Transcript Basic Concepts of Cancer

Basic Concepts of Cancer
Neoplasia
 Disease
of cell growth, division, and
differentiation
 Benign
tumors
• Localized, clear margins (encapsulated), noninvasive, 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,
• 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
Initiation--promotion--progression
theory
 Initiation
genome
is first insult or series of insults to
Types 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 cycle
 Removes review/editing of DNA copying
mistakes
 Typically recessive mutations, so need 2
hits
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 problems
 60-80%
of late stage cancer patients will
experience clinical depression
 Lack of sleep
 Fear
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
II
III
IV
Well differentiated
Moderately well differentiated
Poorly differentiated
Undifferentiated
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
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