15. Neoplasia 3 Flashcards
What is carcinogenesis?
causes of cancer
What is the cause of neoplasia?
Multifactorial: combination of intrinsic and extrinsic factors
Give examples of intrinsic factors that contribute to neoplasia?
Heredity, Age, Sex (especially hormonal)
Give examples of extrinsic factors that contribute to neoplasia?
Environment(chemical, radiation, infection), Lifestyle/Behaviour
What is the biggest cause of increased incidence of cancer?
Prolonged life-span
- cancers take long time to form so more prevalent with old age - as we get older our immune competence decreases so abnormal cell proliferation are less likely to be destroyed by the body
What are the five leading behavioural and dietary risks?
High body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, lack of sun safety and alcohol use
What percentage of cancer deaths are caused by the 5 leading behavioural and dietary risks?
30%
What percentage of cancer deaths are associated with smoking?
25%
What percentage a of a population’s cancer risk is due to extrinsic factors?
85%
What are the 3 main categories of extrinsic carcinogens?
chemicals, radiation and infections
What are the 3 relationships between carcinogens and cancers?
(1) there is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset;
(2) the risk of cancer depends on total carcinogen dosage;
(3) there is sometimes organ specificity for particular carcinogens
Give an example of a specific carcinogen and the type of cancer it produces.
2-napthylamine causes bladder carcinoma
- was used industrially in dye manufacturing
What are the 2 types of carcinogens and what is the difference between them?
Initiators: mutagens
Promoters: cause prolonged proliferation
What test can show mutagenic activity of chemicals?
Ames test
- observing whether they cause mutations in sample bacteria
- tells us what are initiators and what are promoters
Why is the sequence in which carcinogens are administered important?
Initiators much be given first Followed by a second class of carcinogens called promoters
By what process do monoclonal collection of cells become neoplastic?
Progression
What are the classifications of mutagenic chemical carcinogens (i.e. initiators)? give examples.
- polycyclic aromatic hydrocarbons (benzopyrene)
- aromatic amines (2-naphthylamine)
- N-nitroso compounds (Dimethylnitrosamine)
- alkylating agents (Vinyl chloride)
- diverse natural products (Aflatoxin B1, asbestos)
What are pro-carcinogens and how are they converted to carcinogens?
- precursor to carcinognes
- converted to carcinogens by the cytochrome P450 enzymes in the liver
What are complete carcinogens?
Carcinogens that act as both initiators and promoters
What is radiation?
Any type of energy travelling through space and some forms are mutagenic
What are the different types of ionising radiation and how do they damage cells?
X-rays and nuclear radiation (α particles, β particles and γ rays)
- strips electrons from atoms
How far does UV rays penetrate?
does not penetrate deeper than skin
How can radiation damage DNA?
- Directly
- Indirectly through production of free radicals
What is the most important type of radiation and why?
UV because we are exposed daily from sunlight leading to increased skin cancer risk
What is main exposure to ionising radiation?
Natural background radiation from radon, which seeps from the earth’s crust
How does ionising radiation damage DNA?
Damages DNA bases and causes single and double strand DNA breaks
How do infections act as carcinogens?
- directly affect genes that control cell growth
- indirectly by causing chronic tissue injury
How does chronic tissue injury cause carcinogenesis?
Resulting regeneration acts either as a promoter for any pre-existing mutations or else causes new mutations from DNA replication errors
Give 3 examples of infections that can lead to cancer.
HPV, HepB&C, HIV
What cancer does HPV cause and how?
Cervical cancer
- is a direct carcinogen
- Makes 2 proteins E6 and E7
- Virus infects cell, ensures it doesn’t die and then hijacks its DNA replication machinery to make more virus particles
- E6 inhibits p53 which prevents cell from undergoing apoptosis
- Hijacks cell cycle by interfering with Retinoblastoma protein which is important as a cell cycle checkpoint
What cancer does HepB&C cause and how?
Indirect carcinogens that cause chronic liver cell injury and regeneration
How does HIV cause cancer?
Acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur
Give an example of a secondary infection as a result of HIV the cancer it causes.
HHV8 = Kaposi Sarcoma
What is Knudson’s two hit hypothesis?
Most genes require two mutations to cause a phenotypic change
- his hypothesis refers to the tumour suppressor genes (mutation of both alleles required for tumour)
- explains the differences between tumours occurring in families and those occurring in the general population
For familial cancers, when are the hits (genetic mutations) delivered and which cells in the body does this affect?
- First hit was delivered through the germline and affected all cells in the body.
- Second hit is in the second unaffected (tumour suppressor gene) allele - somatic mutation
For sporadic cancers, when are the hits (genetic mutations) delivered and which cells in the body does this affect?
- No germline mutation and so requires both hits to be somatic mutations and to occur in the same cell
- Second hit must be in the exact same cell where the first hit occured
- explains why people without inherited mutatiobn take longer to develop cancer as they need two hits as opposed to one
Mutation of how many (1 or both alleles) tumour suppressor genes does it take to favour neoplastic growth?
Both need to be inactivated
Mutation of how many (1 or both alleles) proto-oncogenes does it take to favour neoplastic growth?
Only one needs to be activated
Describe tumour suppressor genes and give an example
- normal function is to stop cell proliferation
- generally cause a loss of function
- in most instances both alleles must be damaged for tyransformation to occur
- abnormalities in these genes lead to failure of growth inhibition
- retinoblastoma gene
Whats the function of retinoblastoma gene?
- key negative regulator of G1/S cell cycle checkpoint
- also controls cellular differentiation
describe proto-oncogenes
- Multiple functions but all participate in signalling pathways that drive proliferation
- Mutations that activate these generally cause an excessive increase in one or more normal functions
- Sometimes they impart a completely new function on the affected gene - “Gain-of-function” mutations
How are oncogenes created?
- Oncogenes are created by mutations in proto-oncogenes and encode proteins called oncoproteins that have the ability to promote cell growth in the absence of normal growth promoting signals
- They can transform cells despite a normal copy of the same gene
- Oncogenes are dominant over their normal counterparts
What is the first oncogene to be discovered and what is the function of the normal proto-oncogene?
RAS
- normal gene codes for small G protein that relays signals into the cell that eventually pushes the cell past the cell cycle restriction point
- oncogene encodes a protein that is always active, ultimately producing a constant signal to pass through the cell cycle’s restriction point
WHat does the retinoblastoma protein do and happens in inactivation of 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
What does TSGs encode?
Encode proteins in the same pathways but with anti-growth effects (e.g. TP53)
What are caretaker genes?
Encode for proteins that are involved in repairing damaged DNA
- tumour suppressor genes that maintain genetic stability
Give 3 examples of conditions that arise from mutations in caretaker genes.
- xeroderma pigmentosum
- Hereditary non-polyposis colon cancer (HNPCC)
- Breast cancer
What causes xeroderma pigmentosum and what does it result in?
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
What causes HNPCC and what does it result in?
Autosomal dominant, is associated with colon carcinoma and the germline mutation affects one
of several DNA mismatch repair genes
What causes breast cancer?
Associated with either BRCA1 or BRCA2 genes that are important for repairing double strand DNA breaks. These various mutations can also be found in sporadic malignant neoplasms
What may lead to genetic instability and what helps maintain it?
- Chromosome aggregation during mitosis can also be abnormal in malignant cells. These alterations account for the accelerated mutation rate found in malignant neoplasms known as genetic instability
- Genes that maintain stability belong to a class of tumour suppressor genes known as caretaker genes
How does a carcinoma arise from an adenoma?
Step-wise accumulation of mutations in malignant neoplasms (progression)
Therefore cancer evolves by initiation and promotion and finally by progression.
What are the 6 hallmarks of cancer and enabling factor?
(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
(5) resistance to apoptosis;
(6) the ability to invade and produce metastases
Enabling feature: genetic instability
What is the adenoma-carcinoma sequence?
MULTIPLE MUTATIONS ARE REQUIRED TO MAKE A MALIGNANT NEOPLASM: Most malignant tumours require alterations affecting a combination of multiple TS genes and proto-oncogenes. This is illustrated
by colon carcinoma, which usually starts as a colonic adenoma, from which arises a carcinoma. This is known as the adenoma-carcinoma sequence.
MODEL OF CANCER PATHOGENESIS
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 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”
What does proto-oncogenes encode?
- growth factors (e.g. PGDF),
- 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)
