Transcript phl_425_cancer_oncogem_and_tumour_suppressor_genes

CANCER, ONCOGENES AND TUMOUR
SUPPRESSOR GENES
PHL 425
Dr. Mohamed M. Sayed-Ahmed
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SOLID TUMOURS
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Anal carcinoma
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Billary tract carcinoma
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Brain tumours (Gliomas)
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Breast cancer
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Cervical Carcinoma
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Colorectal Carcinoma
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Endometrial carcinoma
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Esophageal carcinoma
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Gastric carcinoma
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Germ cell carcinomas
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Head and neck carcinomaoma
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Hepatocellular carcinoma
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Lung cancer (SCLC and NSCLC)
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Malignant melanoma
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Neuroblastoma
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Ovarian carcinoma
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Pancreatic carcinoma
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Prostatic carcinoma
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Renal cell carcinoma
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Retinoblastoma
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Throid carcinoma
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Wilms’ tumour (Nephroblastoma)
HEMATOLOGIC TUMOURS
• Acute lymphoblastic leukemia (ALL)
• Acute myeloid leukemia (AML)
• Chronic lymphocytic leukemia (CLL)
• Chronic myeloid leukemia (CML)
• Hairy cell leukemia (HCL)
• Hodgkin’s lymphoma (HL)
• Non-Hodgkin’s lymphoma (NHL)
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CANCER
• CANCER is the uncontrolled growth of cells due to damage to
DNA (mutations).
• Cell division (proliferation) is a physiological process that occurs in
almost all tissues and under many circumstances. Normally
homeostasis, the balance between proliferation and
programmed cell death (apoptosis) is maintained by tightly
regulating both processes to ensure the integrity of organs and
tissues.
• Mutations in DNA that lead to cancer disrupt these orderly
processes by disrupting the programming regulating the processes.
In fact, a series of several mutations to certain classes of genes
is usually required before a normal cell will transform into a
cancer cell. Only mutations in those certain types of genes
which play vital roles in cell division, cell death, and DNA repair
will cause a cell to lose control of its proliferation.
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Characteristics of Cancer Cells
1- They are resistant to apoptosis ("programmed" cell death).
2- They have an uncontrolled ability to divide (or, they are immortal),
and they often divide at an increased rate.
3- These cells are self-sufficient with respect to growth factors.
4- They are insensitive to antigrowth factors.
5- They have the ability to invade neighboring tissues, usually through
the secretion of metalloproteinases that can digest extracellular
matrix material. They can form new tumors (metastases) at distant
sites.
6- They secrete chemical signals that stimulate the growth of new
blood vessels (angiogenesis).
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NORMAL CELL
Growth factor
Growth factor receptor
cytoplasm
Signal transduction
nucleus
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Activation of
transcription
NEOPLASTIC CELLS
Increased
In growth
factor
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Increased
In growth
factor
receptors
Increased in
signal
transduction
Increase in
activation of
transcription
Causes of Neoplasia
Environmental causes: (Carcinogens)
Chemicals
Viruses
Radiation
Hereditary causes- Genetic defects.
Combination – common.
All cancer is genetic, not all cancer is
hereditary
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Chemical Carcinogenesis
• Initiation
– DNA damage eg.
DENA (diethylnitrosamine)
Benzpyrene
• Promotion
– Histologic change
Ccl4
Turpentine (co-carcinogens)
– DENA + Ccl4 (Liver Cancer)
• Malignant transformation:
– Visible tumor formation
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INITIATION
Initiation is an irreversible genetic alteration
which result from the interaction of the ultimate
carcinogen with the DNA in the target cell.
(1) Is an irreversible process
(2) Caused only by carcinogenic compounds
(3) Occurs after carcinogen exposure
(4) Initiator alone does not result in tumor formation
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PROMOTION
Promotion refers to a phenomenon of gene activation
in which the latent altered phenotype of the
initiated cells becomes expressed through
selection and clonal expansion.
1- Is a reversible process
2- Acts only after exposure to an initiator
3- Requires repeated administration
4- Promotor is not carcinogenic in itself
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promotr alone does not result in tumor formation
INITIATION AND PROMOTION
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Molecular Basis of Carcinogenesis
Four classes of regulatory genes.
1- Tumour Promotors: Proto-oncogenes
2- Tumour Inhibitors:Tumour-suppressor genes
3- Genes regulating Apoptosis
4- DNA repair genes.
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Non-lethal Genetic damage lies at the
center of carcinogenesis
• Loss/damage to suppressor genes
• Overexpression of promotor genes
• Loss/damage to Apoptosis genes
• Loss/damage of DNA repair genes.
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PROTO-ONCOGENES
are genes which promote cell growth and
mitosis (cell division).
• TUMOUR SUPPRESSOR GENES:
discourage cell growth, or temporarily halts
cell division from occurring in order to carry
out DNA repair. Typically, a series of
several mutations to these genes are
required before a normal cell transforms
into a cancer cell.
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Acquired environmental factors
chemicals ,radiation ,viruses
Genetic factors
Changes in genome
of somatic cells
Activation of growth
promoting oncogenes
Inactivation of tumour
supressor genes
Expression all altered gene products
and loss of regular gene products
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MALIGNANT NEOPLSM
Molecular Basis of Neoplasia
Proto-oncogene
Oncogene
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Tumor suppressor genes
• A tumor suppressor gene is a gene that reduces the
probability that a cell in a multicellular organism will
turn into a tumor cell. A mutation or deletion of such
a gene will increase the probability of the formation
of a tumor.
• Unlike oncogenes, tumor suppressor genes generally
follow the 'two-hit hypothesis,' which implies that
both alleles that code for a particular gene must be
affected before an effect is manifested. This is due to
the fact that if only one allele for the gene is
damaged, the second can still produce the correct
protein. However, there are cases where mutations in
only one allele will cause an effect. A notable
example is the gene that codes for p53.
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Tumor suppressor genes, or more precisely, the proteins for which they
code, either have a dampening or repressive effect on the regulation of
the cell cycle or promote apoptosis, and sometimes do both.
Examples of tumour suppressor Genes Includes:
P53,
Rb,
BRCA-1 and BRCA-2
The first tumor suppressor protein discovered was the pRB
protein in human retinoblastoma; however, recent evidence has also
implicated pRb as a tumor survival factor. Another important tumor
suppressor is the p53 tumor suppressor protein produced by the TP53
gene.
Families in which there is a high breast cancer frequency have
mutations affecting the tumor suppressor gene BRCA-1 and
BRCA-2.
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Role of p53 gene
1- p53 senses DNA damage.
2- Induces G1 arrest.
3- Induces DNA repair process.
4- induces apoptosis in cells with un-repairable DNA.
5- “P53 is a guardian of the genome.
• Its homozygous loss leads to accumulation of
damaged DNA may result in malignancy”
• Homozygous loss of p53 is seen in virtually every
type of cancer.
• Over half of human malignant cells show loss of p53
gene by special tests.
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proto-Oncogenes
* A proto-oncogen is a normal gene that can become an
oncogene, either after mutation or increased expression.
* Proto-oncogenes code for proteins that help to regulate
cell growth and differentiation.
*Proto-oncogenes are often involved in signal transduction
and execution of mitogenic signals, usually through their
protein products.
* Upon activation, a proto-oncogene (or its
product) becomes a tumor inducing agent, an
oncogene.
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C-MYC
C-MYC is a major transcription factor that encodes nuclear DNA
binding proteins that regulate cell growth, transformation,
angiogenesis, cell-cycle control and apoptosis .
This could explain the aggressiveness and poor prognosis
associated with tumours over expressing C-MYC proteins.
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HER-1
HER1 gene, codes for epidermal growth factor receptor (EGFR),
which has extracellular ligand binding domain and cytoplasmic
domain with high tyrosine kinase activity.
It plays an important role in cell proliferation, migration and
protection against apoptosis.
Poor prognosis of breast tumors over expressing HER1 has been
reported.
It is well documented that HER1 protein is targeted by inhibiting its
extracellular legend binding domain using monoclonal antibodies
and/or its tyrosine kinase activity in cytoplasmic domain by tyrosine
kinase inhibitors (TKIs).
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HER2/neu.
HER2/neu gene, codes for the human epidermal growth
factor receptor 2 (HER2), which has extracellular ligand
binding domain and cytoplasmic domain with high
tyrosine kinase activity. It plays an important role in cell
proliferation, migration and protection against apoptosis.
HER2 is overexpressed by many adenocarcinomas,
particularly breast adenocarcinomas. Trastuzumab is a
monoclonal antibody and must only be administered to
female HER-2-positive patients, i.e., in whom the tumours
overexpress the HER-2 protein or amplify the HER-2 gene.
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Cell cycle
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