Basic Concepts of Cancer

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Basic Concepts of Cancer
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Neoplasia

• Disease of cell growth, division, and
  differentiation
• Benign tumors
• Localized, clear margins (encapsulated),
  non-invasive, slow growing, well differentiated
• Functional adenomas if glandular tissue

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Malignant neoplasms

• Rapid growth, no clear margins (invasive)
• Aneuploidy, uncontrolled cellular multiplication,
  lytic enzymes
• Decreased cell adhesion, increased motility
  (metastatic)
• Angiogenesis---abnormal vessels

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Classifications of malignancies

• Carcinoma--epithelial
• SarcomaCT or muscle
• Glioma--glial cells
• Neuroblastoma--neurons
• Lymphoma
• Leukemia

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Cancer is a genetic disorder, but it is rarely
inherited

• Epigenetic modifications
• p53 proteinguardian of the genome
• Errors in p53 show up in 50 of all cancers
• Different mutations seem to prevail in different
  cancers
• Telomeraseprevents normal shortening of
  telomeres at end of chromosomes
• Absent in most somatic cells, present in 85 of
  cancers
• Allows for infinite number of divisions

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Multi-step Model for Cause of Cancer

• One cell suffers multiple genetic mutations,
• Proto-oncogenes induce cell proliferation and
  growth (normal function)
• Defined by what happens when turned on
• Tumor suppressor genes suppress cell growth
• Defined by what happens when turned off
• P53--guardian of genome, halts faulty cycle

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Initiation--promotion--progression theory

• Initiation is first insult or series of insults
  to genome

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Types of Initiation Steps
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Changes in proto-oncogenes? oncogenes

• Point mutationsalways dominant (ras gene,
  telomerase gene)
• Gene amplification
• Chromosomal rearrangement
• Viral insertion and activation
• human papillomavirus, hepatitis B and C, Epstein
  Barr (?)

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Changes in tumor suppressor genes (p53 is 1
example)

• Removes controls on cell cycle
• Removes review/editing of DNA copying mistakes
• Typically recessive mutations, so need 2 hits

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Chemical damage to DNA

• Epigenetic modifications, base substitutions
• Aromatic hydrocarbons, aromatic amines
• Insecticides, asbestos
• Anti-neoplastic drugs
• Aflatoxins
• Nitrosamines and nitrosamides in food, water

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Physical damage to DNA

• Breaks, deletions, translocations
• Sunlight (ultraviolet)
• Radiation--therapy or diagnostic use

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Predisposing factors

• Age, sex, heredity
• 15-20 of all cancers are caused by
  infection(usually viruses)
• Exposure to DNA damaging compounds
• Precancerous lesions
• Colon polyps
• Metaplastic cells

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Promotion Proliferation

• Intracellular antioxidant enzymes should repair
  damaged DNA
• Apoptosis should remove damaged cells
• Cancers become more malignant with each
  generation of transformed cells

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• Immune surveillance by cytotoxic T cells should
  remove transformed cells
• Tumor associated antigens presented by MHC 1
  molecules
• Decrease in thymus activity with age means more
  cancers in older individuals

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Progression--becoming malignant

• Rate of growth depends on cell cycle time and
  rate of angiogenesis
• Epithelial cancers usually grow faster
• To metastasize, must separate from original
  cluster of cells and invade blood or lymph vessel
• Must penetrate basement membrane
• Metastasis is NOT inevitable once penetrate
  vessels
• First downstream capillary bed and lymph node are
  most vulnerable

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Clinical Manifestations of Cancer

• Fatigue is the 1 complaint
• Starts early, for unknown reasons
• May last months after tumor is gone
• Causes most severe decrease in quality of life
• Painmay not arise until late stages
• caused by compression local tissue, inflammation,
  or nerve injury (therapy)

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Cachexia

• Malnutrition from metabolic demands of tumor,
  release of cachectin (TNF)
• anorexia, weight loss
• weakness, anemia

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Additional problems

• 60-80 of late stage cancer patients will
  experience clinical depression
• Lack of sleep
• Fear

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Alterations in carbohydrate metabolism

• Tumors metabolize glucose anaerobically
• Patient must convert lactate back to pyruvate for
  use
• Higher than normal insulin suggests post receptor
  abnormalities
• Metabolic changes persist after tumor removal
• TNF will increase insulin resistance in body

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Alterations in protein metabolism

• Patient loses muscle mass
• Resembles situation in burn/sepsis/hyperthyroid
  patients
• Protein metabolism shifts to support tumor
• Acute phase protein response--liver makes
  proteins for tumor, not the body
• Associated with poor prognosis
• Alterations in amino acid levels that persist
  after tumor removal

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Alterations in fat metabolism

• Decrease in fat synthesis, increase in lipolysis
• Lipid mobilizing factor found in urine
• Increases cAMP levels, acts like lipolytic
  enzymes
• TNF-alpha stimulates lipolysis
• High levels of ?-3 fatty acids may have benefit

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Other complications

• Increased risk of infection due to leukopenia,
  therapy
• Anemia
• Bleeding disordersthrombocytopenia, vascular
  invasion, therapy
• Malnutrition from GI dysfunction

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Prognosis

• Tumor Grading Systembased on microscopic exam of
  cells by pathologist
• I Well differentiated
• II Moderately well differentiated
• III Poorly differentiated
• IV Undifferentiated

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Prognosis

• Staging the tumor
• Stages 1-4
• Depends on number of sites, involvement of lymph
  nodes
• Automatically get Stage 3 if tumor and/or mets
  cross the midline or the diaphragm

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Prognosis

• TNM Classification System
• Tumor 1-4 (based on size)
• Txcannot be assessed
• Tiscarcinoma in situ
• Nodes 0-3
• Metastasis 0-1
• Etiology of cancervarious cancers have specific
  progressions