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