Session 9 - Neoplasia 3 Flashcards
Recap
- steps to reach a malignant neoplasm
— many of these factors can act as both initators and promoters i.e. can cause intitial mutation, then can cause growth of the monoclonal population
*Initiators must be given first, followed by a second class of carcinogens called promoters —- must be given at a sufficient dose with a long enough exposure
*Neoplasia is a multifactoral process, this means, not just one isolated incident leads to cancer developing
Carcinogenesis
- Carcinogenesis means?
- Intrinsic and extrinsic carcinogenesis
- Do some carcinogens need to be activated before becoming carcinogenic?
- What is a complete carcinogen?
- Percentage of cancer that can be prevented?
- Carcinogenesis: causes of cancer
- See pic below for intrinsic and extrinsic list of causes
- Most carcinogens are not carcinogenic until they have been activated by cytochrome P450 in the liver: Pro-carcinogen —–(cytochrome P450)—–> Carcinogen
- Initator + Promoter = complete carcinogen
- 4/10 cases of cancer can be prevented
Recap - germline mutation
Germline mutation means that the neoplastic cells get a ‘head start’, as doesn’t ‘need’ the initial initiator as it already has this mutation
Chemical carcinogen
1. 2-naphylamine — what does this show about carcinogenesis?
Malignant neoplasms caused by 2-napthylamine showed that:
- There is a long delay (sometimes decades) between carcinogen exposure and malignant neoplasm onset
- The risk of cancer depends on total carcinogen dosage
- There is sometimes organ specificity for particular carcinogens
Other carcinogens…
Chemical carcinogen
- Radiation
Chemical carcinogen
- Infections
- HPV example
Radiation
• Any type of energy travelling through space and some forms are mutagenic • Alpha particles, beta particles , gamma rays, xrays, UV rays
• Can damage DNA directly
• Or indirectly by generating free radicals
- 25% of all malignant neoplasms are skin neoplasms – UV
- Ionising radiation: – radon gas - Medical tests
Infections
• Some infections directly affect genes that control cell growth
• Others do so indirectly by causing chronic tissue injury and chronic inflammation e.g. promoter 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 - causes chronic inflammation, chronic inflammation acts as the promoter. Also, results in regeneration, there is more opportunities for mutation to arise
• Reduced Immunity - HIV - so likely to get more infections and less ability to defend themselves against mutations
HPV infection:
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
Familial vs sporadic…
- Tumour suppressor genes
- Retinoblastoma genes
- Proto-oncogenes
- Tumour suppressor genes
• Normal function is to stop cell proliferation
• Generally cause a ‘loss-of-function’
• In most instances both alleles must be damaged for transformation to occur
• Abnormalities in these genes leads to failure of growth inhibition - Retinoblastoma genes
• RB, a key negative regulatir if G1/S cell cycle cgeckpoint
• Also controls cellular differentiation - 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 (example of…..)
Example of protooncogenes
• The first human oncogene to be discovered was RAS
• This is the most common type of abnormality involving protooncogenes in human tumours
• They are mutated in approximately 15-20% of all malignant neoplasms
• Some types of cancers the frequency of RAS mutation is is much higher, e.g. 90% of pancreatic adenocarcinomas.
• They were discovered initially in transforming retroviruses (HIV)
— on pic - Retinoblastoma gene tries to prevent cell growth
Xeroderma Pigmentosa
- Autosomal recessive disease
- Due to mutations in one of 7 genes that affect DNA nucleotide excision repair (this damage is usually repaired by the DNA nucleotide excision repair system, if damage to these genes -> can’t repair the damage to this DNA)
- Very sensitive to UV damage and develop skin cancer at a young age
Hereditary Non-Polyposis Colon Cancer (HNPCC) Syndrome
- Autosomal Dominant
- Associated with colon cancer
- Germline mutation affects one of several DNA mismatch repair genes (proof reading function is lost - these errors can gradually accumulate throughout the geonme, some of these errors by chance, may activate protooncogenes or inactivate tumour suppressor genes)
Familial breast carcinoma
• BRCA1/BRCA2 genes
• Involved in repairing double strand DNA breaks
• Can also be found in sporadic malignant neoplasms
How many mutations does it take to get a malignant neoplasm? — Colorectal cancer
Hallmarks of cancer
- Self sufficiency in growth signals
- Resistance to growth stop signals – TSG’s
- Cell immortilisation (no limitation on the number of times a cell can divide)
- Sustained ability to induce new blood vessels (angiogenesis)
- Resistance to apoptosis
- Ability to invade and produce metastases
1-5 are about increased growth - relevant for benign and malignant neoplasm
Overall model of malignancy
