L5 - Untangling Carcinogenesis Flashcards
Carcinogenesis
• Multistep process
- accumulation of permanent genetic alterationsmutations resulting in abnormal control of growth over time
• tumour progression
- Invasiveness (dysplasia, in situphase, micro invasion, extension)
- excessive growth
- escape from the immune system
- Cells need to divide to maintain the organism
- To achieve net cell gain cells must divide at an increased rate and avoid death by apoptosis
Molecular basis of carcinogenesis
- Carcinogenesis = process that results in transformation of normal cells to neoplastic cells through permanent genetic alterations
- Carcinogen=cancer causing
- The site of action =DNA
- > 1 agent required
- Multistep carcinogenesis hypothesis
Genes encode regulating proteins
- Promoters of cell growth are called protooncogenes and those that restrict are called antioncogenes
- Apoptosis and senescence assist in controlling the health of cells-recognise DNA damage and eliminate the cell
- Proto oncogenes normally control cell proliferation and when activated by changes in adjacent genes or themselves lead to a mutation forming oncogenes that stimulate cell proliferation
Identification of carcinogens
- epidemiological studies
- assessment of occupational risks
- direct accidental exposure
- carcinogenic effects in laboratory animals
- transforming effects on cell cultures
- mutagenicity testing in bacteria
Epidemiology
Epidemiology is the study of the distribution and patterns of health-events, health-characteristicsand their causesor influences in well-defined populations.
Other causes of carcinogenesis
- Chemicals
- Irradiation: X Ray, UV, Ionizing
- Hormones-may be required to promote tumour growth
- Physical agent –Asbestos
- Diet
- Virus/Bacterial Preneoplasticdysplasias
- Autoimmune diseases
Host factors in carcinogenesis
- race - melanoma
- diet - Hi fat
- constitutional factors (sex, inherited risks, etc.) BRCA-1
- premalignant lesions and conditions -HP
- transplacenta lexposure-DES and vaginal clear cell
Initiation
Initiation is where a carcinogen induces the genetic alteration(s) that give(s) the transformed cell its neoplastic potential.
Promotion
Promotion is the stimulation of clonal proliferation of the initiated transformed cell.
Progression
Progression is the climax in malignant behaviour characterised by invasion and its consequences
Abnormalities in genes regulating cell proliferation in neoplasia
• Four main genetic mechanisms
- Activation of Oncogenes to stimulate growth
- Loss of genes controlling proliferation i.e. tumour suppressor genes
- Loss of normal control mechanisms for eliminating genetically damaged cells
- Loss of gene products that repair damaged DNA leading to DNA instability and mutation in oncogenes and tumour suppressor genes
How oncogenes develop tumours
- Proto oncogenes (p -oncs) genes that code for proteins involved in the control of cell growth. They act as on off switches for cell proliferation
- Oncogenes were originally isolated from tumour forming RNA retroviruses(v-oncs)
- Viral oncogenes (v -oncs) are genes within a virus that code for a protein involved in the development of neoplasia • Cellular oncogenes (c-oncs) genes that code for protein in the development of neoplasia
Mechanisms stimulating cell proliferation
- Point mutation-caused by a single nucleotide change resulting in changed amino acid e.g k-ras
- Translocation of a gene or part of to a different chromosome-leads to altered expression of gene product eg abl
- Gene amplification-leads to raised protein levels e.g. HER 2, c myc
Point mutations
- 3 human related genes H,(Harvey) K,(Kirsten) N (Neuroblastoma)
- Frequently mutated in a variety of human tumours notably GIT, Liver, Bladder Thyroid, Melanoma
- Point mutations affecting codons 12/13 or 61
