Biology of Cancer Textbook PDF

Chapter 11 Biology of Cancer Copyright © 2017, Elsevier Inc. All rights reserved.  Cancer  Diseases in which abnormal cells divide without control and are able to invade other tissues  Derived from Greek word for crab, karkinoma  Tumor  Also r...

Chapter 11 Biology of Cancer Copyright © 2017, Elsevier Inc. All rights reserved.  Cancer  Diseases in which abnormal cells divide without control and are able to invade other tissues  Derived from Greek word for crab, karkinoma  Tumor  Also referred to as a neoplasm—new growth Copyright © 2017, Elsevier Inc. All rights reserved. 2  Introduction: Terminology  Differentiation  Each cell types differentiates and carries out particular functions.  The structure reflects the function of the tissue.  Mitosis  Part of the cell cycle  Requires genetic control—DNA and RNA  Mutation  If DNA in parent cell is altered and passed on, offspring cells will carry the mutation  Apoptosis  Programmed cell death  Controlled by genetic elements  Benign and Malignant Tumors  Benign tumors  Usually differentiated cells that reproduce at a higher rate than normal  Encapsulated  Tissue damage This is a result of compression of adjacent structures. It can be life-threatening in the brain.  Malignant tumors  Undifferentiated, nonfunctional cells  Rapid reproduction—abnormal mitotic figures  Infiltrate or spread into surrounding tissue  Spread to distant sites  Benign vs. Malignant Tumors Benign Malignant Grow slowly Grow rapidly Well-defined capsule Not encapsulated Not invasive Invasive Well differentiated Poorly differentiated Low mitotic index High mitotic index Do not metastasize Can spread distantly (metastasis) Copyright © 2017, Elsevier Inc. All rights reserved. 5  Malignant Tumors: Cancer  Lack control of mitosis and do not undergo apoptosis  No normal organization or differentiation  No contact inhibition  Abnormal cell membranes  Altered surface antigens  Do not adhere to each other  Often break loose from mass  Invade other tissues and may spread to distant sites  Malignant Tumors: Cancer (Cont’d)  Mass compresses blood vessels.  Leads to necrosis and inflammation around tumor  Tumor cells may secrete enzymes or hormones.  Break down of proteins and cells  Systemic effects, such as altered calcium levels  Inflammation and loss of normal cells  Lead to progressive reduction in organ integrity and function  Angiogenesis  Some tumor cells secrete growth factors. Stimulate the development of new capillaries in the tumor  Classification and Nomenclature  Benign tumors  Named according to the tissues from which they arise and include the suffix “-oma” Lipoma Leiomyoma Meningioma  May progress to cancer  Several malignant tumors have unique names:  Hodgkin’s disease  Wilms’ tumor  Leukemia Copyright © 2017, Elsevier Inc. All rights reserved. 8  Classification and Nomenclature (Cont.)  Malignant tumors  Named according to the tissues from which they arise Carcinoma  Epithelial tissue Adenocarcinoma  From ductal or glandular tissue Sarcoma  Mesenchymal tissue Lymphoma  Lymphatic tissue Leukemia  Blood-forming cells Copyright © 2017, Elsevier Inc. All rights reserved. 9  Carcinoma in Situ  Carcinoma in situ (CIS)  Preinvasive epithelial malignant tumors of glandular or epithelial origin that have not broken through the basement membrane or invaded the surrounding stroma Copyright © 2017, Elsevier Inc. All rights reserved. 10 1. Which of the following statements is TRUE? A. All neoplasms are cancerous. B. Benign growths are cancerous. C. Malignant tumors have slow growth. D. Cancer refers to a malignant tumor. Copyright © 2017, Elsevier Inc. All rights reserved. 11  Biology of Cancer Cells  Cancer is predominantly a disease of aging  Multiple mutations are required before cancer can develop  Clonal proliferation or expansion  As a result of a mutation, a cell acquires characteristics that allow it to have selective advantage over its neighbors Increased growth rate or decreased apoptosis Copyright © 2017, Elsevier Inc. All rights reserved. 12  Biology of Cancer Cells (Cont.)  Transformation of normal cells  Decreased need for growth factors to multiply  Lack contact inhibition  Anchorage independence  Immortality Copyright © 2017, Elsevier Inc. All rights reserved. 13  Genomic Instability  Increased tendency for genomic mutations during life cycle of the cell  Risk for cancer increases  Caretaker genes  Encode for proteins that are involved in repairing damaged DNA Copyright © 2017, Elsevier Inc. All rights reserved. 14  Genomic Instability (Cont.)  May result from increased silencing or modulation of gene functioning  Promoter regions of genes altered, leading to their silencing or altered gene expression  Chromosome instability  Increase in malignant cells  Results in chromosome loss, loss of heterozygosity, and chromosome amplification Copyright © 2017, Elsevier Inc. All rights reserved. 15  Telomeres and Immortality  Body cells are not immortal and can only divide a limited number of times  Telomeres are protective caps on each chromosome and are held in place by telomerase  Block cell division and prevent immortality  Telomeres become smaller and smaller with each cell division  Cancer cells can activate telomerase  Unlimited division and proliferation Copyright © 2017, Elsevier Inc. All rights reserved. 16  Angiogenesis  Growth of new vessels  Advanced cancers can secrete angiogenic factors (VEGF)  Vascular endothelial GF  Platelet-derived GF  Basic fibroblast GF Copyright © 2017, Elsevier Inc. All rights reserved. 17  Inflammation and Cancer  Chronic inflammation is an important factor in the development of cancer  Cytokine release from inflammatory cells  Helicobacter pylori  Chronic inflammation associated with: Peptic ulcer disease Stomach carcinoma Mucosa-associated lymphoid tissue lymphomas Copyright © 2017, Elsevier Inc. All rights reserved. 18  Inflammation and Cancer (Cont.)  Tumor-associated macrophage (TAM)  Key cells that promote tumor survival  Presence frequently correlates with a worse prognosis  Mimic M2 phenotype  Have diminished cytotoxic response  Develop the capacity to block T-cytotoxic cell and NK cell functions and produce cytokines that are advantageous for tumor growth and spread Copyright © 2017, Elsevier Inc. All rights reserved. 19  Immune System and Cancer  Normal immune system protects against cancer  Immunosuppression fosters cancer  Non-Hodgkin lymphoma (10×)  Kaposi sarcoma (1000×)  Release of immunosuppressive factors into the tumor microenvironment increases resistance of the tumor to chemotherapy and radiotherapy Copyright © 2017, Elsevier Inc. All rights reserved. 20  Viruses and Cancer  Implicated (often involved with)  Hepatitis B and C viruses  Epstein-Barr virus (EBV)  Kaposi sarcoma herpesvirus (KSHV)  Human papillomavirus (HPV)  Human T-cell leukemia-lymphoma virus (HTLV) Copyright © 2017, Elsevier Inc. All rights reserved. 21  Metastasis  Spread of cancer from a primary site of origin to a distant site  Direct invasion of contiguous organs  Known as local spread  Metastases to distant organs  Lymphatics and blood  Requires great efficiency  Usually occurs late Copyright © 2017, Elsevier Inc. All rights reserved. 22  Local Spread  Invasion  Cellular multiplication Mitotic rate vs. cellular death rate  Release of lytic enzymes  Decreased cell-to-cell adhesion  Increased motility Copyright © 2017, Elsevier Inc. All rights reserved. 23  Distant Metastases  Spread through vascular and lymphatic pathways  Selectivity of different cancers at different sites  Breast cancer bones  Lymphomas spleen  Dormancy Copyright © 2017, Elsevier Inc. All rights reserved. 24  Seeding  Seeding is the spread of cancer cells in body fluids or along membranes, usually in body cavities.  Tumor cells break away and travel easily with the movement of fluid and tissue.  The large peritoneal membrane is an example that encourages dispersion of ovarian tumor cells throughout the peritoneal cavity.  Excessive handling of the area containing malignant cells, like diagnostic procedures and surgery, dislodges the malignant cells and leads to further spread. Copyright © 2017, Elsevier Inc. All rights reserved. 25  Warning Signs of Cancer  Unusual bleeding  Unusual discharge  Change in bowel habits, such as prolonged diarrhea  Change in bladder habits, such as hematuria  Change of skin, such as the color, size or shape of a wart or mole  A sore that does not heal  Weight loss  Anemia  Persistent fatigue  Persistent and unexplained cough  Solid, often painless lump Copyright © 2017, Elsevier Inc. All rights reserved. 26  Clinical Manifestations  Pain  Little or no pain is associated with early stages of malignancy  Influenced by fear, anxiety, sleep loss, fatigue, and overall physical deterioration  Mechanisms: Pressure Obstruction Invasion of sensitive structures Stretching of visceral surfaces Tissue destruction Inflammation/Infection Copyright © 2017, Elsevier Inc. All rights reserved. 27  Clinical Manifestations (Cont.)  Fatigue  Most frequently reported symptom  Subjective clinical manifestation  Tiredness, weakness, lack of energy, exhaustion, lethargy, inability to concentrate, depression, sleepiness, boredom, and lack of motivation  Suggested causes: Sleep disturbance Biochemical changes secondary to disease and treatment Psychosocial factors Level of activity Nutritional status Environmental factors Copyright © 2017, Elsevier Inc. All rights reserved. 28  Clinical Manifestations (Cont.)  Syndrome of cachexia  Most severe form of malnutrition  Includes anorexia, early satiety, weight loss, anemia, asthenia, taste alterations, and altered protein, lipid, and carbohydrate metabolism  Anemia  A decrease of hemoglobin in the blood  Mechanisms: Chronic bleeding resulting in iron deficiency Severe malnutrition Medical therapies Malignancy in blood-forming organs Copyright © 2017, Elsevier Inc. All rights reserved. 29  Clinical Manifestations (Cont.)  Leukopenia and thrombocytopenia  Direct tumor invasion to the bone marrow causes leukopenia and thrombocytopenia  Chemotherapy drugs are toxic to the bone marrow  Infection  Risk increases when the absolute neutrophil and lymphocyte counts fall Copyright © 2017, Elsevier Inc. All rights reserved. 30  Clinical Manifestations (Cont.)  Gastrointestinal manifestations  Oral ulcers caused by decreased cell turnover from chemotherapy and radiation  Malabsorption  Diarrhea  Therapy-induced nausea  Hair and skin manifestations  Alopecia from chemotherapy Usually temporary  Skin breakdown and dryness Copyright © 2017, Elsevier Inc. All rights reserved. 31  Diagnosis  Manifestations based on site, tumor size  Diagnostic testing Copyright © 2017, Elsevier Inc. All rights reserved. 32  Staging  Microscopic analysis for staging—based on presence of metastasis  Stage I: No metastasis  Stage II: Local invasion  Stage III: Spread to regional structures  Stage IV: Distant metastasis  World Health Organization’s TNM system:  T for tumor spread  N for node involvement  M for the presence of distant metastasis Copyright © 2017, Elsevier Inc. All rights reserved. 33  TNM System Copyright © 2017, Elsevier Inc. All rights reserved. 34 2. A patient has been diagnosed with prostate cancer that has metastasized to the bone. The stage of this cancer is: A. 1 B. 2 C. 3 D. 4 Copyright © 2017, Elsevier Inc. All rights reserved. 35  A patient is diagnosed with breast cancer (lesion 4cm) that has spread to the lungs and liver, and has nearby lymph node involvement. Based on the TNM staging system, which of the following is the correct classification?  A) T1 N0 M0 B) T2 N1 M1 C) T3 N1 M0 D) T1 N0 M1 Copyright © 2017, Elsevier Inc. All rights reserved. 36  Tumor Markers  Tumor cell markers (biologic markers) are substances produced by cancer cells that are found on or in tumor cells, in the blood, CSF, or urine >Hormones >Enzymes >Genes >Antigens >Antibodies  Tumor markers are used to:  Screen and identify individuals at high risk for cancer  Diagnose specific types of tumors  Observe clinical course of cancer  Problem: false positives and negatives Copyright © 2017, Elsevier Inc. All rights reserved. 37  Histology  Tumors are classified based on immunohistochemical analysis of protein expression for improved treatment  Supplemented by a more extensive genetic analysis of the tumors  Enhanced molecular characterization subdivides cancers into therapeutically and prognostically relevant smaller groups Breast cancers Copyright © 2017, Elsevier Inc. All rights reserved. 38  Cancer Treatment  Surgery  To prevent cancer (colon polyps)  Biopsy for diagnosis and staging  Lymph node sampling  Palliative surgery  Radiation  Goals Eradicate cancer without excessive toxicity Avoid damage to normal structures  Ionizing radiation damages the cancer cell’s DNA Copyright © 2017, Elsevier Inc. All rights reserved. 39  Cancer Treatment (Cont.)  Chemotherapy  Takes advantage of specific vulnerabilities in target cancer cells  Usually given in combinations designed to attack a cancer from many different weaknesses at the same time Copyright © 2017, Elsevier Inc. All rights reserved. 40  Chemotherapy  Induction chemotherapy  For shrinkage or disappearance of tumors  Adjuvant chemotherapy  Eliminate micrometastasis after surgery  Neoadjuvant therapy  Given before localized treatment to shrink tumor Copyright © 2017, Elsevier Inc. All rights reserved. 41  Immunotherapy  Vaccines against oncogenic viruses provide protection and prevent the onset of viral- induced tumors  Numerous potential therapeutic vaccines have been tested with little success  Allogeneic cancer cell vaccines continue to be tested Copyright © 2017, Elsevier Inc. All rights reserved. 42  Cancer Treatment  Targeted disruption  Used in combination with chemotherapy  Highly specific Inactivate oncogenes Block angiogenesis Affect cell metabolism Induce apoptosis Neutralize cytokines/chemokines Copyright © 2017, Elsevier Inc. All rights reserved. 43  Chapter 12 Cancer Epidemiology Copyright © 2017, Elsevier Inc. All rights reserved.  Genetics, Epigenetics, and Tissue  Environmental-lifestyle factors and genetic factors cause cancer  Patterns of cancer are environmental, not genetic  Genetic alterations and abnormalities drive cancer at the cell level  Factors influenced by the greater external environment Copyright © 2017, Elsevier Inc. All rights reserved. 45  Incidence Trends  Major cause of morbidity and mortality worldwide  In the United States, incidence is decreasing  Prostate cancer and breast cancer are the most frequently diagnosed Copyright © 2017, Elsevier Inc. All rights reserved. 46  Cancer Incidence  Most common in men  Prostate cancer  Lung cancer  Colorectal cancer  Most common in women  Breast cancer  Lung cancer  Colorectal cancer  Mortality Trends  Death rates decreasing for children  Death rates for adults decreasing in 7 of the top 15 cancer types  Death rates increasing for cancers of pancreas, liver, and uterus and for melanoma of the skin in men Copyright © 2017, Elsevier Inc. All rights reserved. 48  Environmental-Lifestyle Factors  Tobacco  Leading cause of preventable death in the United States  Multipotent carcinogenic mixture  Linked to cancers of the lung, lower urinary tract, upper aerodigestive tract, liver, kidney, pancreas, cervix, uterus  Linked to myeloid leukemia  Secondhand smoke (ETS) contains many toxic chemicals  Cigar and pipe smoking equally harmful Copyright © 2017, Elsevier Inc. All rights reserved. 49  Environmental-Lifestyle Factors (Cont.)  Diet  Cooking of fat, meat, or protein produces carcinogenic substances  Naturally occurring carcinogens associated with alkaloids or mold byproducts  Nutrigenomics  Study of nutrition on the phenotypic variability of individuals based on genomic differences Copyright © 2017, Elsevier Inc. All rights reserved. 50  Nutrition and Cancer  Many cellular processes affected by nutrition  May directly influence silencing of genes that should be active or activating genes that should be silent  May alter hormonal axes, influence cellular proliferation, and affect phenotypes or expression of key genes Copyright © 2017, Elsevier Inc. All rights reserved. 51  Nutrition and Cancer (Cont.)  Xenobiotics (drugs, pesticides, food additivies, etc.)  Toxic, mutagenic, and carcinogenic chemicals in food  Two defense system for countering effects: Phase I activation Phase II detoxification enzymes Copyright © 2017, Elsevier Inc. All rights reserved. 52  Nutrition and Cancer (Cont.)  Dietary components can be activated into carcinogens or can prevent cancer  Pathways to cancer affected by diet include:  Cell cycle control  Differentiation  DNA repair  Gene silencing  Inflammation  Apoptosis  Carcinogen metabolism Copyright © 2017, Elsevier Inc. All rights reserved. 53  Obesity  Correlates with the body mass index (BMI)  Three factors related to obesity and cancer: Insulin–IGF-1 axis Sex hormones Adipokines or adipocyte-derived cytokines  Mechanism of obesity-associated cancer risks unclear Copyright © 2017, Elsevier Inc. All rights reserved. 54  Alcohol Consumption  Risk factor for oral cavity, pharynx, larynx, esophagus, liver, colorectum, and breast cancers  Genetic factors involved  No “safe limit” of intake Copyright © 2017, Elsevier Inc. All rights reserved. 55 Alcohol Consumption (Cont.) Adapted from Zakhari S: Alcohol metabolism and epigenetic changes, Alcohol Res 35:6-16, 2013. Copyright © 2017, Elsevier Inc. All rights reserved. 56  Physical Activity  Reduces cancer risk (breast, colon, other)  Decreases insulin and insulin-like growth factors  Decreases obesity  Decreases inflammatory mediators and free radicals  Increases gut motility Copyright © 2017, Elsevier Inc. All rights reserved. 57 1. Which of the following is TRUE regarding environmental risk factors and the development of cancer? A. Chronic alcoholism is linked to lung cancer. B. Human papillomavirus can cause liver cancer. C. Ultraviolet radiation (UVR) is linked to breast cancer. D. Physical activity reduces the risk of breast cancer and colon cancer. Copyright © 2017, Elsevier Inc. All rights reserved. 58  Ionizing Radiation  Emission from x-rays, radioisotopes, radon, and other radioactive sources  Exposure causes cell death, gene mutations, and chromosome aberrations  Mutations in germ cells are heritable  Increased use of diagnostic testing of concern Copyright © 2017, Elsevier Inc. All rights reserved. 59  Radiation-Induced Cancer  Targeted effects:  Chromosome aberrations, cell transformation, gene expression, alternative targets, mutagenesis in somatic cells, the biologic effects that occur in nonirradiated cells, and effects on the microenvironment  Nontargeted effects:  Bystander effects  Genomic instability Copyright © 2017, Elsevier Inc. All rights reserved. 60  Radiation-Induced Cancer (Cont.)  Acute, latent, and microenvironmental effects  Organs with highly proliferative cells especially affected by acute radiation exposure Nontargeted radiation effects alter cell and tissue signaling Microenvironment changes  Radiation-induced cancer has latent periods Usually 5-10 years Copyright © 2017, Elsevier Inc. All rights reserved. 61  Ultraviolet Radiation  Causes basal cell carcinoma, squamous cell carcinoma, and melanoma (increased incidence )  Principal source is sunlight  Ultraviolet A (UVA) and ultraviolet B (UVB)  Released TNF-α in epidermis  Produces ROS (reactive oxygen species)  Promotes skin inflammation and release of free radicals Copyright © 2017, Elsevier Inc. All rights reserved. 62  Electromagnetic Radiation (EMR)  Non-ionizing, low-frequency radiation  Microwaves, radar, cell phones, and power frequency radiation associated with electricity and radio waves, fluorescent lights, computers, and other electric equipment  May or may not be carcinogenic Copyright © 2017, Elsevier Inc. All rights reserved. 63  Infection, Sexual and Reproductive Behavior  Top cancer-causing infections  Human papillomavirus (HPV)  Helicobacter pylori (H. pylori) 75%-89% of all stomach cancers  Hepatitis B (HBV)  Hepatitis C (HCV) HBV and HCV account for large majority of liver cancers Copyright © 2017, Elsevier Inc. All rights reserved. 64  Human Papillomavirus (HPV)  Most common STD in United States  50% of sexually active population  Spread through skin contact; oral, vaginal, or rectal sex  150 related viruses Low risk—doesn’t cause cancer High risk—can cause cancer  Causes six types of cancer Cervix Penis Vulva Anus Oropharynx (tongue and tonsils) Copyright © 2017, Elsevier Inc. All rights reserved. 65 2. Change in lifestyle factors or controlling bacterial infection from Helicobacter pylori is responsible for a decrease in which type of cancer? A. Lung B. Stomach C. Leukemia D. Colorectal Copyright © 2017, Elsevier Inc. All rights reserved. 66  Air Pollution  Particulate matter  Particles and liquid droplets made up of acids, organic chemicals, metal, and dust particles  Carcinogenic and causes lung cancer  High proportion of mutagenic agents  Primary particles Emitted directly from source (construction sites, smoke stacks)  Secondary particles Emitted from power plants, industries, and automobiles Copyright © 2017, Elsevier Inc. All rights reserved. 67  Air Pollution (Cont.)  Indoor pollution  Generally worse than outdoor pollution  Tobacco smoke (passive) causes formation of reactive oxygen free radicals and thus DNA damage  Radon gas trapped in houses forms decay products that are carcinogenic  Exposures from heating and cooking sources and asbestos  Inorganic arsenic Copyright © 2017, Elsevier Inc. All rights reserved. 68 Chemical and Occupational Hazards  Present in air, soil, water, household products, toys, workplaces, and homes  Upper respiratory passages, lung, bladder, peritoneum  Substantial number of occupational carcinogenic agents:  Asbestos (mesothelioma and lung cancer)  Dyes, rubber, paint, explosives, rubber cement, heavy metals, air pollution, etc. Copyright © 2017, Elsevier Inc. All rights reserved. 69  Prevention of Cancer  Avoiding or limiting alcohol use  Getting regular exercise and physical activity  Maintaining an appropriate/ideal body mass index  Maintaining healthy dietary habits, such as reduced fat consumption and increased fruit and vegetable consumption  Getting regular colorectal screening; colonoscopy and fecal occult testing after age 50  Getting regular mammography screening age 40 through 74  Pap tests yearly from age 21-65 if normal results  Using sunscreen with an SPF of 15 or higher  Skin exams yearly, especially individuals with high sun exposure  Avoiding cigarette smoking and other tobacco use  Low-dose helical computed tomography of lungs for heavy smokers age 55-74 Copyright © 2017, Elsevier Inc. All rights reserved. 70