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    carcinogenesis carcinogenesis Presentation Transcript

    • Carcinogenesis part 1 By Yasmeen Malik
    • Carcinogenesis  Unregulated cell growth  Invasion and spread of cells  Primary site  Secondary site  Tissue of origin classification  Epithelial cell origin classified as carcinomas  Mesoderm cells classified as sarcomas  Glandular tissue - adenocarcinomas
    • Six hallmarks of cancer cell Evasion of apoptosis Growth signal autonomy Angiogenesis Invasion and metastasis Unlimited replication potential
    • Growth signal autonomy  Normal cells need external signals from growth factors to divide  Cancer cells are not dependent on normal growth factor signalling  Acquired mutations short circuit growth factor pathways  Lead to unregulated growth
    • Evasion of growth inhibitory signals  Normal cells respond to inhibitory signals to maintain homeostasis  Cancer cells do not respond to signals  Acquired mutations interfere with inhibitory pathways
    • Apoptosis  Programmed cellular death  Mutation detected in cell  Cell signalled to repair or die (apoptosis)  Tumour development occurs when apoptosis fails  We have 2 copies of each gene  2 acquired mutations (from each gene) are needed to knock out that gene
    • Evasion of apoptosis  Normal cells removed by apoptosis in response to DNA damage  Cancer cells evade apoptosis process  Loss of apoptotic regulators through mutation  Lead to evasion of apoptosis
    • Unlimited replication potential  Normal cells have a finite number of cell doublings  Cellular counting is the shortening of telomeres  Cancer cells maintain the length of telomeres  Altered regulation  Lead to unlimited replication potential
    • Angiogenesis  Formation of new blood vessels  Normal cells depend on blood vessels to supply oxygen and nutrients  Cancer cells induce angiogenesis  Grow new blood vessels for tumour survival
    • Invasion and metastasis  Normal cells maintain their location in the body  Do not migrate  Cancer cells migrate to other parts of body  Mutations alter activity of enzymes involved in invasion  Alter molecules involved in cell-cell and cell- extracellular adhesion
    • Phenotype of cancer cell In cell culture conditions:  Fail to exhibit contact inhibition  Grow as piles of cells  Grow in conditions of low serum  Adopt a round morphology  Exhibit anchorage independence
    • Carcinogenesis  Unregulated cell growth  Multi-step process  Genetic alterations  Cellular pathway interruption
    • Hereditary mutations  Gene defects  Hereditary mutations major factor in cancer development  Inherited – parent to child  Mutation can be passed on generation to generation
    • Acquired mutations  DNA changes  Acquired, sporadic, somatic mutations  Environment, exposure to radiation or unknown factors  Mutation not in every cell of the body  Can not be passed onto next generation
    • Physiological vs pathological cell death  Necrosis  Apoptosis  Molecular pathway of apoptosis  Initiating phase signal  External trigger receptors on the plasma membrane  Intracellular alterations
    • Cancer development  Two main types of genes  Oncogenes  Cause gain of function effects  Tumour suppressor genes  Cause loss of function effects
    • Proto-oncogenes  Normal gene that can become an oncogene due to mutations or increased expression  Code for proteins  Regulate cell growth and differentiation  Involved in signal transduction  Execution of mitogenic signals  When activated it becomes tumour inducing agent, an oncogene
    • Activation of proto-oncogene  Mutation within proto-oncogene causes a change in the protein structure  Increase in protein enzyme activity  A loss of regulation  An increase in protein concentration  Increase of protein expression  Increase of mRNA stability  Gene duplication
    • Oncogenes  Mutated gene  Protein product is produced in higher quantities  Increased activity  Acts in a dominant manner to initiate tumour formation
    • Oncogenes  Abnormal gene predisposes cells to develop into cancer  Mutated gene that turns normal cell into a tumour cell  Under normal conditions abnormal cells undergo apoptosis  Activated oncogenes survive and proliferate  Additional factors involved  Mutations in another gene, environmental factors, viral infections…
    • oncogene
    • Tumour suppressor gene  Code for proteins  Inhibit both growth and tumour formation  Loss of growth inhibition occurs when mutations cause a loss of function of these genes  Growth is permitted
    • Tumour suppressor genes  Components of same signalling network as proto-oncogenes  Negative grown regulators  Modulate proliferation and survival by antagonising the biochemical functions of proto-oncogenes  Inactivation of both copies of tumour suppressor genes is required for loss of function
    • Mechanisms of carcinogenesis  Single genetic alteration that leads to the activation of an oncogenes or loss of tumour suppressor gene  Malignant progression from normal tissue to tumour metastases occurs in steps over a period of time
    • Carcinogenesis
    • Factors - carcinogenesis Lifestyle factors  Environment  Reproductive life  Diet  Smoking Inherent risk factors  Own physiology  By products of metabolism  Errors during DNA replication  Radical by products that are mutagenic  Inherited metabolic diseases  Etc…
    • Radiation as a carcinogen  EMR  Linear energy transfer (LET)  Amount of energy released by a radiation source during a fixed distance  Ionising radiation  Ultraviolet radiation
    • Chemical carcinogens  Environment  Diet  Polycyclic aromatic hydrocarbons  Aromatic amines  Azo dyes  Nitosamines and nitosamides  Alkylating agents
    • Infectious pathogens as carcinogens  Viruses that are oncogenic  DNA tumour viruses  Encode viral proteins  Block tumour suppressor genes  Retroviruses  Encode mutated forms of normal genes  Oncogenes  Human papilloma  Epstein-Barr viruses
    • Malignant transformation  Three groups of genes involved:  gain-of-function mutations that activate oncogenes  loss-of-function mutations that inactivate tumour suppressor genes  loss of activity of DNA stability (e.g., repair) genes that increases the probability for genomic
    • Oncological management  Target oncogenes  Target cellular pathways  Clinical tests  Antibodies  Cytokines  Gene therapy
    •  Part 2  Oncological management  Gene therapy