Beruflich Dokumente
Kultur Dokumente
Clinical Biochemistry
At the end of the lecture…….
Cell cycle and its control.
Proto-oncogene, oncogene, tumor-suppressor
genes.
Mechanism of carcinogenesis.
Carcinogenesis and environmental factors.
Cytogenetic changes in cancer.
Sporadic and familiar cancers: cytogenetic factors of:
o Cancer breast.
o Cancer colon.
o Leukemia.
Q: A 35-year-old Jewish woman of Ashkenazi descent is evaluated in the
office during a routine examination. Her medical history is noncontributory.
The family history includes a paternal grandmother who had bilateral breast
cancer at ages 42 and 50 years and died of metastatic breast cancer at age
53 years and a paternal great aunt who had ovarian cancer at age 45 years
and breast cancer at age 51 years. Her two sisters, mother, and mother's
relatives have not had breast or ovarian cancer, and her father is healthy
without any cancer.
5
Heterogeneity of cancer progression.
9
The “cell cycle”
S: Replication of DNA
G2:
Cell death M: Mitosis
11
DNA helicases: Unwinding
DNA binding proteins: Prevents winding back
DNA primase: formation of DNA/RNA primer (from free
nucleosides in cell)
DNA polymerase: Catalyse elongation of new strand (5’ - 3’)
Lagging strand:
DNA ligase: Connects Okasaki fragments
12
Control of the Cell Cycle
4- Checkpoints:
G1/S checkpoint.
G2/M checkpoint.
Spindle checkpoint.
All checkpoint examined
require the service of
complex proteins as:
o Retinoblastoma protein
o P53 protein
14
Role of Rb protein in Cell Cycle Control
16
Characters of Caner Cells
• Uncontrolled growth
• Invasion
• Metastasize -- that is, establish new
tumour sites at other locations
throughout the body.
“Secondary tumours”.
Mechanism Of Carcinogenesis
What Are The Genes Involved In
Cancer Development?
19
Types Of Genes Which May Cause Cancer
20
NORMAL CELL
Growth factor
Growth factor receptor
cytoplasm
Signal transduction
Activation of
transcription
nucleus
1. Proto-oncogenes are normal cellular genes whose products promote cell proliferation
Proto-oncogenes include a heterogenous family of genes with many
biochemical effects:
3. Signal transducing
factors
as cytoplasmic kinases
4. DNA binding
5. cell cycle proteins concerned
proteins as cyclin with transcription
D
Oncogenes
• Are genes capable of causing cancer
• Were first recognized as unique genes of tumor
causing viruses.
Proto-oncogenes:
• Are DNA sequences in normal cells that looks
like or identical to oncogenes but don’t cause
cancer.
• Their products may play roles in cell
differentiation.
23
NEOPLASTIC CELLS
Oncogenes can promote uncontrolled cell proliferation by
several mechanisms
Increase Increase in
Increase Increase in
In growth factor activation of
In growth signal
receptors transcription
factor transduction
1 2 3
Point Chromosomal Amplification
mutation translocations
Activation Of Proto-Oncogenes To Oncogenes
Activation means: increased transcription of their genes.
Five mechanisms activate proto-oncogenes:
• 1. promoter insertion
Certain retroviruses integrate their genome as cDNA in host
cells, this cDNA is flanked by sequences termed long terminal
repeats that function as promoters for transcription of proto-
oncogenes
• 2. enhancer insertion:
The integrated viral genome in host cell may be inserted
down stream or upstream from the proto-oncogene but in
the reverse direction (enhancer sequence present in long
terminal repeats)
26
3. chromosomal translocations:
• It is one type of chromosomal
change seen in tumor cells:
• Piece of one chromosome is split
off and joined to an other
chromosome, if the second
chromosome donates material to
the first, then it is reciprocal
translocation.
• An example of translocation is the
philadelphia chromosome involved
in chronic granulocytic leukemia
(chromosome 9 and 22)
• 4. Gene amplification:
One method of bringing about gene
amplification is by administration of the
anticancer drug methotrexate.
Is an inhibitor of dihydrofolate reductase.
tumor cells can become resistant to it by
amplification of its gene and as
consequence there is increased rate of
enzyme activity.
• 5. Point mutation:
Transition
transversion
28
Mechanism of action of oncogenes:
• 1. May act on key intracellular pathways
involved in growth control, uncoupling them
from the need to exogenous stimulus.
• 2. their products may imitate certain growth
factors
• Humans of all ages can develop cancer and
various tissues are affected
29
Types Of Genes Which May Cause Cancer
30
(2)Tumour suppressor genes
31
Types Of Genes Which May Cause Cancer
32
(3) DNA Repair Genes
34
Types Of Genes Which May Cause Cancer
35
(4) Genes that regulate apoptosis
36
Cancer Is A Multistep Process Resulting From A
Series Of Mutations In A Single Cell
point mutations
Translocations
Deletions
Amplification
Aneuploidy.
The Seven fundamental changes in cancer
The carcinogenic
process include
seven fundamental
changes in cell Genomic
instability
physiology that
resulting
together lead to from
cancer defects in
development DNA repair
40
Hereditary in cancer
41
Hereditary breast cancer
42
Hereditary non polyposis colon carcinoma
syndrome
43
Leukemia
Chronic myelogenous leukemia (CML)
In 90% of cases, reciprocal and balanced chromosomal translocation
between chromosomes 9 and 22 that generates the Philadelphia
chromosome.
N.B.:
• Cancer arises from the mutation of a normal gene.
• Mutated genes that cause cancer are called oncogenes.
• It is thought that several mutations need to occur to give rise
to cancer
• A factor which brings about a mutation is called a mutagen.
• A mutagen is mutagenic.
• Any agent that causes cancer is called a carcinogen and is
described as carcinogenic.
Carcinogenic agents
Definition:
Carcinogenic agents are
substances that cause
genetic damage and
produce neoplastic
transformation.
Carcinogenic agents
Types of carcinogens
1. Physical carcinogens
2. Chemical carcinogens
3. Oncogenic viruses
Physical Carcinogens
Types:
(1) (2)
Ultraviolet rays: Ionizing radiations:
Cause skin carcinoma and Cause leukemia
melanoma
(3) X-rays
Physical Carcinogens
49
Carcinogenic chemicals and drugs:
• Polycyclic aromatic hydrocarbons
• Aromatic amines
• Nitrosamines
• Drugs: cyclophosphamide
• Alkylating agents
• Inorganic compounds: arsenic, lead, asbestos…
• Naturally occurring compounds: Aflatoxin which is
produced by aspergillums flavus and contaminate
peanuts.
50
Chemical carcinogens
Indirect-Acting Agents Direct-Acting
Agents
54
Oncogenic Viruses
Types: Oncogenic viruses are either
1. DNA viruses
57
Biochemical Changes In Cancer Cells
• Increased rate of glycolysis
• Change of cell surface glycoprotein, glycolipids
• Alteration of cytoskeleton structures like actin filaments
• Increased secretion of growth factors in the surrounding
medium
• Increased activity of ribonucleotide reductase
• Increased synthesis of DNA and RNA.
• Increased aerobic and anaerobic glycolysis
• Synthesis of fetal proteins e.g carcinoembryonic antigen
• Decreased catabolism of pyrimidines
• Inappropriate synthesis of certain growth factors
58