Pathway to Cancer – lecture notes

I. Understanding Cell Fundamentals
A. Fertilization Occurs in Fallopian tube
B. Zygote
1. Sperm meets egg
2. Single cell contains all DNA
a. Half from mom and half from dad
C. Adult – 75 trillion cells


II. Cell division
A. Single cell (parent) divides into identical daughter cells
B. Daughter cells
1. Identical genetically to each other and parent
2. Half the size of parent
3. Grow to parent cell size before dividing

III. Cell Life Cycle
A. Stages
1. Interphase
a. G1, S, G2 (cell preparing to divide)
b. G0 (cell not preparing to divide)
1) some adult cell never divide ex) muscle cells
2. Mitosis
a. Cell (nuclear) Division
B. Interphase
1. G1 phase (8-12 hrs)
a. Preparations for division
b. Cell makes enough organelles for two cells
2. S phase (6-8 hrs)
a. DNA replication
b. Identical copies of genetic material for daughter cells
3. G2 phase (2-5 hrs)
a. Last minute preps (protein synthesis)
C. Mitosis – M phase
1.  Prophase
a) Two copies of each chromosome (chromatid) from S phase
b) Chromatids attached by centromere
c) Chromosomes coil tightly and become visible
2. Metaphase
a) Chromosomes line up
3. Anaphase
a) Chromatids are pulled apart at centromeres
4. Telophase
a) Each new cell moves back into interphase
b) Cytokinesis – final separation of daughter cells
D. Proteins regulating cell cycle
1. Cyclin
2. Cyclin-dependent kinases (cdk)
E. Beginning of cycle
1. Cyclin levels low
2. Growth factors stimulate production of cyclins
3. High cyclin levels activate cyclin-dependent kinases
4. Moves cycle from G1 to S (activation of enzymes for DNA synthesis)
5. Then from G2 to M
F. Growth Inhibitors keep cyclin levels low

IV. Cancer is a cellular control system problem.
A. Uncontrolled dividing
B. Invade surrounding tissue
C. Break off and spread to other locations

Healthy Cell
|
↓
Damage to cell
|
↓
Damage control (Tumor Suppressor Genes, p53 gene)
-stop cell division
-damage assessment
-cellular repair
|
↓
Successful repair     Failed repair   Extensive damage
-return to cell cycle  -damage accumulation -apoptosis
–Cancer

V. Tumor suppressor Genes (p53 on chromosome 17) over 10 described
A. Encode proteins that
1. Detect damaged DNA
2. Repair DNA and other cell parts
3. Coordinate repair systems
4. Apoptosis

VI. Proto-oncogenes – over 100
A. Normal genes that function in regulating cell cycle
B. When these genes increase activity, cyclin levels are elevated and cell divides

C. Oncogenes – mutated proto-oncogenes
1. Leads to uncontrolled division; cancer cell

VII. Cancerous cell
A. Loss of function mutations of tumor suppressor genes (damage control genes)
1. Cause cell to accumulate mistakes (genetic mutations) without ability to fix or cause cell death
B. Gain of function mutations to proto-oncogenes
1. Generate oncogenes that lead to rapid, uncontrolled cell division
2. Proto-oncogenes are turned on when they are not supposed to be

VIII. Six Hallmarks of Cancer Cells

A. Subject to false growth signals
1. Either oversensitive to small amounts
2. Signal occurs without growth factor present

B. Insensitive to inhibitory growth signals
1. No receptors for growth inhibitors
2. Ignore inhibition of cell to cell contact
C. Evasion of apoptosis
1. Treatment – chemotherapy / radiation increase damage to cells;
especially those that divide rapidly.  Hopefully, increased damage will trigger apoptosis in cancer cells
D. Divide indefinitely
1. Normal cell divide a limited number of times (60-70)
2. Telomeres
a. Repetitive DNA sequences at end of chromosomes
b. Protects ends of chromosomes
c. With each cell division some of telomere is lost
d. As we age telomeres get shorter until their lost = cell dies
3. Telomerase
a. Enzyme that fixes telomere ends
b. Not present in most cells
1) bone marrow stem cells
c. Produced in cancer cells
d. Treatment – try to block telomerase
1) Would also block in blood cells
E. Sustained nutrient supply
1. Angiogenesis
a. Growth of blood vessels
2. Cancer cells release chemicals that stimulate angiogenesis
a. Vascular Epithelial Growth Factor (VEGF)
b. Vessels grow into tumors; deprive surrounding cells
F. Tissue Invasion and Metastasis
1. Cancer cells lose attachments
2. Gain motility – ability to move (crawl)

IX. Possible Pathway to Cancer
A. Growth factor receptor mutation
1. Cell divides faster than normal cells
2. Each division increases the chances of mutation
B. Lose ability of apoptosis mutation
1. Rapidly dividing cells pass on the inability of apoptosis
C.  Stimulate release of VEGF mutation
1. Vessels supply tumors with nutrients
D. Lose anchor and gain motility mutation
E. Activate telomerase
F. Cells break off and move to other organs via blood/lymph
G. Mutation to make cells resistant to chemotherapy
1. Protein pumps

*** Series of mutations — takes time — cancer is largely disease of old age

X. Heredity
A. Cancer is a series of mutations
B. If you inherit one — that is one less you need — increase chances
C. Breast Cancer
1. Two mutations in a series
a. BRCA1 (chromo #17) and BRCA2 (chromo #13)
b. Tumor Suppressor Genes – recognize DNA damage

XI. Mutagens – damage DNA / Chromosomes
A. Smoking
1. 2001 – demonstrated that benzopyrene in cigarette tar is converted to
benzopyrene diol epoxide by the liver.
2. Reacts with DNA — mutates p53 gene
B. Correlation Vs. Causes

XII. Tumor Grading
A. TNM system
B. T – tumor size and tissue invasion
1. T0 – T4
C. N – lymph node involvement
1. N0 – N3
D. M – Metastasis
1. M0 – M1(other tumors have been produced in body)
E. T1N1M0 Vs. T4N2M1

XIII. Treatment
A. Before metastasis
1. Surgical removal
2. Radiation
C. After metastasis
1. Chemotherapy
a. Administer drugs to kill cancerous tissues or prevent division
b. Affects other rapidly dividing cells in the body
1) Hair and digestive tract
2. Complete body radiation
a. Advanced lymphoma
b. Kills blood-forming cells
c. Need for bone marrow transplant