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Tumors are monoclonal proliferation

Tumors carry genetic defect that are not lethal


(inherited or acquired)
Transformed cells acquire gene defects that allow them
to form tumor

A lot of genes!
Like what?
Genes promote growth eg. RAS
Genes inhibit growth eg. P53
Genes control apoptosis eg. Bcl-2
Genes of DNA repair
And others.
Targeted genes:
1. Proto-oncogenes (oncogenes)
2. Tumor suppressor genes
3. Genes controlling apoptosis
4. Genes regulating DNA repair
Other genes involved:
Genes regulating angiogenesis
Genes enhancing invasion and metastasis
Carcinogenesis is a multistep process
At both genetic and phenotypic levels
Progression results from accumulation of genetic
defects

What does a cell need to be cancer?
Independent growth (growth autonomy)
Insensitive to inhibition of growth
Resistant to apoptosis
No aging (continuous dividing)
Sustained angiogenesis
Ability to invade and metastsize

By the action of oncogenes (from protooncogenes)
Promote growth, no control

Normal growth (dividing)
Growth factor Growth factor receptor Signal
transduction Transcription factors Entry of the cell
cycle by cyclins and CDKs

Growth factors
PDGF in Glioblastoma multiforme
TGF-alpha in Sacroma
Growth factor receptors
EGF (epidermal growth factor)
ERBB1 in squamous cell carcinoma of lung
ERBB2 in breast cancer
Signal transducing proteins
RAS: colon cancer, pancreatic cancer
ABL: (BCR-ABL) in Chronic myologenous leukemia
(CML)
Gleevec is a drug used to inhibit ABL action and used in
the treatment of CML
Transcription factors:
MYC: in Burkitt lymphoma

Cyclins and CDK:
Cyclin D: in breast cancer, liver cancer, lymphoma
Retinoblastoma gene RB
Two-hit hypothesis (Knudson)
Mutated in many cancer including retinoblastoma
TGF-beta pathway
Act through RB
Mutated in colon cancer, stomach and endometrial
cancer
APC beta catenin pathway
APC in cytoplasmic protein that regulates the level of
beta-catenin
Beta-catenin activates cell proliferation
APC binds to Beta-catenin and enhance degradation
Inherited mutation of APC in FAP (familial
adenomatous polyposis)
2
nd
hit occurs and adenoma appear
With time more adenoma 100s and 1000s
Cancer develop when other genes affected eg. RAS, P53
P53:
Common in human cancer 70%
Tumor suppressor gene

DNA damage P53 activation by release from MDM2
P53 results in arresting the cell cycle by increasing P21.
P53 enhance repair of the DNA damage by GADD45
P53 induces apoptosis by increasing level of Bax
Li-Fraumeni Syndrome: inherited mutated P53
Bcl-2 family
Level of Bcl-2 vs. BAX, BAD
Bcl-2 prevents apoptosis by preventing the release of
cytochrome C
Bcl-2 overexpressed in lymphoma
Normal cells have 60-70 replication possible, then the
cells cannot divide (aging)
This is done by shortening of Telomere
Tumors have telomerase activity and prevent cell aging
Tumors cannot grow more than 2 mm with no vascular
supply
Hypoxia induces angiogenesis
Tumor associated angiogenic factors
VEGF
bFGF
P53 inhibits angiogenesis
1. Loosening of intercellular junction
E-cadherin mutation
2. Attachment to matrix
Cancer cells have high number of receptors to ECM like laminin
receptor
3. Degradation of ECM
By secreting metalloproteinases
4. Migration
By the action of cytokines and chemokines
5. Homing
Expression of adhesion molecules
DNA mismatch repair genes: hereditary non-polyposis
colon cancer
DNA excision repair gene: Xeroderma pigmentosum
Ataxia telangiectasia (ATM) gene senses the DNA
damage
BRCA1, BRCA2: involved in DNA repair
Colon Cancer:
APC RAS P53
Hyperplasia Adenoma Carcinoma
Tumor progression and heterogeneity
Genetic Damage
1. Chemicals
2. Radiation
3. Microbes

Heredity:
Inherited cancer syndromes
Familial cancer
Autosomal recessive syndromes of defective DNA repair
Heredity:
Inherited cancer syndromes
Autosomal dominant
Eg. Familial Adenomatous Polyposis (FAP)
Retinoblastoma, MEN, Neurofibromatosis, von Hipple-
Lindau
Familial cancer
Not clear transmission pattern
Cancer at early age, multiple, affecting relatives
BRCA1, BRCA2
Autosomal recessive syndromes of defective DNA
repair:
Xeroderma pigmentosum, ataxia telangiectasia
Chemicals:
Scrotal cancer in chimney sweepers
Direct or indirect action
Natural or synthetic
Alkylating agents, hydrocarbons, smoking, Azo dyes,
Aflatoxin B1
Mechanism: mutation of genes (promoters and
initiators)

Carcinogens
Smoking: causes lung cancer, pancreatic cancer, bladder
cancer
Asbestos: found in construction, roofing papers, fire-
resistant textile, causes lung cancer, mesothelioma, GI
cancer
Benzene: found in light oil, printing, paint rubber, dry
cleaning, adhesive, causes leukemia and lymphoma
Cadmium: found in batteries, metal plating, causes
prostate cancer
Vinyl chrolride: found in refrigerant, adhesive, causes
liver cancer
Radiation:
Ultraviolet sun light, x-ray, nuclear radiation
Chromosome breakage, translocation, mutation,
genomic instability
Ultraviolet light causes skin cancer, common in
Australia.

Viruses and microbes
Acute transforming viruses contain viral oncogenes
Slow transforming viruses cause insertional mutation
HTLV-1 causes T-cell lymphoma
HPV: cervical cancer
EBV: lymphoma
HBV: Liver cancer
Helicobacter pylori: gastric cancer

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