Introduction to Cancer PDF

School of Pharmacy AN INTRODUCTION TO CANCER Prof Darius Widera Copyright University of Reading LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Outline What is Cancer? Classification of Cancers Normal cell growth and its control The mammalian cell cycle Cell cy...

School of Pharmacy AN INTRODUCTION TO CANCER Prof Darius Widera Copyright University of Reading LIMITLESS POTENTIAL | LIMITLESS OPPORTUNITIES | LIMITLESS IMPACT Outline What is Cancer? Classification of Cancers Normal cell growth and its control The mammalian cell cycle Cell cycle checkpoints Hallmarks of a cancer DNA mutations in cancer development Stages of cancer and survival Learning objectives part 1 Be able to define and explain the concepts that underpin cancer Discuss the link between cell division and oncogenesis Explain the different classifications of cancer Identify and describe the 6 hallmarks of a cancer What is cancer? Can affect almost any organ/cell type Many different causes Symptoms differ Outcomes vary (treatable to untreatable) Different therapeutic approaches will be employed Not just one disease but a collection of diseases with the shared underlying features of uncontrolled cell growth and invasion Types of cancer The term “cancer” refers to several hundred different diseases. Since cancer can arise from almost any type of cell in the body, there are over 200 types of cancer. However, since the molecular and cellular events that have caused the cancer are random, each individual case of cancer could be classed as unique. Classification of cancers is complex but usually relates to where in the body the cancer arises and the type of cell involved. Types of cancer Cancers are usually named and classified according to the type of tissue they arise from and the cell type or organ in which they originate. Name Type of tissue Examples Carcinoma Epithelial Breast, lung, liver (80- 90% of cancer cases) Sarcoma Connective tissue Bones, muscle, blood vessels Myeloma Bone marrow Plasma cells Leukaemia Bone marrow White blood cells, erythrocytes Lymphoma Lymph nodes/glands Spleen, tonsils, thymus -oma Benign tumours* Lipoma, adenoma Types of cancer Cancers are usually named and classified according to the type of tissue they arise from and the cell type or organ in which they originate. Cancer type and prognosis From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings. Important terminology Neoplasm : new disorganised growth with net increase in numbers of dividing cells (i.e. a tendency to excessive, uncontrolled growth). Synonymous with the more familiar term ‘tumour’ (swelling). Tumour : a mass of abnormal cells. Benign tumours : these enlarge but do not invade the surrounding tissue, nor spread beyond their initial site. Malignant tumours : those that are not benign and spread beyond their initial site. These are the more dangerous tumours. Metastasis : invasion of a tumour to its surrounding tissue and spread beyond the original site. Carcinogenesis : the process of forming a cancer (via carcinogens). Properties of a cancer Cancer cell is formed when a normal cell undergoes specific changes that allow it to proliferate without normal limit and spread to surrounding and/or distant tissues Multiple changes are usually required to transform a “normal cell” into a “cancer cell” Inherited susceptibility and/or lifestyle influences cancer progression Tumorigenesis is a multi-step process CIS- carcinoma in situ; CIN – Cervical intra-epithelial neoplasia; DCIS- ductal CIS; PIN-prostatic intra-epithelial neoplasia Figure 11.7 The Biology of Cancer (© Garland Science 2007) END OF SESSION I Normal cell proliferation Ongoing throughout life to allow development, repair or regeneration of tissues Cell division is regulated at a number of different levels to ensure that it is a tightly regulated process Phases of the cell cycle M phase: mitosis and cytokinesis GAP 0: GAP 2: Quiescent (resting) RNA and protein cells synthesis req’d for M phase GAP 1: ~ 24 hours RNA and protein synthesis req’d S phase: for S phase DNA synthesis Figure 8.3b The Biology of Cancer (© Garland Science 2007) Mitosis and cytokinesis Anaphase Chromotids pull apart and migrate to poles Prophase Chromosomes condense Centrosomes assemble Nuclear membrane begins to break down Telophase Chromotids de-condense New nuclear membrane forms Metaphase Cytokinesis Nuclear membrane completely Chromosomes align and surrounds decondensed attach to spindle chromosomes Contractile ring pinches off, dividing cytoplasm of “mother” cell & Figure 8.3a The Biology of Cancer (© Garland Science 2007) daughter cells are formed Positive regulators of the cell cycle Figure 8.12 The Biology of Cancer (© Garland Science 2007) Regulation of the cell cycle The activity of cyclin:CDK complexes is regulated at multiple levels: Expression of regulatory cyclin component of complex i.e. Expression and activity of the factors that control cyclin expression (i.e. E2F transcription factors and pRB proteins) Regulation of the activivty of the cyclin:CDK complex (i.e. phosphorylation/de- phosphorylation events by CDC25 phosphatases) Direct inhibition of complex activity cyclin- dependent kinase inhibitors (i.e. p27) Cell cycle inhibitors Figure 8.13a The Biology of Cancer (© Garland Science 2007) Cell cycle checkpoints Figure 8.4 The Biology of Cancer (© Garland Science 2007) Hallmarks of cancer HALLMARKS OF CANCER Robert Weinberg Hallmarks of cancer Robert Weinberg THE HALLMARKS OF CANCER Hallmarks of cancer Hallmarks of cancer Hallmarks of cancer Hallmarks of cancer Hallmarks of cancer Hallmarks of cancer Hallmarks of cancer Hallmarks of cancer Hallmark 1: gains growth factor independence Cell loses requirement for growth factors to stimulate cell division (i.e. they gain an oncogene) This might include: Secretion of growth factor normally secreted by surrounding tissue Mutation in growth factor receptor so it is constitutively activated Mutation of components of signaling pathways or transcription factors activated by growth factors Oncogenes Oncogene is the term given to genes which, when mutated or overexpressed, can cause cancer. Mutations in proto-oncogenes lead to a gain of function. Many oncogenes are involved in the regulation of cell proliferation and lead to growth signals to be constantly turned on, even in the absence of any actual signal. Hallmark 1: gain growth factor independence Ras was one of the first oncogenes discovered. In the presence of growth signals, normal Ras (the proto- oncogene) is activated and triggers other signalling events that lead to cell proliferation. In cancer, Ras is often mutated (and becomes an oncogene) and is switched on all the time. This leads to constant signalling to promote cell proliferation, even Increased cell proliferation in the absence of a growth factor or other Hallmark 1: gain growth factor independence Ras is the most common oncogene found in cancer; 20-30% of all tumours have a mutant version of Ras that is permanently switched on. Other oncogenes include Bcr-Abl, myc, Src and PI3 kinase. In all cases oncogenes have increased activity and lead to increased cell proliferation in the absence of specific growth signals (i.e. gain Imatinib is a tyrosine independence from growth factors). kinase inhibitor that prevents growth factor Oncogenes are an important drug signals promoting cell target as blocking their function proliferation Example of growth factor independence Human epidermal growth factor receptor 2 (HER2) is amplified in certain breast (approx. 25-30% cases), gastric (6-35%), ovarian (9- 32%) and prostate cancers http://www.roche.com/pages/facets/9/herc.htm The significance of HER2 expression Her2 positive cancers are typically more aggressive It is associated with early progression, recurrence and poor prognosis Trastuzumab (Herceptin) blocks Her2 receptor Hallmark 2: insensitivity to growth inhibitors Cell loses ability to control abnormal cell proliferation Might result from alterations in cell cycle regulation Loss of tumour suppressor genes (i.e. pRb) Upregulation of positive cell cycle regulators (i.e. CDC25 or cyclins ) Hallmark 2: insensitivity to growth inhibitors Tumour suppressor genes perform the opposite function to oncogenes in that they stop tumours from forming. In many cases, two-hits are required to inactivate a tumour Hallmark 2: insensitivity to growth inhibitors Examples of tumour suppressor genes include pRB, p53 and BRCA. In most cases tumour suppressor genes are involved in detecting DNA damage and mutations and then either triggering apoptosis or DNA repair. Mutations in tumour suppressor p53 bound to DNA genes lead to loss of function. This makes it hard to develop drugs p53 is that targetcommon the most them. mutated gene in cancer - found in 50% of all human cancers. p53 is commonly mutated in cancer Figure 9.4 The Biology of Cancer (© Garland Science 2007) p53 is commonly mutated in cancer Hallmark 3: proliferate without limit Most cells cannot proliferate indefinitely (40-60 cell divisions) Cell division is limited by telomere length Telomeres normally shorten with every cell division (with (apoptosis) exception stem cells and cancers). = apoptosis Hallmark 3: proliferate without limit Tumour cells are effectively immortal and can rebuild their telomeres using the enzyme telomerase. without telomerase with telomerase (normal) (stem cells & cancer) Hallmark 4: avoid apoptosis Apoptosis can be triggered in cells by DNA damage and viral infection, two things which can lead to the development of cancer. Apoptosis is also the mechanism through which chemotherapy and radiotherapy kills cancer cells. Hallmark 4: avoid apoptosis Cancer cell gains ability to “avoid” apoptosis; Resistance to apoptosis signals can be gained from from: Gain of function (over-expression) of pro- survival factors (i.e. IGF) Loss of function of pro-apoptotic factors (i.e. p53) Hallmark 4: avoid apoptosis IGF‐1 is known to promote cancer develop ment by inhibiting apoptosis and stimulating cell proliferation. Epidemiological studies have reported a frequent positive association between circulating IGF‐1 levels and various primary cancers, such as breast, colorectal, and prostate cancer. Hallmark 4: avoid apoptosis Less frequently, over- expression of pro- survival Bcl-2 protein family makes cancer cells less sensitive to apoptosis signals Loss of pro-apoptotic factors mean that a cancer cell can continue to divide, even in presence of DNA damage. Cancers able to avoid apoptosis might be more resistant to From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings. therapy Hallmark 5: promote angiogenesis Tumours stay small until they secure a blood supply (angiogenesis) Increased blood supply (nutrients) to tumour allows continued growth Promote new blood vessel formation through secretion of angiogenic factors (i.e. Vascular Endothelial Growth Factor (VEGF) or Fibroblast Human colorectal adenocarcinoma transplanted in a mouse growth Factor (FGF)) Hallmark 6: invasion and metastasis 90% of cancer deaths are due to the spread of cancer to distant sites – a process called metastasis. Additional cellular changes are required for the cancer cell to overcome the normal containment mechanisms. The acquisition of invasive properties is what distinguishes malignant from benign In manycells. cases, the metastatic tumours are detected first and it is unknown where the primary tumour is. Hallmark 6: invasion and metastasis Most cells in the body don’t move, except in response to injury. Malignant cancer cells acquire the ability to move and start to break away from the main tumour. Cells “crawl” through the extracellular matrix (ECM) until they reach a blood vessel. These abilities may be acquired through the decreased expression of cell adhesion molecules or secretion of proteases to break down the ECM A small percentage of cells can survive in the circulation until they reach a new tissue to grow in. Invasion and metastasis: size matters nvasion and metastasis: sites of metastasis Tumours do not spread Cancer type Main sites of metastasis randomly, but have preferred Breast Lungs, liver, bones sites that they metastasise to. Colon Liver, peritoneum, lungs Kidney Lungs, liver, bones Adrenal gland, liver, Lungs brain Melanoma Lungs, skin/muscle, liver Ovary Peritoneum, liver, lungs Pancreas Liver, lungs, peritoneum Prostate Bones, lungs, liver Liver, lungs, adrenal Rectum gland Stomach Liver, peritoneum, lungs Thyroid Lungs, liver, bones Uterus Liver, lungs, peritoneum Hallmarks of cancer – the next generation The hallmarks of cancer The hallmarks of cancer SUSTAINED PROLIFERATION! The hallmarks of cancer The hallmarks of cancer The hallmarks of cancer The hallmarks of cancer The hallmarks of cancer The hallmarks of cancer The hallmarks of cancer The hallmarks of cancer The hallmarks of cancer The hallmarks of cancer Outline What is Cancer? Classification of Cancers Normal cell growth and its control The mammalian cell cycle Cell cycle checkpoints Hallmarks of a cancer DNA mutations in cancer development Stages of cancer and survival Learning objectives part 2 Understand and explain how cancer leads to increased mortality Describe how mutations in oncogenes are a key factor in the initiation of cancer Discuss the different clinical stages of cancer and understand the link with survival rates How does cancer kill? Interferes with normal organ function - blockage / obstruction - deprivation of nutrients - pressure Interferes with metabolic processes - malnutrition - calcium changes - liver enzyme function - production of blood cells - hormone production Muscle wasting History of a tumour “It takes (at least) two to tango". Alfred G. Knudson The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA. It was first proposed by Carl O. Nordling in 1953, published later by Alfred G. Knudson in 1971. What causes cancer? A single mutation leading to a single acquired property such as increased proliferation is not enough to lead to cancer. A single cell has to be able to acquire (usually after multiple mutations) most or all of the hallmarks in order to progress to cancer. This takes time! What causes cancer? DNA in a typical cell is damaged around 10,000 times per day. Most of this DNA damage is repaired, but the DNA repair mechanisms are not perfect and some damage is occasionally missed leading to a mutation. Mutations occur randomly throughout the genome. In many cases these mutations are in non-coding regions or in regions of genes where they have no effect. Where these mutations occur in key genes such DNA and mutations Types of mutation In gene coding regions; point mutations or small insertions/deletions Alterations in transcription/splicing Amplifications/deletions of chromosomal regions Chromosomal translocations Gains and losses of whole chromosomes Changes in DNA modification, eg., DNA methylation What causes mutations? UV and other types of radiation Free radicals produced during metabolic processes Viruses Chemicals (smoking, asbestos, food etc) Copying / repair errors (often inherited) In cancer, accumulated mutations can lead to genome instability and an increased likelihood of further Chemicals and cancer This study sequenced the genome of lung cancer and compared it with a normal genome to look for mutations and their causes. Found 23,000 mutations in the lung cancer genome. Most of these were caused by exposure to chemicals in tobacco smoke. Viruses and cancer Stages of cancer development There are a number of stages in the development of cancer. The first stage is called initiation in which the first mutations promoting increased proliferation occurs. The next stage is promotion, in which additional mutations promote further proliferation. These two stages are known as carcinogenesis. This is followed by tumour progression which sees growth Stages of cancer and survival east cancer stage at diagnosis Identifying how far a tumour has progressed (stage) is important for determining the treatment and for prognosis. In many cases tumours are staged from 1-4 (or I- IV) e.g. breast cancer, colorectal cancer. Another grading scheme is the TNM scheme. This stands for Tumour (how far the tumour has grown locally; score 1-4), Nodes (is there any invasion to lymph nodes, score 0-2), Survival rates and cancer Leading cancer types Survival rates are improving Why are survival rates improving? Earlier diagnosis screening scanning biomarkers Better treatments surgery radiotherapy chemotherapy Costs to NHS and UK Costs to NHS and UK Cancer screening programmes Cancer screening programmes Early detection, diagnosis and treatment is key to improving patient prognosis Self-checks Skin cancer Breast cancer Testicular cancer NHS screening programmes Bowel cancer Men and women (60-75 years) Cervical cancer Women (25-65 years) Breast cancer Women (50-70 years) Risk factors for cancer Risk factors associated with an increased incidence of cancer include age, genetics and exposure to risk factors Smoking Inactivity/lack of physical activity Obesity Alcohol Diet lack of fruit and vegetables, salt, processed foods, red meats) Infections Infections cause 18% cancers globally The changing face of public health Summary Cancer is group of diseases characterised by loss of control of cell growth. Invasion of surrounding tissues and spread to distant sites (malignant disease) is responsible for most cancer deaths. Multiple genetic and cellular changes in a cell (hallmarks of cancer) lead to the development of cancer. Reduction of risk factors and early diagnosis and treatment are key to improve patient outcomes.