Mechanism of Oncogenesis Flashcards
Summarise the early history of cancer
- Ancient Egypt ( ca. 2500-1600BC) The earliest known descriptions of cancer appear in several papyri from Ancient Egypt. Ancient Greeks were the first to identify it as a distinct illness
- Hippocrates (ca. 460 BC – ca. 370 BC) described several kinds of cancer, referring to them with the Greek word carcinos (crab or crayfish).
- Celsus (ca. 25 BC – 50 AD) translated carcinos into the Latin cancer, also meaning crab.
- Galen (2nd century AD) called benign tumours oncos, Greek for swelling, reserving Hippocrates’ carcinos for malignant tumours. He later added the suffix -oma, Greek for swelling, giving the name carcinoma.
Describe the early treatments for cancer
- Ancient Egypt, Description of a procedure to remove breast tumours by cauterization. It was observed that the disease had no treatment
- In Ancient Greece, Hippocrates suggested the body has four different fluids (humors) - yellow (bile/pustules), red blood (inflammation), black bile (cancer/ depression) and white (phlegm). According to Hippocrates, cancer was the result of an excess in black bile.
- Treatment was based on the humor theory of four bodily fluids and treatment consisted of diet, blood-letting, and/or laxatives.
What surgical treatments existed for cancer before
- Before anaesthesia and antiseptics = rusty knife / barber shop / charring tumours with
soldering iron / searing with sulphuric acid paste / lethal infections / profuse bleeding. - 1846-1867 – ether and carbolic paste
- 1850-1950 - development of new surgical techniques.
- Surgery became radical, innovative and brazen.
- But not all surgery resulted in a cure.
- Cancer could spread locally and systemically
What is the incidence rate of cancer in the uk
- Approx. 375,000 new cases, though 288,753 were
diagnosed in 2020 - Higher incidence in men, overall, but differences
depending on age.
What is the mortality rate of cancer
- Approx. 167,000 per year
- Higher mortality in men
- But… more than 50% now survive 10+ years after
diagnosis, half as many did 40 years ago - Estimated that approx. 40% are preventable – these
can be achieved by lifestyle changes.
List some prevention and reducing risk for cancer
- Smoking
- Hormones
- Obesity and weight
- Alcohol
- Workplace causes of cancer
- Sun and UV
- Infections and HPV
- Physical Activity
- Air pollution
and radon - Diet and healthy eating
- Inherited genes
What is cancer
Cancer is the name for a group of diseases characterised by:
- Abnormal cell proliferation
- Tumour formation
- Invasion of neighbouring normal tissue
- Metastasis to form new tumours at distant sites
How is cancer classified
Over 200 different types of cancer have been classified, often according to their origin:
- Carcinomas: epithelial cancers, most common
- Adenocarcinomas: Glandular tissue
- Squamous cell - Squamous epithelium
- Sarcomas: cancer derived from mesoderm cells
- Leukaemias/Lymphomas: cancers of haematopoetic cells
What is hallmarks of cancer
In 2000, Hanahan and Weinberg defines six hallmarks of most if not all cancers
In 2011, this had been modified to include:
- two enabling characteristics : genome
instability and tumour inflammation - two emerging hallmarks : avoiding
immune destruction and
reprogramming energy metabolism
List some hallmarks of cancer
- Sustaining proliferative signalling
- Evading growth suppressors
- Avoiding immune destruction
- Enabling replicative immortality
- Tumor-promoting inflammation
- Activating invasion & metastasis
- Inducing angiogenesis
- Genome instability & mutation
- Resisting cell death
- Deregulating cellular energetics
List the 3 main causes of cancer
- Infectious agents
- External carcinogens
- Genetics
List some examples of Infectious agents
- Viruses: HBV, EBV, KSHV, HPV
- Bacteria: Helicobacter pylori bacteria, stomach cancer
List some correlations of external carcinogens
- Chimney sweeps and scrotal cancer
- Snuff and mouth cancer
- Smoking and lung cancer
- UV radiation and skin cancer
- Asbestos and lung cancer
- Heavy metals and multiple cancers
List some examples of Genetics
- Chromosomal alterations
- Aneuploidy: Oncogenes, Tumour suppressor genes, Inherited mutations
How do carcinogens cause cancer
- DNA from tumours has been shown to contain many alterations from point mutations to deletions
- The accumulation of mutations over time represents the multi-step process that underlies carcinogenesis
- This accumulation occurs only after the cells defence mechanism of DNA repair have been evaded
- In cases if severe damage cell apoptosis is induced
- Many mechanisms exist for blocking carcinogenesis but over burdening the system increases the possibility
that cells will escape surveillance
The longer we live the more time there is for DNA to accumulate mutations that may lead to cancer
What are the 3 main stages of carcinogenesis
- Initiation
- Promotion
- Progression
Describe initiation in carcinogenesis
There is reversible conversion between normal and initiated cells.
Prevented by chemopreventative agents which act as blocking agents to this stage of carcinogenesis
Describe the promotion stage of carcinogenesis
Initiated cells proliferate to form preneoplastic cells.
this stage is stopped by chemopreventative agents which act as suppressing agents.
Describe the progression step of carcinogenesis
Preneoplastic cells become neoplastic cells.
Stopped by suppressing agents which are chemopreventative agents.
Describe heritable germline mutations
- Point mutations/deletions occur in the egg/sperm
- Increased risk of developing cancer
- Rarely involved in causing cancer immediately
Describe how somatic mutations can cause cancer
- Somatic mutations constitute almost all mutations in
tumour cells - All cells in a primary tumour arise from a single cell,
initiation of the development of cancer is clonal - Only one of the 10 14 cells in the body needs to be transformed to create a tumour
- Continued accumulation of mutations
- Tumour cells can ‘evolve’ - subclonal selection allows a growth advantage and explaining and heterogeneity of cells in a tumour
- Dependent on interaction with other tumour cells and the tumour microenvironment
Why is proliferation and control important
Control of cell division within a tissue is particularly important in rapidly self renewing tissues when proliferation must balance cell loss
Describe how normal cells can become tumour cells
Normal cells proliferate, differentiate, perform their function and undergo apoptosis.
This process is in balance and under tight control.
Mutations in DNA that alter the function of normal genes involved in growth apoptosis and differentiation can affect his balance.
What are oncogenes
- They are normal genes that regulate growth.
- Genes that can be activated to become oncogenes are called proto-oncogenes.
- An oncogene is a proto-oncogene that has been mutated in a way that leads to signals that cause uncontrolled growth.
What are tumour suppressor genes
They inhibit both growth and tumour formation
- They act as braking signals during phase G1 of the cell cycle, to stop or slow the cell cycle before the S phase.
- If tumour-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth, i.e. cancer
What are the three assumptions made with multistage carcinogenesis?
- Malignant transformation of a single cell is sufficient to give rise to a tumour
- Any cell in a tissue is as likely to be transformed as any other of the same type
- Once a malignant cell is generated the mean time to tumour detection is generally
constant
What are the 5 models of carcinogenenesis
- Mutational
- Genome instability
- Non-genotoxic
- Darwinian
- Tissue Organisation
What are the different classes of carcinogens in mutational carcinogenesis
- Chemical
- Physical
- Viral (infectious)
- Genetic/heritable
What are the characteristics of chemical carcinogens
- Cancer is a multi-step process that includes initiation, promotion and progression
- Chemical carcinogens can alter any of these processes to induce their carcinogenic effects
- The presence of multiple mutations in critical genes is a distinctive feature of cancer cells and supports that cancer arises through
the accumulation of irreversible DNA damage - In most instances, chemical carcinogens can induce this DNA damage and act genotoxic.
Describe the Ames test
- Possible mutagens are added to a rat liver extract with a salmonella strain that required histidine to grow
- The solution is grown in an agar plate with minimal histidine.
- A high number of revertants suggests the mutagen causes mutations, shown by salmonella growth
- Control plate is run as well
What are physical carcinogens
Unlike chemical carcinogens physical carcinogens act by imparting energy to the biological material
- Radiation is the primary physical agent
- Several types of radiation can act as carcinogens (ionising radiation)
- Radiation Damage causes DNA pyrimidine dimer breaks
- Failed DNA repair causing translocation mutations
What are heritable carcinogens
- Accounts for 5% of all cancers
- An inherited germline mutation, has an increased risk of developing certain tumours but is rarely involved in causing cancer immediately
-In most known hereditary malignant syndromes the elevated cancer risk is due to a mutation of a single gene (monogenic hereditary diseases) - The affected genes concerned usually have a controlling function on the cell cycle or the repair of DNA damage.
A deficiency in DNA repair would cause more DNA damage to accumulate, and increase the risk for cancer
What are viral carcinogens
- Viruses capable of causing a wide range of human diseases from smallpox to the common cold.
- Most harm is caused when viruses multiply inside the infected cell, kill the cell and release progeny to further infect other cells.
- Oncogenic viruses can work either by direct (insert oncogenes/interfere with existing genes) or indirect (inflammatory) mechanism
Describe the genome instability model of carconogenesis
- First proposed by Carl Nordling in 1953 and then formulated by Knudson in 1971
- Developed for retinoblastoma, which became the basis of the “two-hit” hypothesis and led to the formulation of the theory of “tumour suppressor genes” and then to the discovery of Rb1
- So for example, if the first mutated allele was inherited the second mutation would lead to cancer. In the sporadic forms of the tumour, both mutations had to take place and hence this could explain the difference in age at diagnosis
Describe the non genotoxic model of carconogenesis
- Characterised by an emphasis on non-genotoxic effects
- Several important modulators of cancer risk (diet, obesity, hormones and insulin resistance ) do not seem to act through a structural change in DNA but rather through functional changes including epigenetic events.
What are other carcinogenic factors that work via the non-genotoxic mechanism
- Tumour promoters (1,4-dichlorobenzene),
- endocrine-modifiers (17β-estradiol)
- receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin)
- immunosuppressants (cyclosporine)
- inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium)
Describe the Darwinian model of carconogenesis
- Characterised by mutation and selection model of clonal expansion
- The role of the environment in selecting cells that have some acquired advantage
What are the 2 theories in the tissue organisation model of carcinogenesis
- Somatic mutation theory
- Tissue organisation field theory
Describe the somatic mutation theory of tissue organisation
- Cancer is derived from a single somatic cell
that has successively accumulated multiple
DNA mutations - Those mutations damage the genes which
control cell proliferation and cell cycle - Thus, according to SMT, neoplastic lesions
are the results of DNA-level events
A single catastrophic event triggering carcinogenesis
Describe the tissue organisation field theory
- Carcinogenesis is primarily a problem of tissue
organisation. - Carcinogenic agents destroy the normal tissue
architecture thus disrupting cell-to-cell signaling
and compromising genomic integrity. - The DNA mutations are random and the effect,
not the cause, of the tissue-level events.
Carcinogenesis as the general deterioration of the tissue microenvironment due to extracellular causes.
What is the immune response in cancer
- Protect from virus-induced tumours
- Eliminate pathogens
- Identify and eliminate tumour cells
Despite this tumours can still arise - Cancer immunoediting
Describe Cancer immunoediting
Elimination:
The immune system is able to eradicate developing tumours
Equilibrium:
- Removal is incomplete and some tumour cells remain dormant and enter equilibrium. The tumour may mutate to give rise to genetic variants that survive and grow and enter the next phase
Escape:
- The expanding tumour populations becomes clinically detectable
