2. 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 cell 1,2 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 cancerous First mutation Second mutation Third mutation Fourth or later mutation Genetic mutations, i.e. changes to the normal base sequence of DNA, contribute to the emergence of a cancer cell

3. 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 Inducing angiogenesis Resisting cell death

4. 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 - 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

5. Normal cells rely on antigrowth signals to regulate cell growth 1,2 Cancer cells can become insensitive to these signals One way that this can happen is by disruption of the retinoblastoma protein (pRb) pathway 1 pRb prevents inappropriate transition from the G1 phase of the cell cycle to the synthesis (S) phase 1 In cancer cells, pRB may be damaged, allowing the cell to divide uncontrollably 1 Cell division cycle G1G1 S G2G2 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

6. 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 uncontrollably 1,2 When normal cells become old/damaged, they go through apoptosis (programmed cell death) Normal cell division Cell damage – no repair Apoptosis Cancer cell division First mutation Second mutation Third mutation Fourth or later mutation Uncontrolled growth

7. Another important hallmark of cancer is the ability of the cell to overcome the boundaries on how many times a cell can divide 1 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 cellsCell divisionCancer 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

8. 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 Pericyte Endothelial Smooth muscle Cell wall VEGFRFGFRPDGFR

9. 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 limiting 1 Metastasis causes 90% of deaths from solid tumours 2 Nearby blood vessels grow into the tumour. Oxygen and nutrients Cells escape and metastasise Blood vessel

10. There is evidence that a further two emerging hallmarks are involved in the pathogenesis of cancer 1 The acquisition of these hallmarks of cancer is made possible by two enabling characteristics 1 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 hallmarks The 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