1.nowell, pc. the clonal evolution of tumor cell populations. science (1976) 194:23-28. 2.cavenee,...

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


• 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


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.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

1.nowell, pc. the clonal evolution of tumor cell populations. science (1976) 194:23-28. 2.cavenee,...

Documents