benign: excessive proliferation; single mass malignant: cancer; invade surrounding tissue...
TRANSCRIPT
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• Benign: Excessive proliferation; single mass• Malignant: Cancer; invade surrounding tissue• Classifications: carcinomas, sarcomas, others
Benign Versus Malignant Tumors
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Tumor Progression
• Derived from single abnormal cell• Somatic mutations• Accumulation of multiple mutations in lineage• Evolutionary process
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Evolution Of Tumor
• Natural selection• Cell acquiring further mutation
that enhances proliferation dominates tumor
• Heterogeneity reflects continuing evolution
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Stages Of Progression
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Properties of Cancer Cells
• Cell division• Failure to properly differentiate• Failure to undergo apoptosis• Defective checkpoint control• Genetic instability• Overcome replicative cell senescence• Cell growth, biosynthesis, Warburg effect • Metastasis
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Warburg Effect
• Import vastly more glucose• Small fraction for oxidative
phosphorylation• Building blocks for
macromolecules
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Metastasis
• Invade neighboring tissue; proliferate in new location
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Mutagens
• Most agents that cause cancer damage DNA
• Chemical carcinogens, UV light, ionizing radiation, certain viruses
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Epigenetic Changes
• Heritable gene inactivation through histone modification and DNA methylation
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Cancer Stem Cells
• Small population of stem cells with indefinite self-renewal
• Give rise to rapidly dividing cells with limited self-renewal
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Genes That Contribute To Cancer
• Proto-oncogenes: gain-of-function mutation in single allele drives tumor progression
• Tumor suppressor genes: loss-of-function mutations in both alleles drives tumor progression
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Converting Proto-oncogenes To Oncogenes
• Mutation results in hyperactive or overexpressed protein
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Inactivating Tumor Suppressor Genes
• Both alleles can undergo inactivating somatic mutations• Individual can inherit one inactive allele resulting in
increased susceptibility to cancer • Can be inactivated by epigenetic mechanisms
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Normal Cellular Functions Of Cancer-Causing Genes
• Internal regulators of cell cycle progression and apoptosis
• Molecules involved in cell adhesion and movements
• Components of signaling pathways
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Cancer Genomics
• About 300 cancer-critical genes• About 10 critical genetic or epigenetic
changes in typical cancer• Several key pathways commonly disrupted
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Mechanisms Of Retinoblastoma
• Hereditary form: one inherited and one somatic mutation• Nonhereditary form: two somatic mutations
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Alterations To Rb Pathway
• Overactivation of cyclin D or Cdk4 or inactivation of p16 functionally equivalent to inactivation of Rb
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Ras Proto-oncogene
• Converted to oncogene by point mutation that abolishes GTPase activity
• Downstream effects independent of growth factor stimulation
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p53 Tumor Suppressor Gene
• Functions in checkpoint pathway for DNA damage or other cell stresses
• Can either induce apoptosis or block cell division• Inactivation leads to further genetic alterations
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Bcl-2 Proto-oncogene
• Blocks apoptosis• Overexpression can contribute to cancer• Discovered from chromosomal translocation
in B-cell lymphoma
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Genes Contributing to Metastasis
• Changes that promote metastasis largely unknown
• Rho-family GTPases: proto-oncogene, actin-based cell motility
• E-cadherin: tumor suppressor, cell adhesion at adherens junctions
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Commonly Mutated Genes in Colorectal Cancer
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Apc Tumor Suppressor Gene
• Inherited mutation in familial adenomatous polyposis coli
• Most colorectal tumors have somatic mutations
• Functions in Wnt signaling pathway by inhibiting -catenin
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Sequence of Genetic Changes in Colorectal Tumor Progression
• General sequence in which common mutations often occur
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DNA Repair Genes• Inactivation increases mutation rate• Increased cancer susceptibility from inheriting one inactive
alleleDisease Defective ProcessHereditary nonpolyposis mismatch repaircolon cancer
Xeroderma pigmentosum nucleotide excision repair(susceptibility to skin cancer)
BRCA-1, BRCA-2 mutations repair by homologous(susceptibility to breast cancer) recombination
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Chronic Myeloid Leukemia
• Chromosomal translocation joining Bcr and Abl• Hyperactive Abl tyrosine kinase
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Treatment By Bcr-Abl Inhibitor
• Gleevec: small molecule inhibitor