Hallmarks of cancer
Dr. Nadia Al-ani
Hallmarks of cancer
Changes in physiological characters of cells that
are seen in every cancer.
Cause:
Mutations in genes that regulate these characters.
Mutation
Disturbances in the genes functions.
Malignancy
Hundreds of cancer-associated genes are present.
Hallmarks of cancer include:
1- • Self-sufficiency in growth signals.
2- • Insensitivity to growth inhibitory signals.
3- • Evasion of cell death.
4- • Limitless replicative potential.
5- • Development of sustained angiogenesis.
6- • Ability to invade & metastasize.
7- • Reprogramming of energy metabolism.
8- • Evasion of immune system.
9- • Genomic instability.
10- •Tumor-promoting inflammation.
1. Self-Sufficiency in Growth Signals:
Normal cell: Require stimulation by growth factors
to proliferate.
Cancer cell: Insensitive to normal growth regulators
so they grows continuously .
Steps of normal cell proliferation:
Binding of growth factor to its receptor on cell membrane
Activation of receptor Activation of signal
transducing proteins on plasma memb. Transmission of
signal through cytoplasm to nucleus Induction &
activation of nuclear regulatory factors Initiation of
DNA transcription Entry of cell into cell cycle.
Defects in:
1. Growth factor.
2. Signal transduction cascade induction.
3. Cell cycle regulation.
Continuous proliferation of cancer cells.
1. Growth Factors:
Substances secreted by one cell & act on other cell
stimulating its proliferation.
Cells that produce growth factor do not express its
receptor, so preventing the formation of positive
feedback loops within the same cell.
• Cancer cells have Growth self-sufficiency:
Have the ability to:
1. synthesize the same growth factors to which
they are responsive to.
2. Interact with the stromal cells:
Tumor cells can send signals activating normal
stromal cells to produce growth factors that
promote tumor growth.
2. Growth Factor Receptors:
Cancer cell has:
1. Over expression of receptors:
Make cancer cells hyper responsive to levels of
growth factor that would not normally trigger
proliferation.
2. Mutation of receptors:
Mutant receptor proteins will deliver continuous
mitogenic signals to the cells, even in the absence
of growth factor in the environment.
3. Downstream Signal-Transducing Proteins:
They receive signals from activated receptors &
transmit them to nucleus.
Mutations in the genes encoding these proteins
Continuous transmission of growth signals to the
nucleus.
Continuous proliferation of the cell (Cancer)
Two types of signal transducing proteins:
1. RAS protein.
2. ABL protein.
RAS Protein:
Mutated RAS gene occurs in 30% of cancers.
Mostly mutated in colon & pancreatic cancer.
ABL protein:
Mutation: Translocation of part of ABL gene
from chromosome 9 to chromosome 22 occurs in:
1. Chronic myelogenous leukemia.
2. Acute leukemia.
4. Nuclear Transcription Factors
Mutations of genes that regulate transcription of
DNA Oncoproteins production.
Transcription factors: Products of:
MYC, MYB, JUN, FOS, & REL genes.
Regulate the expression of growth-promoting
genes, such as cyclins causing entry of quiescent
cells into cell cycle.
Mutations of genes of cell cycle Cancers.
MYC gene is involved most commonly in
human tumors.
Normal Cell Cycle
Cellproliferation is tightly controlled process,
involves large number of molecules & interrelated
pathways to achieve DNA replication & division.
Cell cycle consists of:
G0: Quiescent cell: Not entered into cell cycle.
G1: Pre-synthetic phase.
S: DNA synthesis phase.
G2: Pre-mitotic phase.
M: Mitotic phase.
Cell cycle has multiple checkpoints:
Checkpoints:They ensure that cells with damaged
DNA do not complete replication.
1. G0-G1: During emergence from G0 into G1.
2. G1-S: During transition from G1 to S phase.
It monitors integrity of DNA before replication.
3. G2-M: During transition from G2 to M phase.
It checks the DNA after replication & monitors
whether the cell can safely enter mitosis.
• Progression through cell cycle is regulated by:
1. Cyclins proteins that regulates the timing of cell
cycle. (15 types)
2. Enzymes: Cyclin dependent kinases (CDKs).
Forming complexes have catalytic activity.
Cyclins D, E, A, & B appear sequentially during
cell cycle & bind to one or more CDKs.
Cellcycle is tightly controlled by cyclins activators
& inhibitors.
When cells have DNA damage, checkpoint
activation will delays cell cycle & triggers
DNA repair mechanisms.
If DNA damage is too severe to be repaired:
1. Cells are eliminated by apoptosis.
2. Or enter non-replicative state called senescence,
through p53-dependent mechanisms.
Mutations in genes that regulates checkpoints
will allow cells with damaged DNA to divide,
producing daughter cells carrying mutations.
Alterations in proteins controlling cell cycle in
cancer cells:
1- Mutations dysregulate the activity of cyclins &
CDKs.
All cancers have genetic lesions that disable:
G1-S checkpoint
Cells continually re-enter S phase.
2-Mutation of genes that regulates cell senescence
& apoptosis so allow action of oncogenes.
Hallmarks of cancer
2. Insensitivity to Growth Inhibitory Signals:
A. Oncogenes:
Encode proteins that promote cell growth.
[Link] suppressor genes:
Encode proteins that inhibit cell proliferation.
Disruption of tumor suppressor genes:
Cells will be insensitive to growth inhibition.
Cancer
Tumor suppressor genes
1- RB gene: Retinoblastoma gene.
2- TP53 gene.
3- Transforming growth factor-β.
4- Contact inhibition, neurofibromin-2 (NF2)
& adenomatous polyposis coli (APC) genes.
Tumor suppressor genes
1- RB Gene: Retinoblastoma gene:
Governor of Cell Cycle
Mutated RB is seen in retinoblastoma.
Uncommon childhood tumor.
Transmitted as autosomal dominant trait.
Homozygous loss of RB gene is also seen in:
Small cell cancer of lung, bladder & breast cancer.
2- TP53 Gene: Guardian of the Genome
Itis p53-encoding tumor suppressor gene.
Mutated TP53 genes found in carcinomas of:
Lung, colon & breast.
P53 protein prevent neoplastic transformation
by three interlocking mechanisms:
1- Activation of temporary cell cycle arrest.
(Quiescence state).
2- Induction of permanent cell cycle arrest .
(Senescence state).
3- Trigger programmed cell death (Apoptosis).
3. Transforming Growth Factor-β:
Molecules transmit antiproliferative signals to the
cells.
It is a potent inhibitor of proliferation in normal
epithelial, endothelial & hematopoietic cells.
Mutations affecting TGF-β signaling:
Impairment of growth-inhibiting effects of TGF-β
Cancers in:
Colon, stomach, pancreas & endometrium.
4. Contact Inhibition, NF2 & APC:
Cell–cellcontacts in normal proliferating cell will
suppress further cell proliferation. (No cancer)
In cancer cells: Contact inhibition will allows
cancer cells to be crowded on top of each other.
Cell–cell
contacts are mediated by interactions
between trans-membrane proteins called:
Cadherins.
E-cadherin (E = epithelial) mediates cell–cell
contact inhibition in epithelial layers.
E-cadherin maintains normal contact inhibition by
two mechanisms:
1- A mechanism mediated by tumor suppressor
gene NF2, its product, neurofibromin-2, which
facilitates E-cadherin mediated contact inhibition.
Homozygous loss of NF2 gene Neural tumors:
Neurofibromatosis: Tumor of the nerve cells.
2- A mechanism seen in a rare hereditary disease:
Adenomatous polyposis coli (APC):
Characterized by:
1. Numerous adenomatous polyps in the colon.
2. High incidence of transformation to colon cancer.
3. Show loss of tumor suppressor gene: APC gene.
(Named for the disease).
APC gene exerts antiproliferative effects through
effects on E-cadherin contact inhibition.
Behaves as a tumor suppressor gene.
70-80% of colon cancers shows APC mutations.
Hallmarks of cancer
3. Evasion of Cell Death: Apoptosis & autophagy:
Apoptosis: Programmed cell death regulated by:
BCL2 genes.
BCL2 mutations Accumulation of cancer cells.
BCL2 mutation will protect tumor cells from
apoptosis.
Ex.: Follicular B cell lymphomas.
Autophagy:
Tightly regulated catabolic process by which cells
consume their components.
Induced by stress.
Helps in balance between synthesis, degradation &
recycling of cellular products.
Prevent growth of tumor cells.
Cancercells have mutations in genes responsible for
autophagy:
Avoid autophagy.
Hallmarks of cancer
4. Limitless Replicative Potential
Normal cells have capacity of 60-70 doublings,
then the cell lose its capacity to divide & enter into
senescence state.
Cause: Progressive shortening of telomeres
at the ends of chromosomes.
• Short telomeres is recognized by DNA repair
machinery as DNA breaks Cell cycle arrest &
senescence, mediated by:
TP53 & RB check points.
TP53 or RB mutations Disability of cell cycle
Tumor cells also develop ways to avoid both
cellular senescence & apoptosis by:
Telomerase enzyme:
Responsible for telomeres maintenance.
Active in normal stem cells.
Absent or present at low levels in somatic cells.
Tumor cells reactivate telomerase enzyme
Telomere maintenance Continuous proliferation
Telomere maintenance is seen in all types of
cancers, due to reactivation of:
Telomerase enzyme.
Ex.:
Colonic Adenoma:
Benign lesion of colon.
Have low telomerase enzyme expression.
Colonic adenocarcinoma:
Malignant lesions of colon.
Have high levels of telomerase enzyme
expression.
Go to hell
Thank you
