S9) Causes & Mechanisms of Neoplasia Flashcards
Explain how the cause of neoplasia is multi-factorial
- A combination of intrinsic host factorse.g. heredity, age and gender andextrinsicfactors e.g. environment and behaviour account for cancer risk
- Much of the increased cancer incidence over the last century is due to prolonged life- span
About 30% of cancer deaths are due to the five leading behavioural and dietary risks.
What are they?
- High body mass index
- Low fruit and vegetable intake
- Lack of physical activity
- Tobacco use (¼ of all cancer deaths)
- Alcohol use
Extrinsic factors account for approximately 85% of a population’s cancer risk.
Identify the three categories of extrinsic carcinogens
- Chemicals
- Radiation
- Infections
Which important lessons about carcinogenesis do we learn from malignant neoplasms caused by 2-napthylamine?
- There is a long delay between carcinogen exposure and malignant neoplasm onset
- The risk of cancer depends on total carcinogen dosage
- There is sometimes organ specificity for particular carcinogens e.g. 2-napthylamine causes bladder carcinoma
With reference to the Ames test, explain how chemical carcinogenesis involves initiation and promotion
- The Ames test shows that initiators are mutagens, while promoters cause prolonged proliferation in target tissues
- This culminates in a monoclonal expansion of mutant cells
How can chemical carcinogens be classified according to their nature?
Define the following terms:
- Pro-carcinogen
- Complete carcinogen
- Pro-carcinogens are chemicals which are only converted to carcinogens by the cytochrome P450 enzymes in the liver
- Complete carcinogens are chemicals which act as both initiators and promoters
What is radiation?
Radiation is any type of energy travelling through space
Describe the properties of the following types of radiation:
- UV radiation
- Ionising radiation
- Nuclear radiation
- Ultraviolet radiation 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
Describe the effect of radiation on DNA
Radiation can damage DNA directly and also indirectly by generating free radicals
Explain how ionising and UV radiation are mutagenic
- UV radiation is important as we are exposed to it daily from sunlight leading to increased skin cancer risk
- Background ionising radiation from radon damages DNA bases and causes single and double strand DNA breaks
Explain how some infections are carcinogenic and can act directly or indirectly
- Some infections act directly to affect genes that control cell growth
- Other infections act indirectly by causing chronic tissue injury where the resulting regeneration acts either as a promoter for pre-existing mutations / initiator for new mutations
Briefly, explain how the following pathogens act as carcinogens either directly/indirectly:
- Human Papilloma Virus
- Hepatitis B & C Viruses
- Helicobacter pylori
- Parasitic flukes
- Human Immunodeficiency Virus
- HPV expresses E6 and E7 proteins which directly inhibit p53 and pRB protein function in cell proliferation (cervical carcinoma)
- Hepatitis B,C act indirectly and cause chronic liver cell injury and regeneration
- Helicobacter pylori causes chronic gastric inflammation (gastric carcinoma)
- Parasitic flukes act indirectly to cause inflammation in bile ducts and bladder mucosa (cholangio- and bladder carcinomas)
- HIV acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur
Explain why initiation and promotion lead to neoplasms when they affect proto-oncogenes and tumour suppressor genes
- Tumour suppressor genes are genes which inhibit neoplastic growth – both alleles must be inactivated to allow neoplastic growth (two hits)
- Oncogenes are genes which enhance neoplastic growth and are the abnormally activated versions of normal proto-oncogenes – only one allele of each proto-oncogene needs to be activated to favour neoplastic growth
In four steps, illustrate how the restriction point, in the cell signalling pathway for growth control, can be deregulated by the combination of an activated oncogene and an inactivated TS gene
⇒ The RAS proto-oncogene encodes a small G protein that relays signals into the cell & pushes the cell past the cell cycle restriction point
⇒ The mutant RAS oncogene encodes a protein that is always active, producing a constant signal to pass through the cell cycle’s restriction point
⇒ 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
This steady accumulation of multiple mutations is called cancer progression.
In terms of a colon carcinoma, illustrate how multiple mutations are required to make a neoplasm
Illustrate Knudson’s two hit hypothesis for oncogenesis in familial and sporadic cancers
What is Hereditary non-polyposis colon cancer?
- HNPCC is an autosomal dominant familial syndrome due to mutations in the DNA mismatch repair genes (caretaker genes)
- Cancers tend to occur in patients < 50 years old and malignancies are often in the caecum and proximal colon
What is familial adenomatous polyposis?
- FAP is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine
- While these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated
Illustrate the adeno-carcinoma sequence
