessels
5. Resistance to apoptosis
6. Ability to evade and metastasise

Question 31

Are the 6 hallmarks of cancer relevant for benign neoplasms?

Answer 31

The first five (Self sufficiency in growth signals, Resistance to growth stop signals, Cell immortalisation - no limit of number of cell divisions, Angiogenesis - sustained ability to produce new blood vessels, Resistance to apoptosis) are mainly about increased growth, so are also relevant to benign neoplasms.

Question 32

As well as the 6 hallmarks of cancer, malignant neoplasms have an enabling characteristic. What is it?

Answer 32

Genetic instability.

Question 33

Model of cancer pathogenesis (1):
_________ cells are exposed to environmental carcinogens, either initiators or __________, culminating in a ____________ population of mutated cells - in 5% of cancers, inherited _________ in the germ line are present. By chance, some close harbour ____/TSG mutations, whose protein transcripts play crucial roles in cell __________ pathways affecting ‘hallmark’ changes.

Answer 33

Somatic
Promotes
Monoclonal
Mutations
POG
Signalling

Question 34

Model of cancer pathogenesis (2):
During __________, cells acquire further __________OGs/inactivated _____, including ones causing genetic _____________. After many years (even decades), this results in a population of cells with an acquired set of mutations that produce all the __________ of cancer.

Answer 34

Progression
Activated
TSGs
Instability
Hallmarks