Neoplasia 3 Flashcards
Carcinogenesis - causes of cancer
Intrinsic - hereditary, age, sex (especially hormones)
Extrinsic - Environment (chemicals, radiation, infection), behaviour
4 in 10 cases of cancer can be prevented
Stop Smoking
Maintain a healthy weight
Healthy balanced diet
Sun Safety
Cut back on alcohol
Being active - an independent risk factor
Being overweight/obese is the 2nd biggest cause of cancer
Keeping a healthy weight reduces the risk of 13 different types of cancer
Environment plays a role in cancer risk - e.g. study with Japanese migrants to USA - as generations went on stomach cancers decreased (cancer present due to high preference of alkaline in diet) but breast cancers increased in population
Chemicals teach important lessons about carcinogenesis
2-napthylamine is an industrial carcinogen used in the dye manufacturing industry (also present in cigarettes)
Malignant neoplasms caused by 2-napthylamine showed that
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 - small dose (~2 years) little % with bladder cancer - large exposure (~5 years) large % with bladder cancer 3. There is sometimes organ specificity for particular carcinogens
Chemical carcinogenesis involves initiation and promotion
Sequence in which carcinogens are administered is critical i.e. the Initiators much be given first
Followed by a second class of carcinogens called promoters to promote the mutation However it has to be a mutation that doesn’t kill the cell otherwise cell would die rather than divide
Chemicals
A pro-carcinogen is converted to a carcinogen via cytochrome P450
Different groups -
Polycyclic aromatic hydrocarbons - Benzopyrene
Aromatic amines - 2-napthylamine
Alkylating agents - Vinyl chloride
Natural products - Aflatoxin and Asbestos
Radiation
Any type of energy travelling through space is mutagenic
E.g. Alpha particles, beta particles , gamma rays, xrays, UV rays
These can damage DNA directly or indirectly by generating free radicals
25% of all malignant neoplasms are skin neoplasms – From UV rays
Ionising radiation – from radon gas in the ground and from Medical tests
Infections
Some infections directly affect genes that control cell growth
Others do so indirectly by causing chronic tissue injury and the resulting regeneration acts either as a promoter for pre-existing mutation or causes new mutations from DNA replication errors.
Direct effects - HPV
Indirect effects – Hepatitis B Virus
Reduced Immunity - HIV - less ability to destroy DNA damaged cells
Human Papilloma Virus (HPV)
Associated with cervical carcinoma
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
Proto-oncogenes
Multiple functions but all participate at some level 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
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
RAS gene
The first human oncogene to be discovered was RAS
When activated, RAS aids the transcription of cyclin D, which helps the cell cycle progress through one of the checkpoints of the cell cycle
This is the most common type of abnormality involving proto-oncogenes in human tumours
They are mutated in approximately 15-20% of all malignant neoplasms
In some types of cancers the frequency of RAS mutation is much higher, e.g. 90% of pancreatic adenocarcinomas.
They were discovered initially in transforming retroviruses (HIV)
Proto-oncogenes and tumour suppressor genes play opposing rolls in cell signalling pathways
Proto-oncogenes can 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)
DNA repair genes - Caretaker genes prevent accumulation of DNA damage
Familial cancer syndromes help our understanding
Some inherited cancer syndromes have germline mutations that cause malignant neoplasms indirectly by affecting DNA repair
Xeroderma pigmentosa
Autosomal recessive disease
Due to mutations in one of 7 genes that affect DNA nucleotide excision repair
Very sensitive to UV damage and develop skin cancer at a young age
Hereditary Non-polyposis colon cancer syndrome
Autosomal Dominant
Associated with colon cancer
Germline mutation affects one of several DNA mismatch repair genes
Familial breast carcinoma
Mutations in BRCA1/BRCA2 genes
Involved in repairing double strand DNA breaks
Can also be found in sporadic malignant neoplasms
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
Don’t really know how many mutations it takes to make a carcinoma - depends on the person and the tumor type
Hallmarks of cancer
1- Self sufficiency in growth signals
2- Resistance to growth stop signals – TSG’s
3- Cell immortilisation (no limitation on the number of times a cell can divide)
4- Sustained ability to induce new blood vessels (angiogenesis)
5- Resistance to apoptosis
6- Ability to invade and produce metastases
