Cancer Biology Disease States 2024 PDF

CANCER PATHOPHYSIOLOGY Aaron Hilliard Ph.D. Associate Professor College of Pharmacy & Pharmaceutical Sciences Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 1 1 CANCER Is derived from Greek word for “crab”— karkinoma. Is another name for malig...

CANCER PATHOPHYSIOLOGY Aaron Hilliard Ph.D. Associate Professor College of Pharmacy & Pharmaceutical Sciences Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 1 1 CANCER Is derived from Greek word for “crab”— karkinoma. Is another name for malignant tumor. Cancer is not a tumor. – Is an abnormal growth resulting from uncontrolled proliferation; it serves no physiologic function. – Is also referred to as a neoplasm: New growth. Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 2 BENIGN VERSUS MALIGNANT TUMORS Benign Malignant Slow growth Rapid growth Well-defined capsule Not encapsulated Not invasive Invasive Well differentiated Poorly differentiated: Anaplasia Low mitotic index High mitotic index Does not metastasize Can spread distantly (metastasis) Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 3 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 4 CLASSIFICATION AND NOMENCLATURE Benign tumors – Are named according to the tissues from which they arise and include the suffix, -oma. Lipoma: Fat Leiomyoma: Smooth muscle Colonic or Gastric polyps: colon or stomach Nevi: Melanocytes CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 5 5  CLASSIFICATION AND NOMENCLATURE (CONT.) Malignant tumors – Are named according to the tissues from which they arise. Malignant epithelial tumors: Carcinomas – Adenocarcinoma: Ducts or glands Malignant connective tissue tumors: Sarcomas Cancers of lymphatic tissue: Lymphomas Cancers of blood-forming cells: Leukemias CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 6 6 CLASSIFICATION AND NOMENCLATURE (CONT.) Carcinoma in situ (CIS) – Are preinvasive epithelial malignant tumors of glandular or squamous origin. – Have not broken through the basement membrane or invaded the surrounding stroma. – Are not malignant. – Three prognoses: 1. Can remain stable for a long time. 2. Can progress to invasive and metastatic cancers. 3. Can regress and disappear. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 7 7 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 8  CLASSIFICATION AND NOMENCLATURE QUESTION 1 A pharmacist learns that an individual has benign tumors. What does this mean? The tumors 1. are poorly differentiated. 2. are encapsulated. 3. may develop anaplasia. 4. may spread to a distant location. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 9 9 BIOLOGY OF CANCER CELLS Cancer is predominantly a disease of aging. Clonal proliferation or expansion occurs. – Is due to a mutation; that is, a cell acquires characteristics that allow it to have selective advantage over its neighbors. Increased growth rate or decreased apoptosis Multiple mutations are required before cancer can develop. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 10 10  BIOLOGY OF CANCER CELLS (CONT.) Mutation – Alteration in DNA sequence affecting expression or function of a gene – Point mutations: small-scale changes – Driver mutations: “drive” progression of cancer – Passenger mutations: random events Gene amplification – Repeated duplication of chromosome – 10s or 100s of gene copies made Epigenetic changes – DNA methylation, histone acetylation or altered expression of non-coding RNA CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 11 11 BIOLOGY OF CANCER CELLS (CONT.) Chromosome translocation – Large changes in chromosome structure – Piece of one chromosome is translocated to another chromosome. Burkitt’s Lymphoma- t(8:14) Chronic Myeloid Leukemia – Philadelphia Chromosome-t(9:22) Clonal proliferation (clonal expansion) – Cancer cell progeny can accumulate faster than nonmutant neighbors. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 12 12 BIOLOGY OF CANCER CELLS (CONT.) Malignant transformation – Is the process during which a normal cell becomes a cancer cell. – Heterogeneous mixture of cancer cells – Stroma: Tumor microenvironment Cancer heterogeneity: due to proliferation and mutation Cancer development is similar to wound healing. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 13 13 GENETICS, EPIGENETICS, AND TISSUE Environmental–lifestyle behaviors and genetic factors contribute to cancers. Cancer is driven by genetic alterations and changes in epigenetic regulation. Cancer development and progression involve tissue microenvironment or stroma. – Infiltrating immune cells cause chronic inflammation, creating a permissive tumor- progressing environment. Copyright © 2019, Elsevier Inc. All rights reserved. 14  GENETICS, EPIGENETICS, AND TISSUE (CONT.) Epigenetic processes influence cancer initiation, progression, and treatment. Factors that influence cancer risk – Detoxifying enzymes – DNA repair genes – Immune/inflammatory systems – Cell’s immediate environment – Metabolic/hormonal factors Copyright © 2019, Elsevier Inc. All rights reserved. 15 GENETICS, EPIGENETICS, AND TISSUE (CONT.) Copyright © 2019, Elsevier Inc. All rights reserved. 16 INCIDENT AND MORTALITY TRENDS Incident Trends Mortality Trends Overall cancer rates are higher Cancer deaths have decreased for men than women. in men, women, children. Highest cancer rates are found Liver cancer is most in Denmark. predominant cancer. Decline in lung cancer Mortality rates for men with correlates to decreased tobacco liver cancer are more than use. double the rate for women. Cancer rates have increased for ages 0–19. Copyright © 2019, Elsevier Inc. All rights reserved. 17 IN UTERO AND EARLY LIFE CONDITIONS Conditions that increase susceptibility to cancer include: – Prenatal and early life exposure – Parental exposures before conception – Nutrition and DES exposure – Gene and environment interactions Developmental plasticity: Degree to which development is contingent on its environment Reducing cancer risk must start early in life: Avoid sun exposure during peak hours, cover the skin, increase physical exercise, and avoid high-risk sexual practices. Copyright © 2019, Elsevier Inc. All rights reserved. 18 ENVIRONMENTAL–LIFESTYLE FACTORS Tobacco use – Cigarette smoking is carcinogenic and the most important risk factor for cancer. – Is linked to cancers of the lung, mouth, lips, nasal cavity and sinuses, larynx, pharynx, esophagus, pancreas, kidney, uterus, cervix, colon and rectum, liver, and acute leukemia. – Secondhand smoke: Environmental tobacco smoke (ETS) increases the risk for lung cancer. Copyright © 2019, Elsevier Inc. All rights reserved. 19 ENVIRONMENTAL–LIFESTYLE FACTORS QUESTION 1 Which statement indicates the pharmacist has an accurate understanding about the association between tobacco and cancers? “Tobacco use is associated with cancer of the 1. prostate.” 2. endometrium.” 3. esophagus.” 4. breast.” Copyright © 2019, Elsevier Inc. All rights reserved. 20 ENVIRONMENTAL–LIFESTYLE FACTORS Diet – Nutrigenomics: Is the study of nutrition on the phenotypic variability of individuals, based on genomic differences. – Primary dietary potential donors of DNA methylation include: Folate, choline, B vitamins. – Dietary factors Altered micro-ribonucleic acid (miRNA): Predisposes an individual to cancer. Suppress cancer stem cell renewal: Decreases the risk of cancer. – Consuming kiwi fruits, cooked carrots, or supplemental coenzyme Q10 improves DNA repair. Decreases the chance of cancer. Copyright © 2019, Elsevier Inc. All rights reserved. 21 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Diet (cont.) – Xenobiotic chemicals Toxic, mutagenic, and carcinogenic chemicals in food Activated by phase I activation enzymes – Primary substance: Cytochrome P-450 family Defense mechanisms – Phase II detoxification enzymes (liver) and antioxidants Glutathione-S-transferases (GSTs): Enzyme housekeepers that metabolize environmental carcinogens and reactive oxygen species (ROS) – If GSTs are lacking, then the risk for cancer is higher Diets high in red meats and processed meats: Colorectal cancer Copyright © 2019, Elsevier Inc. All rights reserved. 22 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Obesity – Is associated with endometrial, colorectal, kidney, esophageal, breast (postmenopausal), pancreatic, and several other cancers. – Correlates with the body mass index (BMI). – Energy expenditure involves resting metabolic rate, thermic food effects, and physical activity. – Causes a poorer outcome for some cancers. Copyright © 2019, Elsevier Inc. All rights reserved. 23 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Obesity (cont.) – Increases insulin resistance–producing hyperinsulinemia. – Insulin promotes insulin-like growth factor 1. – Adipose tissue secretes adipokines. – Circadian disruptions may affect cancer growth. Copyright © 2019, Elsevier Inc. All rights reserved. 24 Environmental–Lifestyle Factors (Cont.) Copyright © 2019, Elsevier Inc. All rights reserved. 25 ENVIRONMENTAL – LIFESTYLE FACTORS QUESTION 2 A nurse recalls that in women, obesity is associated with 1. small intestinal cancer. 2. prostate cancer. 3. lung cancer. 4. endometrial cancer. Copyright © 2019, Elsevier Inc. All rights reserved. 26 ENVIRONMENTAL–LIFESTYLE FACTORS Alcohol consumption – Is classified as a human carcinogen. – Increases the risk for oral cavity, pharynx, larynx, esophageal, liver, colorectal, and breast cancers. – A combination of cigarette smoking and alcohol consumption increases a person’s risk for malignant tumors. Copyright © 2019, Elsevier Inc. All rights reserved. 27 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Physical activity – Decreases the risk of cancer. Decreases insulin and insulin-like growth factors. Decreases obesity. Decreases inflammatory mediators. Decreases circulating sex/metabolic hormones Improves immune function. – Reduces the risk for breast, colon, and endometrial cancers, independent of weight changes. – After a cancer diagnosis, physical activity is associated with improved cancer-specific and overall survival with early-stage breast, prostate, and colorectal cancers. Copyright © 2019, Elsevier Inc. All rights reserved. 28 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Air pollution – Air pollution is linked to lung cancer. – Outdoor pollution: Smog and particle pollution Smog: Increases daily mortality. Particle pollution: Causes pulmonary inflammation, oxidative stress and oxidation of DNA, nonfatal heart attacks, irregular heartbeat, and decreased lung function. – Indoor pollution Is considered worse than outdoor pollution. Cigarette smoke, radon: Lung cancer Copyright © 2019, Elsevier Inc. All rights reserved. 29 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Ionizing radiation – Is emitted from x-ray machines, radioisotopes, and other radioactive sources. – Is associated with acute leukemias; increased frequencies of thyroid and breast carcinomas; lung, stomach, colon, esophageal, and urinary tract cancers, and multiple myeloma. – Enters cells and randomly deposits energy in tissues. Oncogene activation Tumor-suppressor genes deactivation Chromosomal aberrations and DNA damage Cell transformation Nontargeted/bystander effects Copyright © 2019, Elsevier Inc. All rights reserved. 30 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Ionizing radiation effects – Damage to organs with high proliferative cells (skin, GI systems) – Alters tumor microenvironment (immune system cells) – Long-term risk of developing other cancers (leukemia)/diseases Copyright © 2019, Elsevier Inc. All rights reserved. 31 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Copyright © 2019, Elsevier Inc. All rights reserved. 32  ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Ultraviolet radiation – Causes basal cell carcinoma, squamous cell carcinoma, and melanoma. – Skin cancer is the most commonly diagnosed malignancy in US. – Principal source is sunlight. Ultraviolet A (UVA) and ultraviolet B (UVB) Copyright © 2019, Elsevier Inc. All rights reserved. 33 ENVIRONMENTAL–LIFESTYLE FACTORS QUESTION 3 Which information is correct regarding ultraviolet light? Ultraviolet light causes 1. multiple myeloma. 2. basal cell carcinoma. 3. cervical cancer. 4. glioma. Copyright © 2019, Elsevier Inc. All rights reserved. 34 ENVIRONMENTAL–LIFESTYLE FACTORS Electromagnetic radiation – Is energy in the form of transverse magnetic and electric waves. – Microwaves, radar, mobile and cellular telephones, mobile telephone base stations, appliances, power frequency radiation associated with electricity and radio waves, fluorescent lights, computers, and other electric equipment – Question: Is electromagnetic radiation carcinogenic, especially for brain tumors (gliomas)? Conflicting research exists. Copyright © 2019, Elsevier Inc. All rights reserved. 35 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Infection: Is an important contributor to cancer. – Human papillomavirus (HPV): Cervical cancer – Hepatitis B and C together: Liver cancer – Helicobacter pylori: Stomach cancers – Epstein-Barr virus (EBV): Cancers of the nasopharynx and stomach, Hodgkin disease, and non-Hodgkin lymphoma – Human herpes virus type 8: Kaposi sarcoma – Human T-cell lymphotropic virus type 1: Leukemia and lymphoma Copyright © 2019, Elsevier Inc. All rights reserved. 36 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Sexual and reproductive behaviors and HPVs – HPV is the most common sexually transmitted virus. – HPV types 16 and 18 cause the majority of cancers. Are associated with cervical and anal cancers. Cause almost one-half of vaginal, vulvar, and penile cancers. Are recently associated with cancers of the oropharynx (soft palate, base of the tongue, tonsils). – HPV infects epithelial cells. Mutations lead to cancer. Copyright © 2019, Elsevier Inc. All rights reserved. 37 ENVIRONMENTAL–LIFESTYLE FACTORS (CONT.) Chemicals and occupational hazards – Substantial number of occupational carcinogenic agents exists. Asbestos: Mesothelioma and lung cancer Dyes, rubber, paint, aromatic amines: Bladder cancer Explosives, rubber cement, and dyeing industries: Leukemia Heavy metals Diesel exhaust – Many other chemicals and occupational hazards exist. Copyright © 2019, Elsevier Inc. All rights reserved. 38  ONCOGENES AND TUMOR-SUPPRESSOR Three key genetic mechanisms have a role in human carcinogenesis. GENES 1. Activation of proto-oncogenes, resulting in hyperactivity of growth-related gene products (called oncogenes) 2. Mutation of genes, resulting in the loss or inactivity of gene products that would normally inhibit growth (called tumor-suppressor genes) 3. Mutation of genes, resulting in an overexpression of products that prevent normal cell death or apoptosis, thus allowing continued growth of tumors CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 39 39  ONCOGENES AND TUMOR-SUPPRESSOR GENES (CONT.) Proto-oncogenes – Are normal nonmutant genes that code for cellular growth. Oncogenes – Are mutant genes that, in their nonmutant state, direct protein synthesis and cellular growth. Tumor-suppressor genes – Encode proteins that, in their normal state, negatively regulate proliferation. – Are also referred to as anti-oncogenes. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 40 40 ONCOGENES AND TUMOR- SUPPRESSOR GENES (CONT.) Oncogene activation CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 41 41 HALLMARKS (CHARACTERISTICS) Sustained Proliferative Signaling Evading Growth Suppressors OF CANCER Resisting cell death Genomic Instability (mutator phenotype) Enabling replicative immortality Tumor promoting inflammation Avoiding immune destruction Deregulatory cellular energetics Inducing angiogenesis Activating invasion and metastasis Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 42 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 43 SUSTAINED PROLIFERATIVE SIGNALING Secretion of growth factors (autocrine stimulation) Increase of growth factor receptors Mutation of the signal from cell surface receptor in the “on” position Mutation in the Ras intracellular signaling protein Activation of protein kinases that drive the cell cycle Single genetic event to activate oncogene – Point mutations- eg.RAS – chromosomal translocations- eg. BCR:ABL – gene amplifications- N-myc Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 44 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 45  EVADING GROWTH SUPPRESSORS Inactivation of loss of function genes to allow cancer to occur Also called anti-oncogenes Two genetic events (mutations) must occur to allow cancer to occur (2 copies of tumor suppressor gene) Mutation in RB (retinoblastoma) gene – Lead to persistent cell growth – Hyperphosphorylation- loss of RB function – Mutated in childhood retinoblastoma and lung, breast and bone cancers – Point mutation in one chromosome in one allele and loss of 13q14 region or epigenetic mechanisms in the other allele Mutation in the TP53 gene (tumor-suppressor gene) – Suppression of normal apoptosis “guardian of the genome” – Monitors intracellular signals related to cellular stress (induce stress activated kinases) and activates caretaker genes and suppress cell division. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 46 46 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 47  CARETAKER GENES Caretaker genes – Are responsible for the maintenance of genomic integrity. – Encode proteins that are involved in repairing damaged DNA, such as the damage that occurs with errors in DNA replication, mutations caused by ultraviolet or ionizing radiation, and mutations caused by chemicals and drugs. – Loss of function of caretaker genes leads to increased mutation rates. – Single mutation in germline cells results in transmission of cancer causing genes from one generation to next, producing families with high risk of specific cancers. Eg.BRCA1 and 2 mutations, RB mutations, p53 mutations, APC CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 48 48 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 49  GENOMIC INSTABILITY Increased tendency of alterations (mutability) in the genome during cell life cycle Mutations (inherited or acquired) in caretaker genes that protect genome and DNA repair increase genomic instability and risk of cancer – Eg. Hereditary Nonpolyposis colorectal cancer –DNA base pair mismatch repair defect Results from epigenetic silencing (modulation of gene function). – DNA methylation, histone modifications of chromatin – Changes alter gene promoter regions leading to silencing or altered gene expression CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 50 50  GENOMIC INSTABILITY (CONT.) Gene expression networks can be regulated by changes in miRNAs or miRs. Oncomirs are miRs that stimulate cancer development and progression. Chromosome instability in malignant cells CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 51 51  GENOMIC INSTABILITY (CONT.) Chromosome instability (CIN) also appears to be increased in malignant cells. – May be caused by malfunctions in the cellular machinery that regulates chromosomal segregation at mitosis. – Results in a high rate of chromosomal loss, as well as a loss of heterozygosity and chromosomal amplification; each of these events can accelerate the loss of tumor-suppressor genes and the overexpression of oncogenes. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 52 52 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 53 GENOMIC INSTABILITY QUESTION 2 Chromosome instability may result in the overexpression of 1. tumor-suppressor genes. 2. heterozygosity. 3. oncogenes. 4. point mutations. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 54 54 ENABLING REPLICATION IMMORTALITY (TELOMERES AND IMMORTALITY) Body cells are not immortal and can divide only a limited number of times (Hayflick limit). Telomeres: Are protective caps on each chromosome that are held in place by a telomerase. Telomeres become smaller and smaller with each cell division in normal cells. Cancer cells can activate telomerases, leading to continued division (>90% of cancers). CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 55 55 TELOMERES AND IMMORTALITY (CONT.) CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 56 56 ANGIOGENESIS Is the growth of new vessels. Is also called neovascularization. Access to blood supply is obligatory to growth and spread of cancer Advanced cancers can secrete angiogenic factors to facilitate feeding of the tumor. – Vascular endothelial growth factor (VEGF)- induced by oxygen sensitive HIF1alpha – Basic fibroblast growth factor (bFGF) CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 57 57 ANGIOGENESIS (CONT.) Process CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 58 58 REPROGRAMMING ENERGY METABOLISM (CANCER METABOLISM) Cancer cells perform glycolysis. – Allows lactate and its metabolites to be used for the more efficient production of lipids and other molecular building blocks needed for rapid cell growth. Activated by oncogene overexpression or loss of function of tumor suppressor gene – Reverse Warburg effect: cancer cells generate large amounts of ATP. Use OXPHOS CAFs use aerobic glycolysis to secrete metabolites cancer cells can use in OXPHOS to produce ATP Autophagy of CAFs- release materials needed by cancer cells to make new organelles CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 59 59 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 60 RESISTING CELL DEATH Apoptosis occurs as mechanism to self-destruct under conditions of tissue remodeling or as a protection against aberrant cell growth Extrinsic and Intrinsic pathways may trigger apoptosis Apoptotic pathways dysregulated in most cancers Most common loss of function mutation is TP53 Imbalance between pro-apoptotic and anti-apoptotic molecules. – Eg. Overexpression of Bcl-2 in B-cell lymphomas Down-regulation of caspases or production of caspase inhibitors Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 61 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 62  INFLAMMATION AS A CAUSE FOR CANCER Chronic inflammation: Is an important factor in the development of cancer. Active inflammation predisposes a person to cancer. – By stimulating a wound-healing response that includes proliferation and new blood vessel growth Causes-solar radiation, asbestos, pancreatitis, infection Susceptible organs – Gastrointestinal (GI) tract, pancreas – Thyroid gland – Prostate, urinary bladder – Pleura, skin CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 63 63  INFLAMMATION AS A CAUSE FOR CANCER (CONT.) Examples – Those with ulcerative colitis for 10 years or more have up to a 30-fold increase in developing colon cancer. – Hepatitis B (HBV) or hepatitis C (HCV) increase the risk of liver cancer. – H. pylori increases the risk of stomach cancer. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 64 64 INFLAMMATION AS A CAUSE FOR CANCER (CONT.) A tumor-associated macrophage (TAM) is the key cell that promotes tumor survival. – Develops the capacity to block cytotoxic T cell and natural killer (NK) cell functions. – Produces cytokines that are advantageous for tumor growth and spread. – Secretes angiogenesis factors. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 65 65 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 66 EVADING IMMUNE DESTRUCTION (IMMUNE SYSTEM AND VIRAL- ASSOCIATED CANCERS) Tumor associated antigens: oncogenes, antigens from oncogenic viruses, oncofetal antigens, and altered glycoproteins and glycolipids Immune surveillance hypothesis – Most developing malignancies are suppressed by an efficient immune response against tumor associated antigens Immunotherapy hypothesis – Immune system used to target tumor associated antigens and destroy the tumor clinically CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 67 67 IMMUNE SYSTEM AND VIRAL- ASSOCIATED CANCERS (CONT.) Immunotherapy can be either active or passive. – Active: Immunization with tumor antigens to elicit or enhance the immune response against a particular cancer – Passive: Injecting the patient diagnosed with cancer with antibodies or lymphocytes directed against the tumor-associated antigens Sipuleucel T CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 68 68 IMMUNE SYSTEM AND VIRAL- ASSOCIATED CANCERS (CONT.) Several viruses have been associated with human cancer (account for 15% of cancers worldwide). – Human papillomavirus (HPV 16, 18, 35 and 41)-cervical cancer – Epstein-Barr virus (EBV)- Burkitts lymphoma (t(8:14)) – Kaposi sarcoma herpesvirus (KSHV or HHV8)- linked to immunocompromised groups that develop cancerous lesions on skin or mucous surface including lungs, nasal and oral cavities – Human T-cell lymphotropic virus type I (HTLV-1)- adult T-cell Leukemia – Hepatitis B (HBV) and C (HCV)-liver cancer CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 69 69 EVADING IMMUNE DESTRUCTION (IMMUNE SYSTEM AND VIRAL- ASSOCIATED Promote environment of tissue repair, neovascularization and proliferation CANCERS) Abundance of Tumor infiltrating lymphocytes (T-reg cells) and decrease in natural killer cells – Prevent a destructive antitumor immune response Immunosuppressive cytokines –IL-10 and TGF-beta – Provide cytokines that promote cell proliferation and spread Increase in T-reg cells correlate with poor outcomes in breast and GI tumors Elevated Treg to Tcyto ratio –poor response for NSCLC platinum cpd chemotherapy CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 70 70 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 71 CANCER INVASION AND METASTASIS Metastasis: The spread of cancer cells from the site of the original tumor to distant tissues and organs through the body. Is a complex process that requires cells to have many new abilities. – Spread – Survive – Proliferate in distant locations – Destination must be receptive to growth of cancer Eg. Breast cancer (CXCR4) attracted to lung (CXCL12) CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 72 72 CANCER INVASION AND METASTASIS (CONT.) Epithelial-mesenchymal transition (EMT) – Many epithelial-like characteristics (e.g., polarity, adhesion to basement membrane) are lost. – Migratory capacity increases. – Resistance to apoptosis increases. – Dedifferentiation to a stem cell-like state favors growth in foreign microenvironments and the establishment of metastatic disease. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 73 73 CANCER INVASION AND METASTASIS (CONT.) Invasion: Local spread – Is a prerequisite for metastasis and the first step in the metastatic process. – Cancer often spreads first to regional lymph nodes through the lymphatic system and then to distant organs through the bloodstream. – Invasion then requires that the cancer attach to specific receptors and survive in the specific environment. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 74 74  CANCER INVASION AND METASTASIS (CONT.) Cancer cells (via TAMS & CAFS) secrete protease and protease activators. Proteases digest the extracellular matrix and basement membranes. – Create pathways through which cells can move. Metastatic cells must be able to withstand the physiologic stresses of travel in the blood and lymphatic circulation. – Platelets and clotting factors – Myeloid derived suppressor cells (MDSCs) Metastatic cells must then survive in a new environment. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 75 75 CANCER INVASION AND METASTASIS (CONT.) CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 76 76 CANCER INVASION AND METASTASIS QUESTION 3 Epithelial-mesenchymal transition (EMT) produces which result? 1. Increased resistance to apoptosis 2. Adherence to basement membranes 3. Decreased migratory capacity 4. Promotion of angiogenesis CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 77 77  CLINICAL MANIFESTATIONS OF CANCER Paraneoplastic syndromes – Symptom complexes are triggered by a cancer but are not caused by direct local effects of the tumor mass. – Are caused by biologic substances released from the tumor (e.g., hormones) or by an immune response triggered by the tumor. – Can be life-threatening. – Examples: Small Cell Lung Cancer –Increase in ACTH leads to Cushing Disease Bronchial adenoma-Increase in serotonin and bradykinin-induces Carcinoid Syndrome Hepatocellular Carcinoma-Increase in insulin or IGF-hypoglycemia CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 78 78 CLINICAL MANIFESTATIONS OF CANCER Anemia (CONT.) – Commonly associated with malignancy. – Hemoglobin concentration < 9g/dL – Mechanisms of anemia Chronic bleeding, severe malnutrition, cytotoxic chemotherapy and malignancy in blood forming organs. – Eg. Colorectal or genitourinary malignancy Iron malabsorbed in patients with gastric pancreatic, or upper intestinal cancer Bone Density Loss – Osteoporosis or severe osteopenia due to 2o hormone or steroid treatment F CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 79 79 CLINICAL MANIFESTATIONS OF CANCER (CONT.) Fatigue – Most frequently reported and persistent symptom – Causes: sleep disturbances, chronic inflammation, anemia, depression, level of activity, nutritional status, environmental and physical factors Gastrointestinal Tract – Sensitive to radiation and chemotherapy – Cause malabsorption, diarrhea and infection risk Hair Loss (alopecia) and skin – Temporary hair loss and skin breakdown and dryness CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 80 80 CLINICAL MANIFESTATIONS OF CANCER (CONT.) Cachexia – Is the most severe form of malnutrition. – Leads to protein-calorie malnutrition and progressive wasting. Due ↑ peroxisome proliferator gamma co-activator protein (PGC-1)→ ↑Ca2+ dysregulation Increased apoptosis and impaired capacity to regenerate – Manifestations Anorexia, early satiety, weight loss, anemia, asthenia, taste alterations, and altered protein, lipid, and carbohydrate metabolism CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 81 81 CLINICAL MANIFESTATIONS OF CANCER Infection (CONT.) – Is the most cause of complications and death – Immunosuppression, lymphopenia and granulocytopenia due to cancer or treatment increase risk of serious bacterial and fungal infections. – Prevalence of hospital (nosocomial) acquired increases due to indwelling medical devices, inadequate wound care and introduction of microorganisms from visitors Infertility – 2o to cancer, surgery, radiation or chemotherapy – Freeze, eggs or embryos prior to therapy CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 82 82 CLINICAL MANIFESTATIONS OF CANCER Leukopenia and(CONT.) Thrombocytopenia – Low white blood cell and platelet counts (lead to hemorrhage) – Caused by chemotherapy drugs and radiation since toxic to bone marrow Lymphodema – Fluid accumulation in tissues results from damage to lymphatic system from lymphoid cancer or metastatic disease, surgery or radiation treatment Pain – May occur early in disease but increases with progression – Due to direct pressure, obstruction, invasion of sensitive structure, stretching visceral surfaces, tissue destruction, infection and inflammation – Chronic pain due to nerve damage secondary to surgery, chemotherapy or radiation CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 83 83  CLINICAL MANIFESTATIONS OF CANCER (CONT.) Diagnosing and staging – Involves the size of the tumor, the degree to which it has invaded, and the extent of the spread. Stage 1 – Is confined to its organ of origin. Stage 2 – Is locally invasive. Stage 3 – Has advanced to regional structures. Stage 4 – Has spread to distant sites. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 84 84  CLINICAL MANIFESTATIONS OF CANCER (CONT.) Staging using the World Health Organization TNM system CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 85 85 CLINICAL MANIFESTATIONS OF CANCER QUESTION 4to regional structures is in which Stage? A tumor that has advanced 1. Stage 1 2. Stage 2 3. Stage 3 4. Stage 4 CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 86 86 TUMOR MARKERS Are substances produced by benign or malignant cells. Are found on or in a tumor cell, in the blood, in the spinal fluid, or in urine. – Hormones – Enzymes – Genes – Antigens – Antibodies CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 87 87  TUMOR MARKERS (CONT.) Liver and germ cell tumors – Secrete a protein known as alpha fetoprotein (AFP) into the blood. Prostate tumors – Secrete prostate-specific antigen (PSA) into the blood. If a tumor marker, itself, has biologic activity: – Symptoms are expressed. – A phenomenon known as a paraneoplastic syndrome occurs. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 88 88 TUMOR MARKERS (CONT.) Tumor markers are used to – screen and identify individuals at high risk for cancer. – diagnose specific types of tumors. – follow the clinical course of cancer. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 89 89 TUMOR MARKERS QUESTION 5 Which factor indicates a recurrence of prostate cancer? 1. Decrease in PSA 2. Increase in PSA 3. False negative 4. False positive CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 90 90 SURGERY Is a definitive treatment of cancers that do not spread beyond the limits of surgical excision. Palliative: Is indicated for the relief of symptoms. In selected high-risk diseases, surgery plays a role in the prevention of cancer. – Mutations of the APC gene have close to a 100% lifetime risk of colon cancer: Colectomy. – Women with BRCA1/2 mutations have a significantly increased risk of breast and ovarian cancer: Prophylactic mastectomy or bilateral salpingo-oophorectomy or both. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 91 91 SURGERY (CONT.) Must achieve adequate surgical margins; that is, surgery must get it all. Surgeon provides critical staging information. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 92 92 RADIATION THERAPY Is used to kill cancer cells while minimizing the damage to normal structures. Ionizing radiation – Damages cells by imparting enough ionizing radiation to cause molecular damage to the DNA. – Causes irreversible damage to normal cells. Lifetime radiation dose Brachytherapy – Seeds are implanted. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 93 93 CHEMOTHERAPY Eradicates enough tumor cells to enable the body’s natural defenses to eradicate the remaining cells. Can be a single-agent or combination chemotherapy. Induction chemotherapy: Causes shrinkage or the disappearance of tumors. Adjuvant chemotherapy: Is administered after the surgical excision with a goal of eliminating micrometastases. Neoadjuvant chemotherapy: Is administered before localized (surgical or radiation) treatment. CopyrightCopyright © 2019, © 2014, 2010, 2006Elsevier Inc.Inc., by Mosby, All an rights reserved. imprint of Elsevier Inc. 94 94 Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 95 CELL CYCLE NON-SPECIFIC DRUGS Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 96 IMMUNOTHERAPY Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 97 TARGETED THERAPY Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 98  REFERENCES McCance: Pathophysiology, 8e DiPiro: Pharmacotherapy A Pathophysiological Approach, 12e Accesspharmacy. Mhmedical.com Dr. Selina Darling-Reed Copyright © 2014, 2010, 2006 by Mosby, Inc., an imprint of Elsevier Inc. 99