Transcript Cancer Pathophysiology

Emergence of a cancer cell
Genetic mutations, i.e. changes to the
normal base sequence of DNA, contribute to
the emergence of a cancer cell
Cancers originate
from a single cell1,2
A series of mutations accumulate in successive
generations of the cell in a process known as
clonal evolution
Malignant cell
First
mutation
Second
mutation
Third
mutation
Fourth or
later mutation
Eventually, a cell
accumulates enough
mutations to become
cancerous
1. Nowell, PC. The clonal evolution of tumor cell populations. Science (1976) 194:23-28.
2. Cavenee, WK & White, RL. The genetic basis of cancer. Scientific American (1995) 272:72-79.
The hallmarks of cancer
In order for cancerous cells to develop and form a tumour, mutations
and other alterations that allow the cell to acquire a succession of the
following biological capabilities must occur:1,2
Sustaining proliferative signalling
Resisting cell
death
Evading growth
suppressors
Inducing
angiogenesis
Activating invasion
& metastasis
Enabling replicative immortality
1. Hanahan D & Weinberg RA. The hallmarks of cancer. Cell (2000) 100:57-70.
2. Hanahan D & Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144:646-674
Sustaining proliferative signalling
Normal cells rely on positive growth signals from other cells
Cancer cells can reduce their dependence on growth signals by:1,2
- Production of their own extracellular growth factors - Overexpression of growth factor receptors - Alterations to intracellular components of signalling pathways -
Growth factors
Growth factor receptors
Cell wall
1. Hanahan D & Weinberg RA. The hallmarks of cancer. Cell (2000) 100:57-70.
2. Hanahan D & Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144:646-674
Evading growth suppressors
• Normal cells rely on
antigrowth signals to regulate
cell growth1,2
• Cancer cells can become
insensitive to these signals
• One way that this can
happen is by disruption of the
retinoblastoma protein (pRb)
pathway1
• pRb prevents inappropriate
transition from the G1 phase
of the cell cycle to the
synthesis (S) phase1
• In cancer cells, pRB may be
damaged, allowing the cell to
divide uncontrollably1
M
G2
Cell
division
cycle
G1
S
1. Hanahan D & Weinberg RA. The hallmarks of cancer. Cell (2000) 100:57-70.
2. Hanahan D & Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144:646-674
Resisting cell death
An important hallmark of many
cancers is resistance to apoptosis,
which contributes to the ability of the
cells to divide uncontrollably1,2
When normal cells become
old/damaged, they go through
apoptosis (programmed cell death)
Normal cell
division
Apoptosis
Cell damage –
no repair
Cancer cell
division
First
mutation
Second
mutation
Third
mutation
Fourth or
later mutation
Uncontrolled
growth
Hanahan D & Weinberg RA. The hallmarks of cancer. Cell (2000) 100:57-70. 2. National Cancer Institute, What is Cancer, 2010. 3.
Hanahan D & Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144:646-674. Artwork originally created for the
National Cancer Institute. Reprinted with permission of the artist, Jeanne Kelly. Copyright 2013.
Enabling replicative immortality
Another important hallmark of
cancer is the ability of the cell to
overcome the boundaries on how
many times a cell can divide1
Normal cells
Cell division
Cancer cells
Chromosomes
Telomeres
These limits are usually set by
telomeres (the ends of
chromosomes):1,2
• In normal cells, telomeres get
shorter with each cell division until
they become so short that the cell
can no longer divide
• In cancer cells, telomeres are
maintained, allowing the cell to
divide an unlimited number of
times
Apoptosis
No
apoptosis
1. Hanahan D & Weinberg RA. The hallmarks of cancer. Cell (2000) 100:57-70.
2. Hanahan D & Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144:646-674
Inducing angiogenesis
FGFR
The formation and maintenance
of new blood vessels
(angiogenesis) plays a critical
role in tumour growth.1,2
New blood vessels supply the
cancer cells with oxygen and
nutrients, allowing the tumour to
grow.
VEGFR
PDGFR
Cell wall
Smooth
muscle
Pericyte
Endothelial
Blood vessel
Nearby blood vessels grow into the tumour.
Angiogenesis is mediated
principally through vascular
endothelial growth factor (VEGF)
Other growth factors also play a role,
e.g.:
• Fibroblast growth factor (FGF)
• Platelet-derived growth factor (PDGF)
Oxygen and
nutrients
Blood vessel
1.Folkman J. Clinical applications of research on angiogenesis. N Engl J Med (1995) 333:1757-63.
2. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer (2008) 8:579-591.
Activating invasion & metastasis
Eventually, tumours may
spawn pioneer cells that can
invade adjacent tissues and
travel to other sites in the
body to form new tumours
(metastasis)1
Nearby blood vessels grow into the tumour.
This capability allows
cancerous cells to colonise
new areas where oxygen
and nutrients are not
limiting1
Metastasis causes 90% of
deaths from solid tumours2
Oxygen and
nutrients
Blood vessel
Cells escape
and metastasise
1. Hanahan D & Weinberg RA. The hallmarks of cancer. Cell (2000) 100:57-70.
2. Gupta GP & Massagué J. Cancer metastasis: Building a framework. Cell (2006) 127: 679-695
Enabling characteristics and emerging hallmarks
There is evidence that a further two emerging hallmarks are involved
in the pathogenesis of cancer1
The acquisition of these hallmarks of cancer is made possible by two
enabling characteristics1
The uncontrolled growth and division of
The immune system is responsible for
Emerging
hallmarks
cancer cells relies not only on the
recognising and eliminating cancer cells,
deregulation of cell proliferation, but
and therefore preventing tumour
also on the
reprogramming
of cellular
formation.
Evasion
of this immune
Deregulating
cellular
Evading
immune
metabolism,energetics
including increased
surveillance
by weakly immunogenic
destruction
aerobic glycolysis (known as the
cancer cells is an important emerging
Warburg effect)
hallmark of cancer.
Cancer cells achieve genome instability
by increasing their mutability, or rates of
mutation, through increased sensitivity
Genome
instability
to mutagenic
agents
or breakdown of
and mutation
genomic maintenance
machinery.
Immune cells infiltrate tumours and
produce inflammatory responses, which
can paradoxically enhance
Tumour-promoting
tumourigenesis,
helping tumours acquire
the inflammation
hallmarks of cancer
Enabling characteristics
Click on each hallmark or enabling characteristic for more information
1. Hanahan D & Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144:646-674