Biology Of Cancer Chapter 10 PDF

Chapter 10 Biology of Cancer  Cancer  Diseases in which abnormal cells divide without control and are able to invade other tissues  Derived from Greek word for crab, karkinoma  Tumour Also referred to as a neoplasm—new growth Benign Versus Malignant Tum...

Chapter 10 Biology of Cancer  Cancer  Diseases in which abnormal cells divide without control and are able to invade other tissues  Derived from Greek word for crab, karkinoma  Tumour Also referred to as a neoplasm—new growth Benign Versus Malignant Tumours 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)  Classification and Nomenclature  Benign tumours Named according to the tissues from which they arise and include the suffix “-oma” Lipoma Leiomyoma Meningioma May progress to cancer  Classification and Nomenclature (Cont.)  Malignant tumours Named according to the tissues from which they arise Carcinoma  Epithelial tissue Adenocarcinoma  From ductal or glandular tissue Sarcoma  Mesenchymal tissue  Classification and Nomenclature (Cont.)  Malignant tumours Named according to the tissues from which they arise Lymphoma  Lymphatic tissue Leukemia  Blood-forming cells  Classification and Nomenclature (Cont.)  Carcinoma in situ (CIS) Preinvasive epithelial malignant tumours of glandular or epithelial origin that have not broken through the basement membrane or invaded the surrounding stroma 1. Which statement is TRUE? A. All neoplasms are cancerous. B. Benign growths are cancerous. C. Malignant tumours have slow growth. D. Cancer refers to a malignant tumour.  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 neighbours Increased growth rate or decreased apoptosis  Biology of Cancer Cells (Cont.)  Transformation of normal cells Decreased need for growth factors to multiply Lack contact inhibition Anchorage independence Immortality  Sustained Proliferative Signalling  Proto-oncogenes Normal genes that direct protein synthesis and cellular growth  Oncogenes Mutant genes  Tumour-suppressor genes Encode proteins that in their normal state negatively regulate proliferation Also referred to as anti-oncogenes  Sustained Proliferative Signalling (Cont.)  Oncogene activation Point mutation in RAS gene converts from regulated to unregulated Translocations Burkitt lymphomas Chronic myeloid leukemia Gene amplification  Sustained Proliferative Signalling (Cont.) From Haber, D.A. (2004). Molecular genetics of cancer. In D. C. Dale, & D. D. Federman, [Eds.]. ACP medicine. WebMD.  Evading Growth Suppressors  Mutation (inactivation) of tumour-suppressor genes Allows unregulated cellular growth Retinoblastoma (RB) gene Tumour protein p53 (TP53)  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  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  Genomic Instability (Cont.) A: Kumar, V., Abbas, A. K., & Aster, J. C. [Eds.].. Robbins and Cotran pathologic basis of disease [9th ed.]. Saunders. B, C: Courtesy Arthur R. Brothman, PhD, FACMG, University of Utah School of Medicine, Salt Lake City, UT. Telomeres and Immortality  Telomeres and Immortality (Cont.)  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  Angiogenesis  Growth of new blood vessels  Advanced cancers can secrete angiogenic factors (VEGF) Vascular endothelial GF Platelet-derived GF Basic fibroblast GF  Angiogenesis (Cont.) Reprinted with permission from Macmillan Publishers Ltd: Folkman, J. (2007). Angiogenesis: an organizing principle for drug discovery? Nature Reviews Drug Discovery 6, 273–286.  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 Activated by oncogenes and mutant tumour suppressors  Reverse Warburg effect  Resisting Apoptotic Cell Death  Apoptosis is programmed cell death. Self-destruction  Defects in intrinsic or extrinsic pathways provides resistance to apoptotic cell death. Resisting Apoptotic Cell Death (Cont.) From Kumar, V., et al. (2015). Robbins and Cotran pathologic basis of disease (9th ed.). Saunders.  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  Inflammation and Cancer (Cont.)  Tumour-associated macrophage (TAM) Key cells that promote tumour 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 tumour growth and spread.  Immune System and Cancer  Normal immune system protects against cancer  Immunosuppression fosters cancer Non-Hodgkin’s lymphoma (10×) Kaposi sarcoma (1000×) Release of immunosuppressive factors into the tumour microenvironment increases resistance of the tumour to chemotherapy and radiotherapy  Immune System and Cancer (Cont.) From Kumar, V., et al. (2015). Robbins and Cotran pathologic basis of disease (9th ed.). Saunders.  Viruses and Cancer  Implicated Hepatitis B and C viruses Epstein-Barr virus (EBV) Kaposi sarcoma herpesvirus (KSHV) Human papillomavirus (HPV) Human T-cell lymphotropic virus type 1 (HTLV-1)  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  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 favoured in foreign microenvironments  Epithelial–Mesenchymal Transition (EMT) (Cont.) Modified from Quail, D.F., & Joyce, J.A. (2013). Microenvironmental regulation of tumour progression and metastasis. Nature Medicine, 19, 1423-1437.  Local Spread  Invasion Cellular multiplication Mitotic rate versus cellular death rate Release of lytic enzymes Decreased cell-to-cell adhesion Increased motility  Distant Metastasis  Spread through vascular and lymphatic pathways  Selectivity of different cancers at different sites Breast cancer→bones Lymphomas→spleen  Dormancy  Clinical Manifestations of Cancer  Paraneoplastic Syndromes Triggered by cancer, but not caused by direct local effects of tumour Caused by biological substances released by tumour May be earliest symptom of unknown cancer Serious, irreversible and sometimes life-threatening  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 (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  Clinical Manifestations (Cont.)  Fatigue 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 (Cont.)  Anemia A decrease of hemoglobin in the blood Mechanisms: Chronic bleeding resulting in iron deficiency Severe malnutrition Medical therapies Malignancy in blood-forming organs  Clinical Manifestations (Cont.)  Leukopenia and thrombocytopenia Direct tumour invasion to the bone marrow causes leukopenia and thrombocytopenia. Chemotherapy medications are toxic to the bone marrow.  Infection Risk increases when the absolute neutrophil and lymphocyte counts fall.  Clinical Manifestations (Cont.)  Gastro-intestinal 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 is temporary Skin breakdown and dryness  Diagnosis  Manifestations based on site, tumour size  Diagnostic testing  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 primary tumour size and extent N for node involvement M for extent of distant metastasis TNM System 2. A patient has been diagnosed with prostate cancer that has metastasized to the bone. What stage of cancer does this represent? A. 1 B. 2 C. 3 D. 4  Tumour Markers  Tumour cell markers (biological markers) are substances produced by cancer cells that are found on or in tumour cells, in the blood, CSF, or urine Hormones Enzymes Genes Antigens Antibodies  Tumour Markers (Cont.)  Tumour markers are used to: Screen and identify individuals at high risk for cancer Diagnose specific types of tumours Observe clinical course of cancer  Problem: false positives and negatives  Histology  Tumours are classified based on immunohistochemical analysis of protein expression for improved treatment Supplemented by a more extensive genetic analysis of the tumours Enhanced molecular characterization subdivides cancers into therapeutically and prognostically relevant smaller groups Breast cancers  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 (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.  Chemotherapy  Induction chemotherapy Shrinkage or disappearance of tumours  Adjuvant chemotherapy Eliminate micrometastases after surgery  Neoadjuvant therapy Given before localized treatment to shrink tumour  Immunotherapy  Vaccines against oncogenic viruses provide protection and prevent the onset of viral-induced tumours.  Numerous potential therapeutic vaccines have been tested with little success.  Allogeneic cancer cell vaccines continue to be tested.  Cancer Treatment  Targeted disruption Used in combination with chemotherapy Highly specific Inactivate oncogenes Block angiogenesis Affect cell metabolism Induce apoptosis Neutralize cytokines/chemokines