Post on 16-Jan-2016
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.
Emergence of a cancer cell
Malignant 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
Eventually, a cell accumulates enough mutations to become
cancerousFirst
mutationSecond mutation
Third mutation
Fourth orlater mutation
Genetic mutations, i.e. changes to the normal base sequence of DNA, contribute to
the emergence of a cancer cell
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
The hallmarks of cancer
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
Evading growth suppressors
Activating invasion & metastasis
Enabling replicative immortality
Inducingangiogenesis
Resisting cell death
Normal cells rely on positive growth signals from other cellsCancer 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 -
Sustaining proliferative signalling
Cell wall
Growth factor receptors
Growth factors
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
• 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
Celldivision
cycleG1
S
G2
M
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
Resisting cell death
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.
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 celldivision
Cell damage –no repair
Apoptosis
Cancer celldivision
First mutation
Second mutation
Third mutation
Fourth orlater mutation
Uncontrolledgrowth
Another important hallmark of cancer is the ability of the cell to overcome the boundaries on how many times a cell can divide1
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
Enabling replicative immortality
Normal cells Cell division Cancer cells
Telomeres
No apoptosis
Apoptosis
Chromosomes
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
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.
Inducing angiogenesis
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.
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)
Nearby blood vessels grow into the tumour.
Oxygen and nutrients Blood vessel
Blood vessel
Pericyte
Endothelial
Smooth muscle
Cell wall
VEGFRFGFR PDGFR
Activating invasion & metastasis
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
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
This capability allows cancerous cells to colonise
new areas where oxygen and nutrients are not
limiting1
Metastasis causes 90% of deaths from solid tumours2
Nearby blood vessels grow into the tumour.
Oxygen and nutrients
Cells escape and metastasiseBlood vessel
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
Enabling characteristics and emerging hallmarks
1. Hanahan D & Weinberg RA. Hallmarks of cancer: the next generation. Cell (2011) 144:646-674
Evading immune destruction
Enabling characteristics
Genome instability and
mutation
Deregulating cellular energetics
Tumour-promoting inflammation
Emerging hallmarksThe immune system is responsible for
recognising and eliminating cancer cells, and therefore preventing tumour
formation. Evasion of this immune surveillance by weakly immunogenic cancer cells is an important emerging
hallmark of cancer.
Cancer cells achieve genome instability by increasing their mutability, or rates
of mutation, through increased sensitivity to mutagenic agents or
breakdown of genomic maintenance machinery.
The uncontrolled growth and division of cancer cells relies not only on the
deregulation of cell proliferation, but also on the reprogramming of cellular
metabolism, including increased aerobic glycolysis (known as the
Warburg effect)
Immune cells infiltrate tumours and produce inflammatory responses, which
can paradoxically enhance tumourigenesis, helping tumours acquire the hallmarks of cancer
Click on each hallmark or enabling characteristic for more information