Chapter 11 Biology, Clinical Manifestations, and Treatment of Cancer
advertisement
Chapter 11 Biology, Clinical Manifestations, and Treatment of Cancer Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. Cancer Derived from Greek word for crab, karkinoma Malignant tumor Tumor Also referred to as a neoplasm—new growth Often the result of cellular injury Infection Environmental Genetic Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 2 Benign vs. Malignant Tumors Benign Grow slowly Malignant Grow rapidly Well-defined capsule Not encapsulated Not invasive Well differentiated Invasive Poorly differentiated Low mitotic index High mitotic index Do not metastasize Can spread distantly (metastasis) Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 3 Classification and Nomenclature Benign tumors Named according to the tissues from which they arise and include the suffix “–oma” • Lipoma • Glioma • Leiomyoma • Chondroma Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 4 Classification and Nomenclature Malignant tumors Named according to the tissues from which they arise • Malignant epithelial tumors are referred to as carcinomas Adenocarcinoma and basal cell carcinoma • Malignant connective tissue tumors are referred to as sarcomas Chondrosarcoma and osteosarcoma Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 5 Classification and Nomenclature Cancers of lymphatic tissue are lymphomas Cancers of blood-forming cells are leukemias 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 Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 6 Classification and Nomenclature Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 7 Classification and Nomenclature Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 8 Cancer Cells Transformation Cancer cell’s independence from normal cellular controls Anchorage independent Immortal Anaplasia • Pleomorphic Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 9 Cancer Stem Cells Stem cells self-renew Cell divisions create new stem cells Stem cells are multipotent Ability to differentiate into multiple different cell types Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 10 Tumor Markers Tumor cell markers (biologic markers) are substances produced by cancer cells or that are found on plasma cell membranes, in the blood, CSF, or urine Hormones Enzymes Genes Antigens Antibodies Can be increased by noncancerous as well as cancerous conditions Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 11 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 Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 12 Cancer-Causing Mutations Cancer is predominantly a disease of aging Clonal proliferation or expansion Due to a mutation, a cell acquires characteristics that allow it to have selective advantage over its neighbors • Increased growth rate or decreased apoptosis Multiple mutations required before cancer can develop Epigenetics DNA chemically modified but not mutated Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 13 Gene Mutations That Alter Growth Signals Growth factors (autocrine stimulation) secreted Increase in growth factor receptors Signal from cell-surface receptor is mutated in the “on” position Mutation in the ras intracellular signaling protein Inactivation of Rb tumor suppressor Activation of protein kinases that drive the cell cycle Mutation in the TP53 gene (tumor suppressor gene) Suppression of normal apoptosis Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 14 Oncogenes and Tumor Suppressor Genes Oncogenes Tumor suppressor genes Mutant genes that in their nonmutant state direct protein synthesis and cellular growth Encode proteins that in their normal state negatively regulate proliferation Also referred to as anti-oncogenes Proto-oncogene Normal nonmutant gene that codes for cellular growth Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 15 Mutation of Normal Genes Point mutations Chromosome translocation Changes in one or few nucleotide base pairs Piece on one chromosome is transferred to another Gene amplification Duplication of a small piece of chromosome over and over Results in an increased expression of an oncogene Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 16 Mutation of Normal Genes Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 17 Mutation of Normal Genes Mutation of tumor suppressor genes Loss of heterozygosity Allows unregulated cellular growth Both chromosome copies of a gene are inactivated Gene silencing Whole regions of chromosomes are shut off while same regions in other cells remain active Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 18 Mutation of Normal Genes Caretaker genes Encode for proteins that are involved in repairing damaged DNA Chromosome instability Increased in malignant cells Results in chromosome loss, loss of heterozygosity, and chromosome amplification Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 19 Angiogenesis Growth of new vessels Advanced cancers can secrete angiogenic factors to facilitate “feeding” the tumor Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 20 Telomeres and Immortality Body cells are not immortal and can divide only a limited number of times Telomeres are protective caps on each chromosome and are held in place by telomerase Telomeres become smaller and smaller with each cell division Cancer cells can restore telomeres, leading to continued division Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 21 Telomeres and Immortality Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 22 Genetics and Cancer Exposure to mutagens If the mutation occurs in somatic cells, it is not passed to progeny If the mutation occurs in germline cells, it can be passed to future generations Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 23 Genetics and Cancer Epigenetics Cancer-prone families Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 24 Inflammation and Cancer Chronic inflammation is an important factor in the development of cancer Causes cellular injury • Cytokine release from inflammatory cells • Free radicals • Mutation promotion • Decreased response to DNA damage Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 25 Bacterial Cause of Cancer Helicobacter pylori Chronic infections are associated with: • Peptic ulcer disease • Stomach carcinoma • Mucosa-associated lymphoid tissue lymphomas Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 26 Viruses and Cancer Implicated Hepatitis B and C viruses Epstein-Barr virus (EBV) Kaposi sarcoma herpesvirus (KSHV) Human papillomavirus (HPV) Human T cell leukemia–lymphoma virus (HTLV) Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 27 Tumor Spread Direct invasion of contiguous organs Metastases to distant organs Known as local spread Lymphatics and blood Metastases by way of implantation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 28 Tumor Spread: Overview Detachment and invasion Survival and spread in circulation Selective adherence Escape from circulation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 29 Local Spread Invasion Cellular multiplication • Mitotic rate vs. cellular death rate Mechanical pressure Release of lytic enzymes Decreased cell-to-cell adhesion Increased motility • Intravasation • Extravasation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 30 Three-Step Theory of Invasion Tumor cell attachment Degradation or dissolution of the matrix Fibronectin and laminin Enzymes Locomotion into the matrix Invadopodia (pseudopodia) Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 31 Metastasis Spread of cancer from a primary site of origin to a distant site Steps • Direct or continuous extension • Penetration into lymphatics, blood vessels, or body cavities • Transport into lymph or blood • Transport to secondary sites • Entry and growth in secondary sites Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 32 Angiogenesis Growth of cancerous colonies depends on an adequate blood supply Angiogenesis is the development of new blood vessels TP53 gene Proangiogenic factors Angiogenesis inhibitors Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 33 Distant Metastases Metastasis often occurs in the first capillary bed encountered by circulating cells Organ tropism Preferential growth of cancerous cells in certain organs • Growth factors, chemokines, hormones, tissue-selective homing receptors, and chemotactic factors Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 34 Staging Involves the size of the tumor, degree to which it has invaded, and extent of spread Stage 1 • Cancer is confined to its organ of origin Stage 2 • Locally invasive Stage 3 • Regional structures Stage 4 • Distant sites Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 35 Staging World Health Organization TNM system Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 36 Clinical Manifestations of Cancer 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, and inflammation Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 37 Clinical Manifestations of Cancer Fatigue 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 from circulating cytokines, secondary to disease and treatment, psychosocial factors, level of activity, nutritional status, and environmental factors Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 38 Clinical Manifestations of Cancer Syndrome of cachexia Most severe form of malnutrition Present in 80% of cancer patients at death Includes: • Anorexia, early satiety, weight loss, anemia, asthenia, taste alterations, and altered protein, lipid, and carbohydrate metabolism Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 39 Cachexia Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 40 Clinical Manifestations of Cancer Anemia A decrease of hemoglobin in the blood Mechanisms • Chronic bleeding resulting in iron deficiency, severe malnutrition, medical therapies, or malignancy in bloodforming organs Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 41 Clinical Manifestations of Cancer Leukopenia and thrombocytopenia Direct tumor invasion to the bone marrow causes leukopenia and thrombocytopenia Chemotherapy drugs are toxic to bone marrow Infection Risk increases when the absolute neutrophil and lymphocyte counts fall Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 42 Clinical Manifestations of Cancer Paraneoplastic syndromes Symptom complexes that cannot be explained by the local or distant spread of the tumor or by the effects of hormones released by the tissue from which the tumor arose Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 43 Treatment Chemotherapy Began with mustard gas in WWII Now extensive cancer chemo “cocktails” Induction chemotherapy Neoadjuvant Adjuvant Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 44 Chemotherapy Single-agent chemotherapy Combination chemotherapy Principle of dose intensity Therapeutic index Neoadjuvant chemotherapy Hormone therapy Receptor activation or blockage Interferes with cellular growth and signaling Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 45 Cancer Treatment Chemotherapy Use of nonselective cytotoxic drugs that target vital cellular machinery or metabolic pathways critical to both malignant and normal cell growth and replication Goal • Eliminate enough tumor cells so the body’s defense can eradicate any remaining cells Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 46 Cancer Treatment Chemotherapy Compartments • 1: cells undergoing mitosis and cytokinesis • 2: cells capable of entering the cell cycle in the G1 phase • 3: cells not dividing or that have irreversibly left the cell cycle Cells in compartment 3 will die a natural death Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 47 Cancer Treatment Ionizing radiation Damages cells by imparting enough ionizing radiation to cause molecular damage, especially to DNA-killing cancerous cells Causes irreversible damage to normal cells • Lifetime radiation dosage Brachytherapy Seed implants Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 48 Cancer Treatment Surgery Biopsy and lymph node sampling • Sentinel nodes Debulking surgery Palliative surgery Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 49 Treatment Surgery Must achieve adequate surgical margins (get it all) Must place needle tracks and biopsy incision scars (that may be contaminated with cancer cells) carefully so they can be removed in subsequent incisions Must avoid the spread of cancer cells during surgical procedures Must obtain adequate tissue specimens to confirm the diagnosis Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 50 Cancer Treatment Immunotherapy Theoretically, antitumor responses can selectively eliminate cancer cells while sparing normal cells Immune memory is long lived Numerous immunologic mechanisms are capable of rejecting different types of cancer Biologic response modifiers (BRMs) Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 51 Cancer Treatment Other forms of immunotherapy Interferon administration Antigens Effector cell lymphokines Monoclonal antibodies Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 52 Side Effects of Cancer Treatment Gastrointestinal tract Bone marrow Hair and skin Reproductive tract Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 53 Disease and Treatment Complications Pain Fatigue Cachexia Anemia Leukopenia and thrombocytopenia Infection Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc. 54
