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

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

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

Basal lamina normally provides barrier

Malignant tumor cells can:
1)
2)
3)
4)
5)

Break free of attachments to adjoining cells

Attach to basal lamina
Secrete enzymes that digest extracellular proteins
Migrate into circulatory system
Penetrate back out of circulatory system to
colonize another tissue

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 growth-promoting 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 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

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