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Cell and Molecular Biology
Molecular Biology of
Cancer
Behrouz Mahmoudi
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Cancer cells – The Basics
Neoplasia is an abnormal accumulation of cells that occurs because of
an imbalance between cellular proliferation and cellular attrition. Cells
proliferate as they pass through the cell cycle and undergo mitosis.
Attrition, due to programmed cell death, removes cells from a tissue.
•Mutations leading to oncogenesis can be inherited or familial (1%) (single-gene
or multifactorial disorders) or sporadic (99%).
•Mutations can occur in coding DNA but also in non-coding DNA such as in
microRNAs.
•Cancer cells have lost their contact inhibition properties.
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Once it is initiated, a cancer progresses by accumulating
additional genetic damage through mutations in caretaker genes
encoding the cellular machinery that repairs damaged DNA and
maintains cytogenetic normality
The original clone of neoplastic cells serves as a reservoir of
genetically unstable cells, referred to as cancer stem cells.
Stages in the evolution of cancer
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1. Immortal (grow and divide indefinitely).
2. Clonal origin from one ancestral cell that
becomes more mutated, deregulated over
time, causing genetic instability such as
chromosomal rearrangement and
phenotypic mutations.
3. No longer subject to contact inhibition.
4. Evade apoptosis (programmed cell death)
and senescence.
5. Reduced requirement for growth factors.
6. Insensitive to anti-growth signals.
7. Ability to metastasize (invade other tissues).
8. Sustained angiogenesis (formation blood
vessels).
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Cancer Cells Types of Genes
The genes implicated in cancer
development are classified into
three types:
•Oncogenes stimulate cell division
excessively. They are mutated from
normal genes called protooncogenes that encode components
of the cell's normal growth, such as
growth factors.
•Tumor Suppressor Genes inhibit
cell division and/or cause apoptosis.
Mutations in tumor suppressor
genes would promote cell division
or allow genetically damaged cell to
grow out of control.
•DNA Repair Genes correct
mutation of a gene.
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Cancer Cells - Oncogenes and Proto-oncogenes
Oncogenes can lead to hereditary cancer syndromes or
sporadic cancers.
The mutation can be:
•an activating gain-of-function mutation
in the coding sequence of the oncogene.
•a mutation in the regulatory elements
of the oncogene.
•an increase in the genomic copy
number of the oncogene.
α-tubulin (violet), γ- tubulin (yellow) and DAPI (blue). Casimiro et al.
show that in contrast to Cyclin D1-/- cells (left), those overexpressing
Cyclin D (right) develop multiple centrosomes and abnormal spindle
architecture, resulting in chromosomal instability.
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Cancer Cells – Tumor-suppressor Genes
Mutation or deletion of tumor
suppressor genes is believed to
initiate many forms of cancer.
For tumors to develop, both
alleles of the tumor suppressor
gene must be inactivated (VERY
DIFFERENT FROM ONCOGENES).
In familial cancer syndromes, a
mutant allele of a tumor
suppressor gene is inherited and
is present in every cell. However,
tumorigenesis is not initiated
until the second allele is
inactivated in a somatic cell. In
non-familial cases, inactivation
of both alleles occurs via somatic
mutation or deletion. The end
result is the same in both cases,
the lack of a functional tumor
suppressor gene leads to tumor
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development.
2-hit hypothesis of tumor suppression, in which the sequential
inactivation of 2 gene alleles results in the development of retinoblastoma.
Oliveira AM, Ross JS, Fletcher
JA. p53 and tumor suppressor
genes in breast cancer. In: Ross
JS, Hortobagyi GH, eds. The
Molecular Oncology of Breast
Cancer. Sudbury, MA: Jones and
Bartlett; 2005:358-372
The first hit is usually a mutation in the DNA sequence of the gene (a small deletion or base substitution; star). This
mutation can be transmitted through the germline, giving rise to an inherited form of cancer. The second hit (loss of
heterozygosity [LOH]) is often a gross chromosomal mechanism that occurs at higher rates in somatic cells and that
leads to hemizygosity or homozygosity of the chromosome region containing the mutation. This includes nondisjunctional
loss with reduplication of the chromosome carrying the mutated TSG, subchromosomal deletion, unbalanced
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translocation, and mitotic recombination.
Hereditary Cancer Syndromes
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Retinoblastoma is a rare relatively
tumor (1:20,000 incidence) that
originates in the retina.
•Sporadic (unilateral and 60% of cases)
•Familial and autosomal dominant inheritance
(most bilateral some unilateral and some
asymptomatic and 40% of cases)
•Induced by mutation in the tumor suppressor
gene Rb (ch 13) encoding the Retinoblastoma
protein (RB).
G1/S transition
regulation
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In sporadic retinoblastoma, two somatic mutations occur
in the same retinal cell, thus triggering tumorigenesis.
normal
retina cell
precursor
retina cell
1st somatic hit
(mutation)
Tumor
retina cell
2nd somatic hit
(mutation)
The first mutation is recessive at the
cellular level, although the clinical
condition follows an autosomal
dominant mode of inheritance
A white pupillary reflex is the presenting
manifestation of retinoblastoma in about
90% of patients in the United States.
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In familial retinoblastoma, the 1st Rb mutation is inherited
through the germline and is therefore present in all retinal
cells.
In this case, only one somatic hit is necessary to inactivate
the tumor suppressor gene.
precursor
retina cell
Tumor
retina cell
somatic hit
(mutation)
Here too, the Rb gene is recessive
at the cellular level, although the
clinical condition follows an
autosomal dominant mode of
inheritance.
The presence of bilateral tumors indicates
that the affected patient is a carrier of
familial retinoblastoma who can transmit
the tumor to progeny.
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Genetic mechanisms for the loss of
heterozygosity (LOH) of wildtype RB1 uncovers
the recessive allele.
Heterozygosity should normally protect
from mutant allele; however, frequently,
there is loss of the normal Rb allele,
uncovering the mutant allele.
Extra-ocular
retinoblastoma
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Is RB sporadic, familial?
What is the mode of
inheritance? Penetrance?
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Breast and ovarian cancers are the most common form of
tumors in women (1:700 incidence in the US) that
originate in breast and ovarian tissues.
•Sporadic (90 to 95 of % of cases)
•Familial and autosomal dominant inheritance (5-10% of cases)
•Most hereditary cancers involves the tumor suppressor genes BRCA1
(Ch7) and BRCA2 (Ch13) encoding DNA repair proteins.
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A pedigree of Li-Fraumeni syndrome showing autosomal
dominant inheritance
p53 therapy in a patient with Li-Fraumeni
syndromeFusion PET/CT scan of the treated
pelvic tumor (arrow) before (left) and after four
intratumoral injections of Advexin depicting
complete resolution of 2,3-FDG uptake at 2 mo
(right) and progression of the untreated lesion
(cross-hairs)
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Genetic of the Acute Leukemias
Acute leukemias often involve translocations:
 Cells of hematopoietic system rapidly divide: bone marrow
stem cells leading to red blood cells and white blood cells.
 Ex. promoter fusions of an Immunoglobulin promoter to a
proto-oncogene will overexpress the normal protein in B
lymphocytes - promote excessive cell division.
 Ex. gene fusions: CML = chronic myeloid leukemia: fusion
of Bcr and abl genes by chromosome 9-22 translocation
overactive tyrosine kinase.
 Ex. PMLRAR = acute promyelocytic leukemia = fusion of
PML and RAR (retinoic acid receptor); fusion protein
defective.
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Translocations that aberrantly activate transcription
factors in acute leukemias.
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Chronic Myelogenous Leukemia (CML) is an example of translocation
leading to cancer.
The Philadelphia chromosome translocation,
t(9;22)(q34;q11). The Philadelphia
chromosome (Ph1) is the derivative
chromosome 22, which has exchanged part of
its long arm for a segment of material from
chromosome 9q that contains the ABL
oncogene. Formation of the chimeric BCR-ABL
gene on the Ph1 chromosome is the critical
genetic event in the development of chronic
myelogenous leukemia.
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