basic concepts of cancer. neoplasia b b disease of cell growth, division, and differentiation b b...
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Basic Concepts of CancerBasic Concepts of Cancer
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
Malignant neoplasms
Rapid growth, no clear margins (invasive) Aneuploidy, uncontrolled cellular
multiplication, lytic enzymes Decreased cell adhesion, increased motility
(metastatic) Angiogenesis---abnormal vessels
Classifications of malignancies
Carcinoma--epithelial Sarcoma—CT or muscle Glioma--glial cells Neuroblastoma--neurons Lymphoma Leukemia
Cancer is a genetic disorder, but it is rarely inherited
Epigenetic modifications p53 protein—guardian of the genome
– Errors in p53 show up in ~50% of all cancers– Different mutations seem to prevail in different
cancers Telomerase—prevents normal shortening of
telomeres at end of chromosomes– Absent in most somatic cells, present in 85% of
cancers– Allows for infinite number of divisions
Multi-step Model for Cause of Cancer
One cell suffers multiple genetic mutations, One cell suffers multiple genetic mutations, • Proto-oncogenes induce cell proliferation and Proto-oncogenes induce cell proliferation and
growth (normal function)growth (normal function)– Defined by what happens when turned onDefined by what happens when turned on
• Tumor suppressor genes suppress cell growthTumor suppressor genes suppress cell growth– Defined by what happens when turned offDefined by what happens when turned off
– P53--guardian of genome, halts faulty cycleP53--guardian of genome, halts faulty cycle
Initiation--promotion--progression theory
Initiation is first insult or series of insults to genome
Types of Initiation StepsTypes of Initiation Steps
Changes in proto-oncogenes oncogenes
Point mutations—always dominant (ras gene, telomerase gene)
Gene amplification Chromosomal rearrangement Viral insertion and activation
• human papillomavirus, hepatitis B and C, Epstein Barr (?)
Changes in tumor suppressor genes (p53 is #1 example)
Removes controls on cell cycleRemoves controls on cell cycle Removes review/editing of DNA copying Removes review/editing of DNA copying
mistakesmistakes Typically recessive mutations, so need 2 Typically recessive mutations, so need 2
hitshits
Chemical damage to DNA
Epigenetic modifications, base substitutions Aromatic hydrocarbons, aromatic amines Insecticides, asbestos Anti-neoplastic drugs Aflatoxins Nitrosamines and nitrosamides in food,
water
Physical damage to DNA
Breaks, deletions, translocations Sunlight (ultraviolet) Radiation--therapy or diagnostic use
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
Promotion = Proliferation
Intracellular antioxidant enzymes should repair damaged DNA
Apoptosis should remove damaged cells Cancers become more malignant with each
generation of transformed cells
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
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
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
Pain—may not arise until late stages• caused by compression local tissue,
inflammation, or nerve injury (therapy)
Cachexia
Malnutrition from metabolic demands of tumor, release of cachectin (TNF)• anorexia, weight loss• weakness, anemia
Additional problemsAdditional problems
60-80% of late stage cancer patients will 60-80% of late stage cancer patients will experience clinical depressionexperience clinical depression
Lack of sleepLack of sleep FearFear
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
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
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 Ω-3 fatty acids may have benefit
Other complications
Increased risk of infection due to leukopenia, therapy
Anemia Bleeding disorders—thrombocytopenia,
vascular invasion, therapy Malnutrition from GI dysfunction
Prognosis
Tumor Grading System—based on microscopic exam of cells by pathologist
• I Well differentiated• II Moderately well differentiated• III Poorly differentiated• IV Undifferentiated
PrognosisPrognosis
Staging the tumorStaging the tumor Stages 1-4Stages 1-4
• Depends on number of sites, involvement of Depends on number of sites, involvement of lymph nodeslymph nodes
• Automatically get Stage 3 if tumor and/or mets Automatically get Stage 3 if tumor and/or mets cross the midline or the diaphragmcross the midline or the diaphragm
Prognosis
TNM Classification System• Tumor 1-4 (based on size)
– Tx—cannot be assessed
– Tis—carcinoma in situ
• Nodes 0-3 • Metastasis 0-1
Etiology of cancer—various cancers have specific progressions