Hormonal and Cellular-.pptx

Chapter 11 Biology of Cancer Cancer Diseases in which abnormal cells divide without control and are able to invade other tissues Well-differentiated cancer cells look more like normal cells and tend to grow and spread more slowly than poorly differentiated or undifferentiated cancer cells. Poorly-di...

Chapter 11 Biology of Cancer Cancer Diseases in which abnormal cells divide without control and are able to invade other tissues Well-differentiated cancer cells look more like normal cells and tend to grow and spread more slowly than poorly differentiated or undifferentiated cancer cells. Poorly-differentiated cells look less like normal cells and tend to grow and spread quickly Benign vs. Malignant Tumors  Benign       Grow slowly Encapsulated Not invasive Well differentiated Low mitotic index Do not metastasize  Malignant       Grow rapidly Not encapsulated Invasive Poorly differentiated High mitotic index Can spread distantly (metastasize) Benign Tumors Named according to the tissues from which they arise Lipoma (fat cells) Leiomyoma (smooth muscle of uterus) Meningioma (meninges) May progress to cancer Malignant Tumors Named according to the cell type from which they arise Carcinoma (epithelial tissue) Adenocarcinoma (ductal or glandular tissue) Sarcoma (mesenchymal tissue) Lymphoma (lymphatic tissue) Leukemia (blood-forming cells) Carcinoma in Situ Early-stage cancers Preinvasive epithelial tumors of glandular or squamous cell origin Have not broken through the basement membrane or invaded the surrounding stroma Outcomes Remain stable Progress to invasive and metastatic cancers Regress and disappear Biology of Cancer Cells (1 of 2) Cancer is complex Tumor is a heterogenous mixture of cells (cancerous and benign) Stages of cancer development Initiation Promotion change in the cell’s genetic material primes the cell to become cancerous promoters allow a cell that has undergone initiation to become cancerous (hormones, etc) Progression Spread through lymph or bloodstream Biology of Cancer Cells (2 of 2) Multiple mutations are required before cancer can develop Driver mutations “drive” progression of cancer After critical number of driver mutations, cell becomes cancerous Clonal proliferation or expansion Mutations cause cell to acquire characteristics that give it selective advantage over its neighbors Increased growth rate or decreased apoptosis Hallmarks of Cancer (1 of 3) Primarily genomic alterations Sustained proliferative signaling-proliferative growth Genomic instability-inherited/acquired mutations Evading growth suppression-tumor suppressor genes (retinoblastoma gene, TP53) Replicative immortality-maintain telomeres Secondary to genomic change Angiogenesis-formation of vasculature Reprogramming energy metabolism-hypoxic environment Hallmarks of Cancer (2 of 3) Tumor resistance to destruction Resistance to apoptotic cell death-protection against abnormal cell growth Tumor-promoting inflammation Use the inflammatory response to protect rather than attack TAMs (macrophages) block T-cytotoxic cells and NK Avoiding immune destruction Culmination of other hallmarks Activating invasion and metastasis Cellular dormancy Hallmarks of Cancer (3 of 3) Adapted from Hanahan D, Weinberg RA: Cell 144:646, 2011. Sustained Proliferative Signaling Foremost hallmark of cancer: uncontrolled cellular proliferation Proto-oncogenes Genes that direct normal cellular proliferation Oncogenes Normal cells in proliferative phases in response to growth factors Mutated or overexpressed proto-oncogenes Cause uncontrolled cell growth Autocrine stimulation Ability of cancer to secrete growth factors that stimulate their own growth Evading Growth Suppressors Tumor-suppressor genes (anti-oncogenes) Regulate cell cycle Inhibit proliferation Stop cell divisions if cells are damaged Prevent mutations Evading Growth Suppressors Inactivation of tumor-suppressor genes Allows unregulated cellular growth Retinoblastoma (RB) gene Tumor protein p53 (TP53) Humans have two copies of each tumor-suppressor gene Both copies must be inactivated in cancer Two mutations are necessary A single germ-cell mutation (sperm or egg) results in transmission of cancer-causing genes Genomic Instability Increased tendency for genomic mutations during life cycle of the cell Risk for cancer increases Caretaker genes Involved in repairing damaged DNA Mutations increase genomic instability May result from increased epigenetic silencing or modulation of gene functioning Chromosome instability Replicative Immortality Normal body cells are not immortal and can only divide a limited number of times Telomeres are protective caps on each chromosome Get smaller and then cell dies Cancer cells can activate telomerase Restore and maintain telomeres Telomerase is present in 90% of cancers Angiogenesis Growth of new blood vessels Essential in tissue undergoing repair Essential to growth and spread of cancer Reprogramming Energy Metabolism Warburg effect Use of glycolysis under normal oxygen conditions (aerobic glycolysis) Allows products of glycolysis to be used for rapid cell growth Reverse Warburg effect Oncogenes drive metabolic reprogramming so cancer cells can: Withstand oxygen and nutrient challenges Corrupt surrounding microenvironment to assist tumor growth Resisting Apoptotic Cell Death Apoptosis is programmed cell death Self-destruction Defects in intrinsic or extrinsic pathways provides resistance to apoptotic cell death Tumor-Promoting Inflammation Chronic inflammation is an important factor in the development of cancer Some organs more susceptible to oncogenic effects of inflammation Successful tumors can alter inflammation to benefit tumor growth Helicobacter pylori Chronic inflammation associated with: Peptic ulcer disease Stomach carcinoma Mucosa-associated lymphoid tissue lymphomas Tumor-Promoting Inflammation Tumor-associated macrophage (TAM) Key cells that promote tumor survival Develop the capacity to block T-cytotoxic cell and NK cell functions and produce cytokines that are advantageous for tumor growth and spread Presence frequently correlates with a worse prognosis Evading Immune Destruction Normal immune system protects against cancer Tumor-associated antigens Immune surveillance hypothesis—predicts developing malignancies are suppressed by efficient immune response Immunotherapy—products immune system could be used to target these antigens and destroy tumors Evading Immune Destruction Tumor-infiltrating lymphocytes Cancers actively recruit immune response Remodel tissues Form new blood vessels Promote metastasis Activating Invasion and Metastasis Invasion Local spread Prerequisite for metastasis Recruitment of TAMs is critical Metastasis Spread of cancer from a primary site of origin to a distant site Changes in tumor microenvironment initiate metastasis and cause cancer cells to evolve Epithelial-Mesenchymal Transition (EMT) Model for transition to metastatic cancer cells Epithelial characteristics lost Increased migratory capacity Increased resistance to apoptosis Dedifferentiated stem cell–like state Growth favored in foreign microenvironments Clinical Manifestations Paraneoplastic syndromes Symptom complexes triggered by cancer Causes Biologic substances from tumor Immune response to tumor Not caused by direct local effects of tumor Can be earliest symptoms of unknown cancer Cachexia Multiorgan, energy wasting syndrome Most severe form of malnutrition Muscle weakness and fatigue Clinical Manifestations of Cancer         Pain Fatigue Cachexia Anemia Leukopenia and thrombocytopenia Infection Gastrointestinal problems Hair and skin 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 Clinical Manifestations  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  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 Clinical Manifestations Anemia A decrease of hemoglobin in the blood Mechanisms: Chronic bleeding resulting in iron deficiency Severe malnutrition Medical therapies Malignancy in blood-forming organs 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 Clinical Manifestations 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 Cancer 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 Cancer Staging Tumor Markers Biochemical markers 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 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 Classification of Tumors Classified based on immunohistochemical analysis of protein expression Extensive genetic analysis of the tumors Improved treatment: personalized medicine Enhanced molecular characterization subdivides cancers into therapeutically and prognostically relevant smaller groups Breast cancers have four types that respond to therapy differently Common Diagnostic Tests     Radiographic tests: x-rays, magnetic resonance imaging (MRI), computed tomography (CT), radioisotope scans, ultrasound, diagnostic mammography Direct visualization: colonoscopy, endoscopy Laboratory tests: complete blood count, chemistry panel, genetic or tumor marker tests Pathology: examination of cells and tissues for a diagnosis of malignancy, tissue type, grade of tumor Cancer Treatment Classic approaches Surgery Chemotherapy Radiation therapy Immunotherapy Therapy undergoing rapid evolution Genetic analysis of each individual’s cancer 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 Cancer Treatment 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 Complication: death of rapidly dividing cells that are not cancerous Cancer Treatment Induction chemotherapy For shrinkage or disappearance of tumors Adjuvant chemotherapy Eliminate micrometastasis after surgery Neoadjuvant therapy Given before localized treatment to shrink tumor Cancer Treatment Immunotherapy Tumor cell vaccines effective in protecting against infective agents Numerous potential therapeutic vaccines have been tested with little success Immunotherapy for metastatic prostate cancer has been approved by FDA Cancer Treatment Targeted disruption Used in combination with chemotherapy Highly specific making them less toxic than conventional chemotherapy Chapter 12 Cancer Epidemiology Genetics, Epigenetics, and Tissue Environmental-lifestyle factors and genetic factors cause cancer Genetic and epigenetic alterations at the cell level result in cancer Factors influenced by the external environment Stromal tissue immune cells promote chronic inflammation Can precede and initiate cancer changes Incidence Trends Major cause of morbidity and mortality worldwide Incidence in United States Decreasing for men Staying same for women Increased for people 0-19 years Liver cancer incidence much higher in men Lung cancer incidence decreased, corresponding with decrease in tobacco use Mortality Trends Death rates in United States Decreasing for men, women, and children Death rates for liver cancer increased at highest rate of all cancer types Men have more than double the rate of women Environmental-Lifestyle Factors Important risk factor for cancer Environmental factors Pollution, radiation, sunlight, occupational hazards Estimates on the risk they cause vary Lifestyle factors Smoking, alcohol intake, diet/nutrition, physical exercise, obesity, sexual practices, infections Environmental-Lifestyle Factors Tobacco Use Most important cause of preventable cancer Linked to cancers of lung, lower urinary tract, upper aerodigestive tract, stomach, kidney, pancreas, cervix, uterus, and myeloid leukemia Affects nearly every body organ Also harmful Environmental tobacco smoke (ETS) Cigar and pipe smoking Electronic cigarettes (E-cigarettes) Diet Influence of diet on cancer is complicated Research is ongoing Nutrigenomics Study of nutrition on the phenotypic variability of individuals based on genomic differences Culture and geographic location play a role Many cellular processes affected by nutrition Modifications in cancer stem cell self-renewal DNA repair Nutrition Diet Cooking of fat, meat, or protein produces carcinogenic substances Naturally occurring carcinogens associated with alkaloids or mold byproducts Xenobiotics Toxic, mutagenic, and carcinogenic chemicals in food and drugs Two defense system for countering effects: Detoxification enzymes Antioxidant systems Obesity Impacts energy balance and cancer risk, recurrence, and survival Three factors related to obesity and cancer: Insulin–IGF-1 axis-proliferation of cancer cells Sex hormones Adipokines or adipocyte-derived cytokines Mechanism of obesity-associated cancer risks unclear Alcohol Consumption Risk factor for mouth, pharynx, larynx, esophagus, liver, colorectum, and breast cancers No “safe limit” of intake Effects come from ethanol content Not affected by type of drink Genetic factors involved Physical Activity Reduces risk of breast, colon (in men), and endometrial cancer Independent of weight changes Mechanisms for reducing cancer risk Decreases insulin, IGF, obesity, sex and metabolic hormones, and oncogenes Increases free radicals scavenger systems, gut motility, myokines Alters inflammatory mediators Improves immune function Air Pollution Leading environmental cause of death worldwide Outdoor air pollution Particulate matter Tiny particles and liquid droplets made up of acids, organic chemicals, metal, and dust particles Carcinogenic and causes lung cancer Primary or secondary particles Research focused on fine/ultrafine particles Easily absorbed by lungs and phagocytosed Inflammatory mediators cause pulmonary inflammation Air Pollution Indoor air pollution Generally worse than outdoor pollution Radon gas trapped in houses forms decay products that are carcinogenic Exposures from heating and cooking sources increase risk for lung cancer Tobacco smoke (passive) causes formation of reactive oxygen free radicals and thus DNA damage Ionizing Radiation Increased risk for acute leukemias, multiple myeloma, and thyroid, breast, lung, stomach, colon, esophagus, and urinary tract cancers Age at time of exposure is a main factor in cancer Bimodal distribution Early ages and older ages have highest risk Mutations in germ cells are heritable Medical exposure is increasing significantly Ionizing Radiation Nontargeted effects Cells not directly touched by radiation, but nearby cells or ones in communication with irradiated cells Genomic instability Effects stemming from previous generations of irradiated cells Bystander effects Effects to cells that received no direct radiation exposure Ionizing Radiation Acute exposure especially affects organs with highly proliferative cells Microenvironment changes Radiation-induced cancer has latent periods Nontargeted radiation effects alter cell and tissue signaling Usually 5-10 years Risk estimates for low dose ionizing radiation exposure are debated Ultraviolet Radiation Principal source is sunlight Ultraviolet A (UVA), UVB, and UVC Essential for vitamin D and calcium/phosphorus absorption Increased risk for skin cancer Melanoma: melanocytes, most lethal Squamous cell carcinoma: surface of skin, sun exposed areas Basal cell carcinoma: lower epidermis or outer layer of skinslowest growing Electromagnetic Radiation (EMR) Energy in form of magnetic and electric waves Broadcast antennas, security monitors, cell phones, smart meters, portable wireless devices May or may not be carcinogenic Infection, Sexual, and Reproductive Behavior Top cancer-causing infections Helicobacter pylori (H. pylori) Hepatitis B and C viruses Account for large majority of liver cancers Epstein-Barr virus Causes 75% of all stomach cancers Nasopharyngeal carcinoma, various lymphomas, and gastric adenocarcinoma Human papillomavirus (HPV) Infection, Sexual, and Reproductive Behavior HPV Most common STD in United States More than 200 related viruses High risk—can cause cancer HPV types 16 and 18 responsible for majority of cancers Causes cancer of the cervix, penis, vulva, vagina, anus, and oropharynx (tongue, tonsils, pharynx) Low risk—not associated with cancer HPV vaccine reduces risk for cervical cancer Pap test for screening Chemical and Occupational Hazards Present in air, soil, water, household products, toys, personal care products, 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. Chapter 13 Cancer in Children and Adolescents Incidence and Mortality Incidence Rare, but is leading cause of death from disease in children Bimodal distribution Slightly more common in males Mortality 2015 mortality rate was 2.5 and 2.1 per 100,000 cases for males and females (respectively Survival rates have dramatically improved since 1960s Characteristics (1 of 2) Most originate from the mesodermal germ layer Layer gives rise to connective tissue, bone, cartilage, muscle, blood, blood vessels, gonads, kidneys, and the lymphatic system Often diagnosed during peak growth periods Fast growing and without early signs Characteristics (2 of 2) Most common childhood cancers are leukemias, sarcomas, lymphomas, and embryonal tumors Embryonal tumors Originate during intrauterine life Diagnosed early in life Immature embryonic tissue unable to mature or differentiate into fully developed cells Name includes root term “blast” Neuroblastoma, retinoblastoma Etiology Most do not have predisposing environmental factors Short latency period: less chance of early warning signs Multiple causation model Studies show a chemical causes a cancer, but not all children exposed to the chemical get cancer Genetic and Genomic Factors Mutations in oncogenes and tumor-suppressor genes Fanconi anemia, Bloom syndrome Retinoblastoma Li-Fraumeni syndrome Chromosome abnormalities Abnormalities in number or structure Congenital syndromes and cancers occur together Down syndrome and leukemia Wilms tumor associated with several abnormalities Environmental Factors Prenatal exposure Drugs Ionizing radiation Diethylstilbestrol (DES) Increased risk of childhood leukemia Childhood exposure Ionizing radiation, drugs, electromagnetic fields, and viruses associated with higher risk of cancer Infections May help “prime” immune system, providing protective effect Epstein-Barr virus and AIDS have strong associations with cancer development Prognosis More than 80% of children cured Combination chemotherapy Multimodal treatment Advances in biotherapy Improvements in nursing and supportive care Survival rates higher in children under 15 years Younger children are more likely to be enrolled in clinical trials Prognosis Survivors have increased risk of cancer later in life Residual and late effects of treatment Physical impairments Reproductive dysfunction Soft tissue and bone atrophy Learning disabilities Secondary cancers Psychologic sequelae Exemplar: Breast Cancer Most frequently diagnosed cancer in women Leading cause of death in women ages 40-44 Risk related to timing, duration, and pattern of exposures 76 Breast Cancer (Cont.) Reproductive factors: Pregnancy Reduced risk if pregnancy at young age Pregnancy-associated breast cancer Breast cancers that occur during pregnancy and risk may persist to at least 5 years postpartum and longer 77 Breast Cancer (Cont.) Hormonal factors Six factors that affect risk of breast cancer: Protective effect of an early (i.e., in the 20s) first pregnancy Relationship between types of fat, free estrogen levels, and oxidative changes in estrogen metabolism Hormone-dependent development and differentiation of mammary gland structures Efficacy of antihormone therapies for treatment and prevention of breast cancer Protective effect of removal of the ovaries and pituitary gland Increased risk associated with early menarche, late menopause, and nulliparity 78 Breast Cancer (Cont.) Hormonal factors (Cont.) Vast majority of breast cancers are initially hormone dependent Estrogens play prominent roles in cellular proliferation, differentiation, and apoptosis Androgen receptor (AR) has been implicated in prostate cancer and now in the development and progression of breast cancer 79 Breast Cancer (Cont.) Hormone replacement therapy and breast cancer risk: estrogen plus progesterone therapy (MHT) and estrogen-only therapy (ET) Estrogen-progestogen menopausal therapy and estrogen-progestrogen contraceptives are carcinogenic agents for breast cancer 80 Breast Cancer (Cont.) Prolactin and growth hormone GH induces the production of IGFs in the liver; IGF signaling is important for breast development and is implicated in breast carcinogenesis Oral contraceptives Combined estrogen-progestogen oral contraceptives (OCs) increase the risk for breast, cervix, and liver cancers 81 Breast Cancer (Cont.) Mammographic breast density Radiologic appearance of the breast, reflecting variations in breast composition Strong and consistent risk factor for breast cancer Environmental factors Environmental causes of breast cancer possibly affect the breast the most during critical phases of development Mitotic activity and cell division are greater than they are later in life Copyright © 2017, Elsevier Inc. All rights reserved. 82 Breast Cancer (Cont.) Radiation Ionizing radiation is a known mutagen and established carcinogen for breast cancer Accidentally or medically induced radiation Women treated with chest radiation for a pediatric or young adult cancer have a substantially increased risk of breast cancer 83 Breast Cancer (Cont.) Diet Prospective epidemiologic studies on diet and breast cancer risk fail to show an association that is consistent, strong, and statistically significant except for alcohol intake, being overweight, and weight gain after menopause 84 Breast Cancer (Cont.) Obesity Increases cancer risk from cellular pathways that involve hormonal regulation, cellular proliferation, and immunity Associated with a reduced risk of premenopausal breast cancer Associated with poor survival among women with breast cancer 85 Breast Cancer (Cont.) Environmental chemicals Difficult to link to breast cancer Must consider life history of chemical exposure Xenoestrogens Synthetic chemicals that mimic the actions of estrogens Found in many pesticides, fuels, plastics, detergents, and drugs May contribute to breast cancer 86 Breast Cancer (Cont.) Physical activity May reduce overall risk of breast cancer May reduce the invasiveness of breast cancer Sedentary lifestyle may increase risk Increased insulin resistance Inflammation Decreased immune function 87 Cancer Highlights Esophagus Risk factors include chronic alcohol use combined with smoking or chewing tobacco, hot and irritant (alcohol) drinks, food containing nitrosamines, and achalasia Frequent symptoms are chest pain and dysphagia Stomach Associated with atrophic gastritis and Helicobacter pylori Consumption of heavily salted and preserved foods, low intake of fruits and vegetables, and use of tobacco and alcohol Vague symptoms early such as loss of appetite, indigestion Later symptoms weight loss, upper abdominal pain, vomiting, change in bowel habits, and anemia Cancer Highlights Colon and rectum Family history of colorectal cancer Colorectal polyps Neoplastic polyps-usually benign Symptoms depend on the location, size, and shape of the lesion and are silent in the early stages Liver Usually caused by metastatic spread from a primary site elsewhere in the body History of Hep B or C Hepatocellular carcinoma Usually asymptomatic Cancer Highlights Pancreas Chronic pancreatitis and inflammatory cytokines support tumor growth When symptoms occur, there usually has been a malignant transformation Cervical cancer Almost always associated with HPV infection Other risk factors include multiple sexual partners, young age at first sexual intercourse, high parity, immunosuppression, oral contraceptives, use of nicotine PAP Usually slow progression Cancer Highlights Lung (bronchogenic) Most common cause is cigarette smoking Heavy smokers have a 20-times greater chance of developing lung cancer than nonsmokers Smoking is related to cancers of the larynx, oral cavity, esophagus, and urinary bladder Environmental or occupational risk factors are also associated Small cell general Brain tumors Primary brain tumors (gliomas) Low grade-good prognosis Glioblastoma Multiformevery aggressive Many brain tumors are from metastasis Question 1 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. Note: No input needed to proceed Question 2 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 Note: No input needed to proceed Question 3 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 Note: No input needed to proceed Question 4 1. Which of the following is TRUE regarding childhood cancer? A. Most cancers are carcinomas. B. Tumors of the nervous system are rare. C. The most common type of cancer is leukemia. D. The types of malignancies are similar to adult malignancies. Note: No input needed to proceed Question 5 2. Children with Down syndrome have an increased susceptibility to which type of cancer? A. Wilms B. Osteosarcoma C. Acute leukemia D. Retinoblastoma Note: No input needed to proceed