Introduction to Carcinogenesis

Robbins 9th ed.

Pages 173- 204, copyrighted
 Introduction to Carcinogenesis
1. Discuss the epidemiology and prevention of cancer.
2. Discuss the molecular basis of carcinogenesis.
3. Discuss karyotypic changes.
4. Discuss the molecular basis of multistep carcinogenesis and monoclonal.
5. Explain paraneoplastic syndromes.
6. Explain laboratory diagnosis of cancer
7. Discuss grading and staging of cancer.
Incidence of Leading
Cancer Type in Puerto
Rico:1987-2004

P R H Sci J 2010
3:317-329

Fig. 3
Cancer Incidence
distribution PR 2000-
2004
Incidence and Mortality of Leading
Cancer Type in Puerto Rico:1987-
2004

Fig.4 Cancer Mortality PR 2000-

2004

P R H Sci J 2010 3:317-329

Robbins 9th ed. Page
171, copyrighted
 Introduction to Carcinogenesis

Nonlethal genetic damage

Normal regulatory genes
1. growth promoting prot-oncoge
2. growth-inhibiting tumor suppressor genes
3. Genes that regulate programmed cell death
4. genes involved in DNA repair
 The Components of Carcinogenesis

Self-sufficient growth Oncogene activation

Insensitive to stop signals

Tumor suppressors
genes-TP53
Defective DNA repair
Apoptosis inhibition
Limitless replication bcl-2 (immortal)
Angiogenesis Telomeres
Invasion and Metastasis
 Cancers are genetic diseases
The current developments may provide the means to
diagnosed and treat CA
DNA array (genome chip)

Carcinogenesis is a multi-step process

Knusons two-hit theory
 Adenoma Carcinoma sequence
Normal colon mucosa at risk adenomas carcinomas

Germ-line or methylation protooncogene homozygous loss additional

Somatic inactivation of mutation additional tumor mutations
mutationsfirst hit normal alleles suppressor genes
second hit

APC at 5q21 APC K-RAS at 12p12 18q21 many

TP53 at 15p53 genes
Nonreceptor Tyrosine Kinases
c-ABL translocation t(9;22)
produces a fusion protein
with tyrosine kinase activity
 Transcription
factors
MYC is a potent transcriptional activator
Over-express due to translocation in Burkitts
lymphoma and amplified in neuroblastomas
Tumor progression and generation of
heterogeneity

Robbins 9th ed., page

177, copyrighted
Oncogenes Synergic Effect
Hallmarks of Cancer

Robbins 9th ed., page

178, copyrighted
Retinoblastoma and cell-cycle
regulation
Robbins 9th ed.,
page 186,
copyrighted
 Growth Factor Receptors
ERB B2 HER2/Neu amplified in 25% of breast CA
EGFR over-expressed in SCC and colorectal CA
RET MEN 2A / 2B and familial medullary Thy. CA
 Oncogenes
Discovered within acute
transforming retroviruses
(v-oncs) fes, sis etc..

Analogous to mutated
protooncogenes and tumor
suppressor genes (antioncogenes)

Other genes involved in neoplasia

related to: Apoptosis and DNA repair

Mechanism of activation
Over-expression
amplification
rearrangement
 Oncogenes Products
Growth Factors
Growth Factor Receptors
Signal Transducing
Proteins
Nuclear Transcription
Proteins
Cyclin kinases
 The RAS oncogene
RAS mutation The single most common abnormality of dominant
oncogenes in human tumors
Transducing growth factor signal and cell cycle regulation roles
 Angiogenesis
Blood supply is essential for tumors
Neovascularization: Supplies nutrients and
stimulates growth
Angiogenesis (micro-vessel density)
Angiogenic - Antiangiogenic balance p53
and thrombospondin-1
Endostatins are potent antiangiogenic factors
 Telomeres
Specialized structures called telomeres
suffer shortening with each cell
division(acting as biologic clock) replicative
senescence
An enzyme (telomerase ) prevents telomeres
shortening (telemorase hypothesis of
cellular aging)
Telomerase activity has been detected in
human tumors
 Invasion of Epithelial Basement
Membrane
Down regulation of E-
cadherins
Attachment to laminin
and fibronectin
Degradation: Type IV
collagenase &
plasminogen activator
Locomotion: Autocrine
motility factor
 Vascular Invasion

Up-regulation of v-adhesion
molecules
Chemokine receptors
Permissive enviroment

CD44 homing receptor

 Metastasis Theories
Clone within clone
Gene expression pattern
Clonal evolution and gene expression pattern
Tumor stromal response
Infectious Diseases and Neoplasia

Human Papillomavirus
Helicobacter Pylori
Epstein-Barr Virus (EBV)
H. pylori
EBV Model
HPV

Immunohistochemistry
 Laboratory Diagnosis of Cancer
Histologic and cytologic methods Biopsies,
smears, frozen sections
Immunophenotype
Immunohistochemistry
Flow cytometry
Tumor markers
Molecular diagnosis
FISH, PCR, Cytogenetics
Laser capture micro-dissection
Cytologic (Pap) smears
Cytogenetics
Karyotyping
Fluorescence in-situ hybridization
FISH
 Tumor markers
Prostate Specific Antigen - PSA
Immunoglobulins SPEP
Alpha fetoprotein -fetoprotein
Carcinoembriogenic antigen - CEA
CA-125
 Chemical Carcinogenesis
Soot: Cancer of the scrotum
("chimney sweep's cancer" --
* discovered by Percival Pott)
 Radiation Carcinogenesis
Radiant energy: UV rays - Ionizing radiation
Ultraviolet Rays - UVA (320-400 nm)
UVB (pyrimidine dimers) MM, SCC, BCC
UVC (filtered out by the ozone layer)
The NER pathway and xeroderma pigmentosum
Ionizing radiation (electromagnetic / particulate)
Rocky Mountain miners - Lung CA
Hiroshima/Nagasaki AML, CML, & solid CA
Chernobyl Thyroid Cancer
 Depleted Uranium
The U remaining after removal of the enriched fraction.
DU: Applications: aircraft counterweights, radiation
shields (containers) and heavy munitions.
UNEP reported DU contamination at impact sites in
Kosovo
The Navy used shells with DU in 02/99
Toxicity: chemical & radiological
Kidneys, lung, skin
Increased risk of lung CA
Paraneoplastic syndromes
Syndrome Mechanism Example
Cushing's Syndrome ACTH-like substance Lung (oat cell) carcinoma
Hypercalcemia Parathormone-like substance Lung (squamous cell)
carcinoma
Hyponatremia Inappropriate ADH secretion Lung (oat cell) carcinoma

Polycythemia Erythropoietin-like substance Renal cell

carcinoma
Trousseau's Syndrome Hypercoagulable state Various
carcinomas
Hypoglycemia Insulin-like substance Various carcinomas and
sarcomas
Carcinoid Syndrome 5-hydroxy-indoleacetic acid (5-HIAA) Metastatic
malignant carcinoid tumors
Agents or Groups of Human Cancer Site for Which Reasonable
Agents Evidence Is Available Typical Use or Occurrence

Arsenic and Lung, skin, hemangiosarcoma Byproduct of metal smelting. Component of alloys, electrical and semiconductor devices, medications and
arsenic herbicides, fungicides, and animal dips
compounds

Asbestos Lung, mesothelioma; gastrointestinal tract Formerly used for many applications because of fire, heat, and friction resistance; still found in existing
(esophagus, stomach, large intestine) construction as well as fire-resistant textiles, friction materials (i.e., brake linings), underlayment and roofing
papers, and floor tiles

Benzene Leukemia, Hodgkin lymphoma Principal component of light oil. Although use as solvent is discouraged, many applications exist in printing
and lithography, paint, rubber, dry cleaning, adhesives and coatings, and detergents. Formerly widely used as
solvent and fumigant

Beryllium and Lung Missile fuel and space vehicles. Hardener for lightweight metal alloys, particularly in aerospace applications
beryllium and nuclear reactors
compounds

Cadmium and Prostate Uses include yellow pigments and phosphors. Found in solders. Used in batteries and as alloy and in metal
cadmium platings and coatings
compounds

Chromium Lung Component of metal alloys, paints, pigments, and preservatives

compounds

Ethylene oxide Leukemia Ripening agent for fruits and nuts. Used in rocket propellant and chemical synthesis, in fumigants for
foodstuffs and textiles, and in sterilants for hospital equipment

Nickel compounds Nose, lung Nickel plating. Component of ferrous alloys, ceramics, and batteries. Byproduct of stainless steel arc welding
Radon and its Lung From decay of minerals containing uranium. Can be serious hazard in quarries and underground mines
decay products

Vinyl chloride Angiosarcoma, liver Refrigerant. Monomer for vinyl polymers. Adhesive for plastics. Formerly inert aerosol propellant in
pressurized containers

Modified from Stellman JM, Stellman SD: Cancer and workplace. CA Cancer J Clin 46:70, 1996.
Target therapies
Gleevec (imatinib) - Bcr-abl
kinase: CML & GIST
Erbitux (cetuximab)- EGFR:
Colorectal cancer
Avastin (bevacizumab)- VEGF:
Colorectal cancer
Rituxan (rituximab)- CD20:
Lymphoma
Herceptin (trastuzumab)- HER-
2/neu) Breast cancer
Campath-CD52: CLL
Mylotarg- CD33: AML