Introduction to Cancer PDF

Introduction to Cancer Cara Martin MSc Molecular Medicine 20th September 2023 [email protected] Learning objectives PART 1 Basic Cancer Facts Define the risk factors for developing cancer Cancer prevention strategies PART 2 Understand the basis of tumour classification, nomenclature, a...

Introduction to Cancer Cara Martin MSc Molecular Medicine 20th September 2023 [email protected] Learning objectives PART 1 Basic Cancer Facts Define the risk factors for developing cancer Cancer prevention strategies PART 2 Understand the basis of tumour classification, nomenclature, and staging Understand the basic concept of oncogenesis, oncogenes and tumour suppressor genes Trinity College Dublin, The University of Dublin  Cancer facts Cancer is among the most common causes of morbidity and mortality worldwide, with an estimated 18 million new cases and 9.6 million deaths per annum, projected to continue to rise to 29 million in 2040 70% by 2030. Globocan 2018 Trinity College Dublin, The University of Dublin Trinity College Dublin, The University of Dublin Trinity College Dublin, The University of Dublin Trends in cancer incidence Trinity College Dublin, The University of Dublin  What is Cancer? Cancer is a term used to describe a large collection of related diseases that are characterised by abnormal cell functioning. Health cells are programmed to “know what to do and when to do it”. Cancer cells do not have this ability and therefore grow and replicated uncontrolled. An abnormal mass of cells, known as a neoplasm develops. This mass persists in the same excessive manner after cessation of the stimuli. Trinity College Dublin, The University of Dublin  Factors in Carcinogenesis The main carcinogenic factors can be grouped into: primary determining factors; chemical, viral, bacterial etc secondary determining factors; hereditary eg Retinoblastoma favoring factors; lifestyle, nutrition, geographical factors, sex age etc Trinity College Dublin, The University of Dublin Causes of carcinogenesis Kathleen Y. Wolin et al. The Oncologist 2010;15:556-565 Trinity College Dublin, The University of Dublin Heredity Genes isolated for several classic familial cancer syndromes: – RB1 (retinoblastoma) – APC (familial polyposis) – Human Non Polyposis Colon Cancer (HNPCC)- Lynch syndrome – Mismatch repair genes – BRCA 1&2 (breast and ovarian cancer) – p53 (many cancers – Li Fraumeni Syndrome)- Trinity College Dublin, The University of Dublin  Chemical Carcinogens Alcohol Asbestos Wood dust Rubber, plastics, dyes Tar / bitumen Aflatoxin Alkylating agents Tobacco Trinity College Dublin, The University of Dublin  Smoking Smoking causes over a quarter (28 per cent) of cancer deaths in the UK and nearly one in five cancer cases. 25-40% smokers die in middle age 9 in 10 lung cancers First shown in 1950 Trinity College Dublin, The University of Dublin Tobacco and Cancer Trinity College Dublin, The University of Dublin cytochrome P450 (CYP)-mediated effects of polycyclic aromatic hydrocarbons (PAHs) Trinity College Dublin, The University of Dublin Trinity College Dublin, The University of Dublin  Alcohol and Cancer Damages cells Breaks down cancer causing chemicals Weakens ability to absorb nutrients Increases levels of hormone oestrogen linked to breast cancer Increases weight gain Trinity College Dublin, The University of Dublin  Infectious diseases Worldwide, infectious agents are responsible for an estimated 2 million new cancer cases annually (16.1% of all cancers). The burden of these infection-related cancers is much higher in less-developed regions (22.9% overall and 32.7% in sub-Saharan Africa) versus more-developed regions (7.4%). The four main cancer-causing infectious agents Helicobacter pylori, human papillomavirus, hepatitis B and C viruses, Others: Epstein Barr Virus, Human herpes virus 8 Trinity College Dublin, The University of Dublin  Obesity and Cancer Lifestyle: Highly caloric diet, rich in fat, refined carbohydrates and animal protein Low physical activity Trinity College Dublin, The University of Dublin  How does obesity lead to cancer? Oestrogen Adipocytes – post menopausal women Uncontrolled cell growth Insulin and Growth factors Free fatty acids Re-programming growth factors Inflammation Macrophages Chronic inflammation Trinity College Dublin, The University of Dublin Lifestyle Age Diet Ethnicity Occupation Deprivation Trinity College Dublin, The University of Dublin  Age and Cancer Percent of New Cancers by Age Group: All Cancer Sites Advancing age – risk factor Median age diagnosis – 66 years One quarter of new cases diagnosed in people aged 65-74yrs SEER 18 2007-2011, All Races, Both Sexes Trinity College Dublin, The University of Dublin Diet and Cancer Haem Nitrates and nitrites Heterocyclic amines (HCAs) and polycyclic amines (PCAs) Trinity College Dublin, The University of Dublin  Cancer Prevention and Control ❑ Between 30–50% of all cancer cases are preventable Reducing impact of: Smoking Alcohol Physical activity, lifestyle, dietary factors, being overweight and obesity Radiation exposure Environmental pollutants Occupational carcinogens Infections Trinity College Dublin, The University of Dublin  Cancer Prevention and Control ❑ Primary Prevention- reducing exposure to risk factors ▪ Public information and education ▪ Legislation ▪ National and International co-ordination ▪ Cancer prevention and control strategy ▪ Vaccination ❑ Secondary Prevention Early detection ▪ Cervical screening ▪ Breast screening ▪ Colorectal screening Trinity College Dublin, The University of Dublin  Population Screening Trinity College Dublin, The University of Dublin Screening for cancer Early detection provides the best opportunity for successful treatment Cancer screening examinations are medical tests performed when you’re healthy Reliable screening tests are available for certain cancers Ex: Cervix, Breast, Colon etc. Trinity College Dublin, The University of Dublin  PART 2 Cancer Definitions and nomenclature Cancer is caused by an accumulation of genetic alterations that confer a survival advantage to the neoplastic cell. Genetic Changes affect multiple facets: – Cell proliferation – Apoptosis – Tissue invasiveness – Production of growth and angiogenic factors – Ability to escape immune surveillance Trinity College Dublin, The University of Dublin Neoplasia Cell proliferation: escape from normal control →immortalisation → most instances, single cell type; numbers inappropriate for anatomical site → tumour Cell differentiation: impaired differentiation of cell line. Poor degree of differentiation → worse behaviour of neoplasm. Relationship between cells and surrounding stroma: Growth in compact mass → benign neoplasm Growth in invasive manner → malignant neoplasm Trinity College Dublin, The University of Dublin  Dysplasia A pre-malignant change in cells (usually epithelium) characterized by disordered growth and morphologic changes in the cell nucleus The nuclear changes are similar to those seen in neoplasms and include: – crowded and overlapping nuclei, – large and irregular nuclei, – uneven chromatin distribution and – increased mitotic activity Trinity College Dublin, The University of Dublin Neoplasia Trinity College Dublin, The University of Dublin Trinity College Dublin, The University of Dublin Classification of Tumours Benign (non-cancerous) Malignant (cancerous) Enclosed in a fibrous shell or Not usually contained – capsule metastasis Take up space Invaded disrupt surrounding tissues Concerned if they interfere with surrounding tissue or vessels or impeded function of the body Trinity College Dublin, The University of Dublin Tumour Shapes Downloaded from: StudentConsult (on 19 April 2013 12:02 PM) Trinity College Dublin, The University of Dublin © 2005 Elsevier Classification of Neoplasms As a general rule neoplasms are classified according to the type of normal tissue they most closely resemble. – MAJOR CATEGORIES Epithelial Connective tissue Lymphoid and haemopoietic tissue Germ cells Trinity College Dublin, The University of Dublin  Cancer types As defined by microscopic morphology and immunophenotype Carcinomas – cancers of epithelial cells Sarcomas – cancers of mesenchymal cells Lymphomas – solid cancers of lymphoid cells Leukaemias – blood-based cancers of white blood cells Often prefixed by the specific cell Adenocarcinoma – glands Leiomyosarcoma – smooth muscle cells Liposarcoma – fat cells Also classified anatomically according to organ of origin Trinity College Dublin, The University of Dublin Growth and Spread of Malignant Neoplasms DIRECT: May infiltrate and destroy immediately adjacent structures LYMPHATIC INVASION: To regional lymph nodes and beyond BLOOD VESSEL SPREAD: Usually to the lungs or liver or both ACROSS SEROSAL SURFACES: Pleura, pericardium and peritoneum Trinity College Dublin, The University of Dublin Grading and staging of tumours Grade: Cytological differentiation, mitotic rate, grade I-IV (Broder) Well, moderately, poorly differentiated Low, intermediate, high grade Stage: Size of primary tumour, invasion, extent of spread, lymph nodes metastasis TNM (tumour, node, metastasis) Stage I-IV (lymphoma, carcinoma; criteria defined for each form of neoplasm) Trinity College Dublin, The University of Dublin  TNM Classification of Malignant Tumours T (a,is,(0),1-4): size or direct extent of the primary tumour N (0-3): degree of spread to regional lymph nodes N0: tumour cells absent from regional lymph nodes N1: tumour cells spread to closest or small number of regional lymph nodes N2: tumour cells spread to an extent between N1 and N3. N3: tumour cells spread to most distant or numerous regional lymph nodes M (0/1): presence of metastasis M0: no distant metastasis M1: metastasis to distant organs (beyond regional lymph nodes) Trinity College Dublin, The University of Dublin Other parameters G (1-4): the grade of the cancer cells (i.e. they are "low grade" if they appear similar to normal cells, and "high grade" if they appear poorly differentiated) R (0/1/2): the completeness of the operation (surgery- boundaries free of cancer cells or not) Trinity College Dublin, The University of Dublin Examples Small, low grade cancer, no metastasis, no spread to regional lymph nodes, cancer completely removed, resection material seen by pathologist - pT1 pN0 M0 R0 G1; this would be considered Stage I. Large, high grade cancer, with spread to regional lymph nodes and other organs, not completely removed, seen by pathologist - pT4 pN2 M1 R1 G3; this would be considered Stage IV. Most Stage I tumours are curable; most Stage IV tumours are not Trinity College Dublin, The University of Dublin  Genetic basis of Cancer Cancer is caused by an accumulation of genetic alterations that confer a survival advantage to the neoplastic cell. 2 distinct processes – Mutation – Clonal selection Genetic Changes affect multiple facets: – Cell proliferation – Apoptosis – Tissue invasiveness – Production of growth and angiogenic factors – Ability to escape immune surveillance Trinity College Dublin, The University of Dublin Types of Mutations Deletions – ranging from 1bp to megabases Insertions- include duplications Single base substitutions – Missense mutations replace one amino acid with another – Nonsense mutations replace one amino acid codon with a stop codon – Splice site mutations [exon/intron splicing] Frameshift mutations caused by deletions, insertions or splicing errors Trinity College Dublin, The University of Dublin Loss of function mutations Inactivate [complete loss of partial loss] of gene function Phenotypes associated with such mutations are most often recessive. Trinity College Dublin, The University of Dublin Gain of function mutations Gain-of-function mutations change the gene product such that it gains a new and abnormal function. These mutations usually have dominant phenotypes. Trinity College Dublin, The University of Dublin Basic Concepts in Oncogenesis Monoclonality – initial mutation occurs in a single cell – mutated cell is effectively “immortalized”, either by replicating uncontrollably or not dying off normally – replication of this cell results in “(mono)clonal expansion” Trinity College Dublin, The University of Dublin  Clonal Selection ❑ All the cells in a tumour originate from a single ancestral cell. ❑ But, not all cells in a tumour have the same genotype because cancer cells are genetically unstable. ❑Variation gives rise to selection. ❑Clonal selection of variant progeny with the most robust growth properties play major contributing roles. Monoclonal growth reflects the acquisition of somatic mutations that confer survival advantage. Trinity College Dublin, The University of Dublin  Clonal selection of cancer cells Normal Tumour Variants over time Trinity College Dublin, The University of Dublin Basic Concepts in Oncogenesis Tumour progression – initial mutation is NOT sufficient to produce a clinical “tumour” – genome appears to be unstable (?DNA repair defect) leading to further mutations – sequential mutations lead to subclones with progressively more “malignant” phenotypes (a nasty form of natural selection) Trinity College Dublin, The University of Dublin  Cancer Associated Genes All of these genes exist and function in normal cells as 1. proto-oncogenes 2. tumor suppressor genes depending on their normal function they may contribute to a cancer by overactivity or underactivity and may behave in a dominant or recessive fashion in the cell. Overactivity may result from increased expression or decreased degradation (e.g.. mutations that prolong protein half-life) Trinity College Dublin, The University of Dublin Types of Genes associated with cancer “Classic” Oncogenes – promote cell growth and division – ras, myc and erb-B2 are examples Tumour Suppressor Genes – normally inhibit cell division – p53, Rb and BRCA-1 and -2 are examples Trinity College Dublin, The University of Dublin “Classic” Oncogenes Genes which normally function to PROMOTE cell growth/division in a controlled manner Ras - Mutation or overexpression associated with overactivity of gene - genetically dominant effect -example: ras point mutations are very common in human tumours – mutant ras signal transducer doesn’t need growth factor binding to be active Trinity College Dublin, The University of Dublin Sites of action of “classic” oncogenes Growth factors Growth factor receptors Signal transduction proteins Nuclear regulatory proteins Cell cycle regulators Trinity College Dublin, The University of Dublin  Tumor Suppressor Genes General features – genes that normally function to suppress cell replication (not specifically to prevent tumors) – can be considered to function in opposition to effects of “classic” oncogenes – normal cell growth depends on a balance between the effects of proto-oncogenes and TSG’s Trinity College Dublin, The University of Dublin Tumour Suppressor Genes - Genetics Display “recessive” genetics at a cellular level BUT - familial defects inherited in a dominant fashion. Here’s how this works: – defects in one TSG allele may be inherited, but the cell still functions normally, using the wild type allele – a chance mutation of the second normal allele results in both functioning alleles being knocked out – referred to as “loss of heterozygosity”. The function of the TSG is lost. – the odds of this chance 2’nd mutation occurring in one of the billions of dividing cells at risk are very high E.g. Rb, p53 Trinity College Dublin, The University of Dublin  Oncogenes/proto- Tumour suppressor oncogene Genes Prevents cell growth and cell Promotes cell growth and cell division division Loss of function Gain of function Car brake car accelerator 2 hit One hit Trinity College Dublin, The University of Dublin Multistep mutations in colon cancer Trinity College Dublin, The University of Dublin RECAP PART 1 Basic Cancer Facts- statistics et Define the risk factors for developing cancer Cancer prevention strategies PART 2 Understand the basis of tumour classification, nomenclature, and staging Understand the basic concept of oncogenesis, oncogenes and tumour suppressor genes Trinity College Dublin, The University of Dublin  Thank you Trinity College Dublin, The University of Dublin