Molecular basis of
carcinoma
Dr Iram Khurshid
MBBS,FCPS (Histopath)
Assistant prof CKMC
Fundamental principles
➢ Genetic damage lies at the heart of
carcinogenesis
➢ Tumors are monoclonal
➢ Four classes of normal regulatory genes:
1. Growth promoting proto oncogenes,
2. Growth inhibiting tumor suppressor genes
3. Genes that regulate programmed cell
death (i.e., apoptosis)
4. Genes involved in DNA repair
are the principal targets of genetic damage
Fundamental changes in cell
physiology in Carcinogenesis
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Limitless replicative potential (i.e., overcoming
cellular senescence and avoiding mitotic
catastrophe)
5. Development of sustained angiogenesis
6. Ability to invade and metastasize
7. Genomic instability resulting from defects in DNA
repair
1. Self Sufficiency in
growth signals
Growth factors
🠶 Most soluble growth factors are made by
one cell type and act on a neighboring
cell to stimulate proliferation (Paracrine
action)
🠶 Many cancer cells acquire growth self-
sufficiency, however, by acquiring the
ability to synthesize the same growth
factors to which they are responsive.
🠶 For example, many glioblastomas
secrete platelet-derived growth factor
(PDGF) and express the PDGF receptor.
Growth factor receptors
🠶 Mutant receptor proteins deliver
continuous mitogenic signals to cells,
even in the absence of the growth factor
in the environment
🠶 Overexpression of growth factor
receptors is more common than
mutation, e.g epidermal growth factor
(EGF) receptor family, which can render
cancer cells hyper responsive to levels of
the growth factor that would not normally
trigger proliferation.
Signal transducing
proteins
🠶 A relatively common mechanism by
which cancer cells acquire growth
autonomy is mutations in genes that
encode various components of the
signaling pathways downstream of
growth factor receptors
🠶 Two important members in this
category are RAS and ABL
🠶 RAS is the most commonly mutated proto-
oncogene in human tumors
🠶 Normal RAS proteins flip back and
forth between an excited signal
transmitting state and a quiescent state
🠶 RAS proteins are inactive when bound
to GDP; stimulation of cells by growth
factors leads to exchange of GDP for
GTP and subsequent conformational
changes that generates active RAS
🠶 The activated RAS in turn stimulates
regulators of proliferation, such as
the RAF-mitogen-activated protein
(MAP) kinase mitogenic cascade,
which floods the nucleus with signals
for cell proliferation
🠶 Mutations at these locations interfere
with GTP hydrolysis that is essential to
convert RAS into an inactive form. RAS
is thus trapped in its activated GTP-
bound form, and the cell is forced into
a continuously proliferating state.
🠶 In addition to RAS, several non
receptor associated tyrosine
kinases function as signal
transduction molecules.
🠶 In this group, ABL is the most
well defined with respect to
carcinogenesis.
🠶 The ABL proto-oncogene has
tyrosine kinase activity that is
dampened by internal
negative regulatory domains.
🠶 In chronic myeloid leukemia,
this activity is unleashed because
the ABL gene is translocated
from its normal abode on
chromosome 9 to chromosome
22, where it fuses with (BCR)
gene. The BCR-ABL hybrid
protein has potent, unregulated
tyrosine kinase activity, which
activates several pathways,
including the RAS-RAF cascade.
Nuclear transcription
factors
🠶 The ultimate consequence of
signaling through oncogenes like
RAS or ABL is continuous
stimulation of nuclear
transcription factors thatregulate
transcription of DNA → Growth
autonomy.
A host of oncoproteins, including
products of the MYC, MYB, JUN,
FOS, and REL oncogenes, function
as transcription factors that regulate
the expression of growth promoting
genes, such as Cyclins.
Cyclins and cyclin
dependent kinases
🠶 The ultimate outcome of all growth
promoting stimuli is the entry of
quiescent cells into the cell cycle
🠶 Cancers may become autonomous if the
genes that drive the cell cycle become
dysregulated by mutations or amplification
🠶 With this background it is easy to appreciate
that mutations that dysregulate the activity of
cyclins and CDKs would favor cell proliferation
🠶 Mishaps affecting the
expression of cyclin D or
CDK4 seem to be a common
event in neoplastic
transformation of many
cancers, including those
affecting the breast,
esophagus, liver, and a
subset of lymphomas.
2. Insensitivity to growth-
inhibitory signals
🠶 Disruption of such genes renders cells
refractory to growth inhibition and
mimics the growth-promoting effects
of oncogenes
🠶 Two important tumor suppressor
genes
RB gene
p53 gene
Retinoblastoma/ RBgene
🠶 (RB) gene, the first and prototypic
cancer suppressor gene to be
discovered
🠶 Approximately 60% of
retinoblastomas are sporadic, and
the remaining ones are familial, the
predisposition to develop the tumor
being transmitted as an autosomal
dominant trait
🠶 loss of normal RB genes was
discovered initially in
retinoblastomas, it is now evident
that homozygous loss of this gene is
a fairly common event in several
tumors, including breast cancer,
small-cell cancer of the lung, and
bladder cancer.
🠶 Patients with familial retinoblastoma
also are at greatly increased risk of
developing osteosarcomas and
some soft tissue sarcomas.
Two hit hypothesis of RBgene
🠶 Two mutations (hits) are required to produce
retinoblastoma
🠶 These involve the RB gene, located on
chromosome 13q14
🠶 In familial cases, children inherit one
defective copy of the RB gene in the germ
line; the other copy is normal,
Retinoblastoma develops when the normal
RB gene is lost in retinoblasts as a result of
somatic mutation.
🠶 In sporadic cases, both normal RB alleles
are lost by somatic mutation in one of the
retinoblasts. The end result is the same: a
retinal cell that has lost both of the normal
copies of the RB gene becomes cancerous.
Sequence of events in sporadic
cases of retinoblastoma
Sequence of events in Familial
cases of retinoblastoma
