What is cancer? Cancer is not just one disease More than 200 different types of cancer have been identified CANCER Defining cancer Cancer is an accumulation of abnormal cells that multiply through uncontrolled cell division and spread to other parts of the body by invasion and/or distant metastasis via the blood and lymphatic system Normal cells Abnormal cells Tumour growth Metastasis Uncontrolled cell division Invasion into surrounding tissues Spread via blood or lymphatic system Incidence of cancer across the globe (2008, estimate)1 Estimated number of new cancer cases (% of total) Africa (6%) Asia (48%) Europe (25%) Latin America and Caribbean (7%) Northern (13%) Oceania (1%) 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No.10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr, accessed on 06/06/2013. Changing prevalence of cancer Global cancer incidence and mortality rates continue to rise1 2030 25 M 75 M people living with cancer*2 predicted to be living with cancer2 2008 21.3 M GROWING AND AGEING POPULATION 13.1 M 12.7 M 7.6 M CASES DEATHS ADOPTION OF UNHEALTHY LIFESTYLES IMPROVEMENT IN DIAGNOSIS/SCREENING 2002 *Diagnosed in last 5 years 2030 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No.10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr, accessed on 14/01/2013. 2. The International Agency for Research on Cancer. World Cancer Report 2008. Available from: http://www.iarc.fr/en/publications/pdfs-online/wcr/, accessed on 06/06/2013. Common cancers in men and women worldwide1 Men (%) Women (%) Lung (16.5) Breast (22.9) Prostate (13.6) Colorectum (10.0) 8.5 16.5 3 13.6 Bladder (4.4) 4.9 7.9 10 29.7 Liver (7.9) Oesophagus (4.9) 9.7 3 4.4 Non-Hodgkin lymphoma (3.0) Leukaemia (3.0) Other and unspecified (27.0) Colorectum (9.4) Stomach (5.8) Stomach (9.7) 27 Lung (8.5) 2.7 22.9 9.4 5.8 3.7 4.8 8.8 3.7 Liver (3.7) Cervix uteri (8.8) Corpus uteri (4.8) Ovary (3.7) Thyroid (2.7) Other and unspecified (29.7) 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No.10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr, accessed on 06/06/2013. Global cancer mortality Lung, stomach, liver, colorectal and female breast cancers cause 50% of all cancer deaths1 25 Mortality (% of all cancer types) Approximately 7.56 million people died from cancer in 2008,1 accounting for 13% of all deaths (from any cause)2 Lung 20 Stomach 15 Liver 10 Colorectal 5 0 Both sexes Men Women Female breast 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No.10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr, accessed on 06/06/2013. 2. American Cancer Society. Global Cancer Facts and Figures 2nd Edition. Atlanta: American Cancer Society; 2011. Common terms Localised Invasive Metastatic the cancer is still confined to the site of origin and has not yet invaded the surrounding tissues or spread to other sites the cancer has spread from the site of origin into the surrounding tissues the cancer has spread to distant sites in the body to form new tumours Grade Stage how abnormal cancer cells appear in comparison to normal cells and how aggressive the cancer is Low grade – nearly normal in appearance; slow rate of growth and metastasis High grade – very abnormal-looking cells; high rate of growth and metastasis classification of the cancer, important for treatment decisions, based on the size, presence or absence of metastasis and involvement of lymph nodes Cancer categories Carcinoma Sarcoma Leukaemia cancer of the skin or tissues that line or cover the internal organs cancer of bone, cartilage, muscle, fat, blood vessels, and connective tissues cancer of the bone marrow affecting the white blood cells Lymphoma cancer arising in the lymph glands Central nervous system cancers cancer of the brain or spinal cord Making sense of cancer names Artwork originally created for the National Cancer Institute. Reprinted with permission of the artist, Jeanne Kelly. Copyright 2013. Risk factor definitions 013 RISK FACTOR Intrinsic risk factor Extrinsic risk factor …is related to an individual’s own actions …is an integral part of and environment the individual and Something that increases (tobacco, pollution, the chances of getting cannot be changed diet, etc.) a disease (genetics, age, etc.) Risk factors are multiple and differ according to the cancer type Smoking tobacco Radiation Chemicals RISK FACTORS Hereditary Viruses Age HPV EBV HBV General health Hormones Diet Obesity Sun exposure Bacteria H.pylori Absolute risk vs. Relative risk Absolute risk Relative risk The risk of an individual developing cancer during their entire lifetime The risk of a group of people developing cancer in comparison to another group Benefits of assessing risk ! Allows the individual at risk to undertake prevention strategies (e.g. stop smoking, avoid radiation) ! Alerts physicians to those individuals at risk of developing cancer ! Enables screening procedures to detect cancer at an early stage ! Early detection enables physicians to initiate treatment, whist the tumour is still in the initial stages 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 How is cancer diagnosed? ‘Cancer’ is an umbrella term for a broad group of diseases There is no single test that can diagnose all cancers1 Diagnostic tests include: • Physical examination • Laboratory tests • Imaging • Endoscopic examination If there are symptoms suggestive of cancer a broad range of tests allow HCPs to make an accurate and detailed diagnosis • Biopsy • Surgery • Molecular testing 1. Stanford Cancer Institute, Cancer Diagnosis, 2012 Laboratory tests Assess the general health of the body and levels of certain compounds Typically, blood and/or urine samples Marker Cancer CA 125 Ovarian Blood is assessed for its composition, and can give an indication of liver and renal function CEA Colorectal AFP Liver, ovarian, testicular Blood, proteins and other compounds in the urine indicate there could be a problem HCG Testicular, ovarian, liver, stomach, pancreatic, lung CA 19-9 Colon, stomach, bile duct CA 15-3 Ovarian, lung, prostate CA 27-29 Colon, stomach, kidney, lung, ovarian, pancreatic, uterus, and liver Tumour markers detected in blood or urine are substances created by the body in response to cancer cells • Currently, markers are used to monitor treatment efficacy and recurrence • May become more important in diagnosis in the future CEA, carcinoembryonic antigen, several cancers can raise CEA levels; AFP, alpha-fetoprotein; HCG, human chorionic gonadotropin; CA 15-3 and CA 27-29 are most useful in assessing advanced breast cancer treatment 1. Stanford Cancer Institute, Cancer Diagnosis, 2012. Imaging Produce images of the organs and structures Imaging Reveal location and extent of disease Transmitted radio waves Emitted radio waves Three main types: • Transmission imaging: highenergy photons beamed through body – the ‘opacity’ of different structures/tissues varies > X-ray, CT scan, bone scan, mammogram, lymphangiogram • Reflection imaging: high frequency sound reflected differentially depending on structures/tissues > Ultrasound • Emission imaging: atoms excited to emit energy waves detected by a scanner > MRI, PET 1. Stanford Cancer Institute, Cancer Diagnosis, 2012. magnetic field direction Endoscopy An endoscope is a small, flexible tube with a light, lens and tools • Bronchoscopy Used to examine the airways and obtain tissue samples from the lungs Oesophagus • Colonoscopy and sigmoidoscopy Used to view the large intestine or just the sigmoid colon Endoscope • Endoscopic retrograde cholangiopancreatography (ERCP) Combined with X-ray to examine the liver, gallbladder, bile ducts, and pancreas Light • Oesophagogastroduodenoscopy (upper endoscopy) Used to view the inside of the oesophagus, stomach, and duodenum • Cystoscopy (cystourethroscopy) Device inserted through the urethra to examine the bladder and urinary tract Stomach Interior of stomach Endoscope Light Stomach lining 1. Stanford Cancer Institute, Cancer Diagnosis 2012. Biopsy sample Biopsy Biopsy type Tissue or cells from the body for examination under a microscope Performed in the doctor’s office or hospital, depending on the type of biopsy and location of the tumour Description Endoscopic Tissue sample removed via an endoscopy Bone marrow Bone chip or cells aspirated from the sternum or hip Excisional or incisional Full thickness of skin even whole tumour removed Fine needle aspiration (FNA) Tiny pieces of tumour extracted via a thin needle Punch Short cylinder of tissue taken Shave Top layer of skin removed Skin Small sample of skin taken 1. Stanford Cancer Institute, Cancer Diagnosis, 2012. Pathology Tests on biopsies and samples of patient tissue or body fluids reveal a great deal about the cancer Biopsy Pathology Blood sample or tissue sample Proteomic profile Microscopic examination can reveal the presence of cancer cells, the origin of the cancer cells (sub-type), and information on stage, etc. 1. National Cancer Institute, Understanding Cancer, 2009. Artwork originally created for the National Cancer Institute. Reprinted with permission of the artist, Jeanne Kelly. Copyright 2013. Genomic profile What is TNM? ! TNM is a system for classifying malignant tumours ! It is a cancer staging system, which describes the extent of a person's cancer ! Most types of cancer have TNM designations, but some do not1 ! Most medical facilities use this system as their main method for cancer reporting1 1. National Cancer Institute, Cancer Staging, 2010 How does the TNM system work? The 3 parameters of the TNM system1: A number is added to each letter to indicate1: T = extent of the tumour the size or extent of N = the extent of spread the primary tumour to the lymph nodes M = presence of distant the extent of cancer spread metastases 1. National Cancer Institute, Cancer Staging, 2010 T = extent of primary tumour T is classified as follows:1 Tx: Primary tumour cannot be evaluated | T0: No evidence of primary tumour Tis: Carcinoma in situ (CIS)2 | T1, T2, T3, T4: Size and/or extent of the primary tumour T0 organ T1 T2 T3 local tissues 1. National Cancer Institute, Cancer Staging, 2010 2. CIS – abnormal cells are present but have not spread to neighbouring tissue; although not cancer, CIS may become cancer and is sometimes called pre-invasive cancer N = extent of spread to lymph nodes N is classified as follows1: Nx: Regional lymph nodes cannot be evaluated | N0: No local lymph node involvement N1: Tumour has spread to local lymph nodes | N2, N3: Involvement of local and distant lymph nodes (number of lymph nodes and/or extent of spread) N0 N1 distant nodes local nodes 1. National Cancer Institute, Cancer Staging, 2010 N2 M = presence of distant metastases M is classified as follows1: Mx: Distant metastasis cannot be evaluated | M0: No distant metastasis M1: Distant metastasis is present M0 M1 Mx ? lung bone liver 1. National Cancer Institute, Cancer Staging, 2010 Intrinsic vs. extrinsic factors Cancer caused by intrinsic factors, i.e. inherited mutations, can only be prevented by screening and appropriate early intervention Cancer caused by extrinsic factors can be prevented by reducing or eliminating exposure to these factors (e.g. chemicals, tobacco, radiation, viruses) Cancer Prevention Radiation Viruses or bacteria 1. National Cancer Institute, Understanding Cancer, 2009. Carcinogenic chemicals Tobacco products The use of tobacco products is implicated in ~33% of all cancer deaths1 ~1 person dies every 6 seconds Lung Cancer Risk Increases with Cigarette Consumption1 due to tobacco2 15x The combination of tobacco and alcohol products appears to be particularly dangerous1 As well as lung cancer, tobacco products have also been implicated in cancer of the mouth, larynx, oesophagus, stomach, pancreas, kidney, and bladder1 Avoiding tobacco is the single 10x Lung Cancer Risk 5x 0 Non-smoker 15 Cigarettes Smoked per Day most important factor in reducing cancer risk 1. National Cancer Institute, Understanding Cancer, 2009. 2. WHO Fact Sheet 339, 2012. Artwork originally created for the National Cancer Institute. Reprinted with permission of the artist, Jeanne Kelly. Copyright 2013. 30 Excessive exposure to UV radiation Excessive UV exposure, particularly in fairskinned individuals can cause:1 • cutaneous malignant melanoma • squamous cell carcinoma • basal cell carcinoma In 2000, >200,000 cases of melanoma were diagnosed worldwide1 Sun exposure Stratosphere UV-C Ozone UV-B Epidermis Dermis Hypodermis 1. WHO Fact Sheet 305, 2009. UV-A Diet radiation and alcohol, dietary components that influence cancer risk have been difficult to determine1 Limiting fat and calorie intake appears to reduce cancer risk1 A diet rich in meat increases cancer risk, especially colon cancer1 Correlation Between Meat Consumption and Colon Cancer Rates in Different Countries1 Number of Cases (per 100,00 People) Unlike tobacco products, UV 40 N.Z. U.S.A. 30 DEN. CAN G.B. SWE NETH NOR 20 JAM 10 ISR GERMANY ICE FIN P.R. POL 15 YUG CHILE ROM HUNG JAPAN COL NIG 0 80 100 200 300 Grams (per person per day) National Cancer Institute, Understanding Cancer, 2009. Artwork originally created for the National Cancer Institute. Reprinted with permission of the artist, Jeanne Kelly. Copyright 2013. Viruses Worldwide, 15% of all cancers may be caused by viruses, including:1 • Epstein-Barr virus • Human papilloma virus (HPV) • Hepatitis B virus HPV Infection Increases Risk for Cervical Cancer2 High • Human herpes virus-8 • Human T lymphotrophic virus type 1 • Hepatitis C virus Cervical Cancer Risk Reducing exposure to these viruses reduces cancer risk In the case of HPV, avoiding unprotected sex with many partners reduces the risk of contracting this virus2 Low Non-infected women Women infected with HPV 1. Liao JB. Viruses and Human Cancer. YJBM 2006 (79);115-122. 2.National Cancer Institute, Understanding Cancer, 2009. Artwork originally created for the National Cancer Institute. Reprinted with permission of the artist, Jeanne Kelly. Copyright 2013. Strategies for prevention Education about cancer and risk factors (warnings on cigarette packets, campaigns about sun and exposure to UV radiation) Awareness pink ribbons for breast cancer, campaigns world cancer day Risk avoidance don’t smoke, stay out of the sun, avoid toxic chemicals and polluted areas Screening cervical smear, mammography, colonoscopy Vaccines HPV vaccine to reduce risk of cervical cancer; Hep B vaccine to reduce risk of liver cancer Lifestyle normal weight, healthy diet, exercise Healthcare regular check-ups, seek medical attention early What is screening? Screening is the name given to a range of tests that can detect cancer at an early stage before symptoms appear Breast Cancer Screening Finding cancer early usually means it is easier to treat/cure By the time symptoms appear, the cancer may have grown and spread and therefore be more difficult to treat/cure 1. National Cancer Institute, Cancer Screening Overview, 2012. Screening: the rationale For screening to be effective, two requirements must be met: ! A test or procedure must be available to detect cancers earlier than if the cancer were detected as a result of the development of symptoms ! Evidence must be available that treatment initiated earlier as a consequence of screening results in an improved outcome 1. National Cancer Institute, Cancer Screening HCP, 2012. Screening tests A variety of tests are used in cancer screening: Cervical Cancer Screening • Physical exam and history: check general health and review medical history Normal Pap smear • Laboratory tests: investigate samples of tissue, blood, urine, etc. • Imaging: visualise the insides of the body using e.g. x-ray, ultrasound, CT, MRI, etc • Molecular tests: look for specific mutations that are linked to some types of cancer Abnormal Pap smear Biopsy Pathology Patient‘s blood sample or tissue sample Proteomic profile Genomic profile National Cancer Institute, Cancer Screening Overview, 2012. Artwork originally created for the National Cancer Institute. Reprinted with permission of the artist, Jeanne Kelly. Copyright 2013. Screening: pros and cons Pros Cons • Reduction in cancer deaths • Some screening procedures carry their own risks • 3–35% of premature deaths due to cancer could be avoided with screening • Improved outcomes (does not apply in all cases) • False negative results – patient wrongly assured there is no problem • False positive results – patient may receive treatment they do not need 1. National Cancer Institute, Cancer Screening HCP, 2012. Screening and high risk populations By focusing on high-risk populations, screening resources can be better applied Patients with a personal history/strong family history of cancer are deemed to be high-risk The ability to test for specific genetic mutations has further refined the identification of high-risk patients Heredity and cancer All Breast Cancer Patients Inherited factor(s) Other factor(s) Genes and Cancer Chromosomes are DNA molecules Heredity National Cancer Institute, Cancer Screening HCP, 2012. Artwork originally created for the National Cancer Institute. Reprinted with permission of the artist, Jeanne Kelly. Copyright 2013.