Cancer
• Cancer originates in dividing cells
– Intestinal lining (colon)
– Lung tissue
– Breast tissue (glands/ducts)
– Prostate (gland)
– White blood cells (leukemia)
– Stem cells
• Skin (melanoma)
• Liver
• Hematopoietic (myeloma)
• Does not occur in quiescent cells
Cells and Their Half-Lives
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Intestinal cells
Erythrocytes
White blood cells
Liver
Muscle
Neurons
Skin cells
Endothelial cells
Less than a week
100 days
Brief life spans
Infrequently replaced
Irregular activation
Little or no replacement
Regularly replaced
Frequently replaced
Cancer
• Loss of cell-cycle control
– Cloned cells divide unchecked
• Results from multiple genetic mutations
– Cell cycle genes
– DNA repair genes
– Apoptosis genes
– Growth regulation genes
• Classified as carcinomas, sarcomas or
leukemias (200 types recognized)
Benign Tumors
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Generally localized and small
Fairly common (warts, colon polyps, etc.)
Do not break out of originating organ
Function very much like cells of origin
Generally are easily removed by surgery
Malignant Tumors
• Remain localized for a time but then
invade surrounding tissue
• Spread by forming metastases
– Cells travel through circulation
– Can invade any other body tissues
• Produce few markers of original tissue
• Very difficult to treat
Cancer Metastasis
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Basal lamina normally provides barrier
Malignant tumor cells can:
1) Break free of attachments to adjoining cells
2) Attach to basal lamina
3) Secrete enzymes that digest extracellular
proteins
4) Migrate into circulatory system
5) Penetrate back out of circulatory system to
colonize another tissue
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Rare cells succeed (1 in 106)
Tumor Angiogenesis
• 106 cells is a mass of ~2mm
• Can not grow more without blood supply
• Malignant cells overcome this limitation
– Secrete growth factors that stimulate
angiogenesis (FGF, VEGF,etc.)
• Requirement for vascular supply
suggests possible treatment approach
Cancer is Caused by DNA Mutations
• DNA from transformed cells can
transform normal cells
• More than 1 mutation is required
– E.g., 3T3 cells that already lack p16 (cyclin
dependent kinase inhibitor) and then
develop mutation to overproduce growthpromoting signal (ras) becomes cancerous
• Mammals have evolved to prevent
accumulated mutations
Genes Associated with Cancer
• Oncogenes
– Mutated forms of proto-oncogenes
– Overproduction or over activity is
associated with cancer
• Gain-of-function agents
• E.g., Myc – Transcription factor that leads to
progression through cell cycle
– Mutation in one allele is adequate to cause
cancer risk
Genes Associated with Cancer
• Tumor suppressor genes
– Encoded proteins that inhibit cell cycle
progression or promote apoptosis
• E.g., APC or Rb
– Loss of function agents
– Mutations in both alleles are required
Inherited Mutations
• Some mutations pass through germ line
• Causes hereditary predisposition
– Insufficient alone to cause cancer
– ~10% of all cancers have hereditary component
• E.g., Inherited dysfunctional APC gene
leads to colon polyps early in life
• E.g., Inherited dysfunctional Rb gene leads
to hereditary retinoblastoma early in life
Cell Cycle Problems
• Over expression of Cyclin D
• Loss of p16 function
• Loss of Rb function
Loss of DNA Repair Problems
• p53 is an essential checkpoint protein
– Prevents proliferation with damaged DNA
– Loss of function associated with ½ of all cancers
– Cells with p53 arrest in G1 after irradiation
– Activated only after cell stress or damage
– Induces p21 to inhibit Cdk-cyclin complexes
– Falls off to low level if DNA repair is successful
– Active as tetramer of 4 units
• Mutation in one allele creates loss of function
P53 Mutation Frequency in Various Cancers
Chemical Carcinogens
• Direct acting vs. indirect
– Indirect results from non-reactive chemicals
being metabolized in liver to carcinogen
• Oxidative reactions by p450 enzyme complexes
rid body of fat soluble toxins
– Active carcinogen binds to DNA and causes
mutations (e.g., benzopyrene in cigarette
smoke causes G to T transversions in DNA –
causes mutations of p53 at codons 175, 248
and 273)
Initiators vs. Promoters
• Initiators
– Carcinogens that interact with and cause
mutations in DNA
• Promoters
– Interact with cells to promote growth, block
differentiation
– Leads to additional permanent changes after
initiator damage
– Does not cause cancer by itself
– No reliable test yet found to identify promoters
Radiation Mutations
• Ultraviolet radiation
• Ionizing radiation
– Gamma- and X-rays
– Particle radiation (alpha, beta)
• Electromagnetic radiation
– Power lines, cell phones, etc.
– May act as promoter
Cancer Treatments
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Surgery
Chemotherapy
Radiation therapy
Photodynamic therapy
“Magic bullets”
Angiogenesis inhibitors
Transplantation of hematopoietic stem cells
– Whole body radiation to treat metastases
• Gene therapy
– Reintroduce p53 or other tumor suppressor genes
– Must get into each and every cancer cell