Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Why is cancer so difficult to cure?
Document related concepts
Transcript
Cellular and Molecular Basis of Cancer Overview Why is cancer so common? Why is cancer so difficult to cure? Cancer is a common disease 1 in 3 of us get cancer 1 in 4 of us die of cancer 7 million deaths per year worldwide Why is cancer so common? Cancer is a disease of eukaryotic cells MEMBRANE CYTOPLASM NUCLEUS DNA Cancer starts in a single cell 200 different cell types 1013-14 cells/human Large number of cells Cancer is a genetic disease DNA vulnerable during cell division 23 pairs of chromosomes 4 bases (A-T;C-G) 3x109 base pairs/cell (6000 million bases) Cell division 6000 million bases One hour Large number of cell divisions 1010 new colon epithelial cells every day 3x1011 new blood cells every day 1016 cell divisions/lifetime Each cell division – on average one error Environmental Causes DNA damaging agents Smoking Diet Environmental Carcinogens May account for up to 50% of cancer incidence Cancer incidence increases with age 2000: 6 million; 2020: 20 million deaths Why is cancer so common? Large number of cells Large number of cell divisions Environmental pollution Aging population So why is cancer not more common? Cancer requires alterations in many genes Cancer is clonal Most genetic changes occur by chance 5-10 genes need to be altered Takes a long time for 5-10 genetic changes to accumulate in one cell Cancer takes a long time to develop Aniline dye workers DNA repair protects Base excision repair Nucleotide excision repair Mismatch repair Recombinational repair DNA repair reduces risk of cancer Thousand of freckles and multiple cancers on face of child with xeroderma pigmentosum XP: 1000x higher risk of skin cancer Cancer may be a stem cell disease Most cells have a limited lifespan (a few weeks or months) Stem cells are long-lived (potentially immortal) Stem cells are very rare (perhaps less than 0.1% of cells) Immunity and cancer 40% of immunosuppressed renal transplant patients develop cancer in 20 years (compared to 6% of controls) Immune system kills cancer-inducing infections and can kill developing cancer cells Summary – Why is cancer not more common? Takes a long time to develop DNA repair protects Stem cells are rare? Immunity protects Normal (stem) cell Genetic changes Cancer stem cell More genetic changes Local invasion More genetic changes Spread (metastasis via lymph/blood/nerves) The progression of cancer Cancer is a common disease 1 in 3 of us get cancer 1 in 4 of us die of cancer Why is cancer difficult to cure? Cancer or Normal Cell? MEMBRANE CYTOPLASM NUCLEUS DNA 100 % Cell Survival Narrow therapeutic window Cancer cells 1 0 1 2 Normal cells 3 4 Increasing Dose (mg.h/ml) 40 1012 30 109 20 Cell number Population Doublings Cancer is detected late 10 Limit of detectability: 7 mm 106 103 1 7.5 x 108 cells/g 0.1g = 7mm diameter 1g 1mg 1g 1kg Fractional Cell Kill Hypothesis Double the dose, double the log cell kill 106 105 Cell Number 104 103 102 101 1 0 0 1 2 3 4 mg.h/ml 5 6 7 Fractional Cell Kill Hypothesis Dose killing 99.99% cells Cells treated Cells Surviving 1012 108 108 104 104 100 Small cancers are easier to cure L1210 mouse leukemia Cells innoculated ip 200mg/kg cyclophosphamide day 1 Cell Number Mice surviving 106 0/10 105 5/9 104 10/10 Skipper HE, 1968 TNM staging T (primary tumour) T1 and T2 – clinically localised T3 and T4 – locally advanced N (lymph node) N0 (absent) or N1 (present) M (metastasis) M0 (absent) or M1 (present) Bladder cancer T staging Why is cancer difficult to cure? Cellular basis Cancer cells similar to normal cells Cancer is detected late Large ca needs higher dose Large ca more likely metastatic Molecular basis Many genes can cause cancer 300+ genes associated with cancer development Oncogenes (accelerator) Tumour suppressor genes (brake) Each gene can be altered many ways Mutation Amplification Chromosomal loss Translocation Methylation Compare with cystic fibrosis 70% patients have same mutation in one gene P53 has many functions Transcription factor DNA damage recognition protein Arrest cell growth Trigger apoptosis Different treatment may be needed depending which function altered Each cancer is unique 5-10 genetic alterations needed for each cancer Each cancer contains thousands of changes in gene expression Cancer is genetically unstable Higher mutation rate than normal cells Evolves new variants constantly Resistant variants selected Normal (stem) cell Genetic changes Cancer stem cell More genetic changes Local invasion More genetic changes Spread (metastasis via lymph/blood/nerves) More genetic changes Resistant cancer cells Why is it difficult to cure cancer? Cellular basis Molecular basis Many cancer genes Each gene can be genetically altered many ways Each gene has many functions Each cancer has many changes and is unique Genetic instability Why does everyone with cancer not die of it? 5 year survival with distant spread Prostate Breast Melanoma Cervix Colorectal Bladder Lung 30% 20% 16% 9% 7% 6% 2% More men die with than of prostate cancer Surgery or radiotherapy can cure cancer that is local and has not spread beyond the primary site Metastatic testis cancer Cured in over 85% of patients Cisplatin Bleomycin Etoposide When does cancer not kill? When the patient dies of something else before the cancer kills them When the cancer is localised and can be eradicated with surgery or radiotherapy When the cancer is cured with drugs (adjuvant or definitive therapy) Principles of Cancer Disease of (stem) cells Starts in a single cell (clonal) Genetic disease Requires changes in many genes
