BSN 2107-2012: WEEK 9 CANCER OVERVIEW Cancer is a heterogeneous set of many malignant diseases.

In Canada, the incidence and prevalence of cancer is steadily rising. On average, every week 3,075 Canadians will be diagnosed with cancer and 1,398 Canadians will die of cancer. Based on current incidence rates, 39% of Canadian women and 44% of Canadian men will develop cancer during their lifetime (Canadian Cancer Society, 2007). Cancer is fundamentally genetic and tumors occur when certain changes or mutations occur in genes. Environment and heredity interact to modify both the risk of developing cancer and the response to treatment (Huether & McCance, 2008).

ENDS-IN-VIEW Upon completion of the unit, the learner will be able to: y Define the terms tumor, neoplasia, cancer, benign, malignant, and carcinoma in situ. o Tumor is a growth of tissue caused by the uncontrolled replication of cells. Any swelling that is caused by inflammation. o Cancer refers to a malignant tumor. Cancer is the uncontrolled growth of abnormal cells in the body. o A benign tumor is a tumor that lacks the ability to metastasize (Is the spread of a disease from one organ to another non-adjacent organ). Which are not referred to as cancers, are made of fairly well-differentiated cells and well-organized stroma, the surrounding well-differentiated cells and well-organized stroma. o Neoplasia the abnormal proliferation of benign or malignant cells. o Malignant tumors are distinguished from benign tumors by more rapid growth rates and specific microscopic alterations, including loss of differentiation and absence of normal tissue organization. o Carcinoma in situ is an early form of cancer that is defined by the absence of invasion of tumor cells into the surrounding tissue, usually before penetration through the basement membrane. y Identify and differentiate among types of cancers based on cell type, such as adenocarcinoma, lymphoma, or sarcoma. o Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. o Lymphoma is a cancer of the lymphocytes, a type of cell that forms part of the immune system. Lymphomas present as a solid tumor of the lymphoid cells. o Sarcoma is a cancer that arises from transformed cells derived from embryonic mesoderm (is one of the three primary germ cell layers in the very early embryo). A Define the following and relate the terms to cancer cell growth and behaviour: autonomy, transformation, anchorage-independence, immortal, anaplasia, pleomorphic and clonal proliferation. o Growth signal autonomy, which means the cell grows even when it s not getting a message to grow; not paying attention to the stop signs, which means the cell ignores messages telling it to stop growing; evasion of apoptosis, which means a cell avoids all the messages that tell it to die; angiogenesis, which means the ability to grow new blood vessels. o Cancer cells are sometimes called as transformed cells, because they can be created from normal cells. Once transformed, cancer cells display distinct growth properties in the laboratory. o Cancer cells are often anchorage-independent; that is, they continue to divide even when suspended in a soft agar gel. Normal cells have a limited life span in the

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laboratory; they may divide in a petri dish 10 or 50 times, but then they cease growing. Lack of contact inhibition, and Cancer cells usually are immortal in that they seem to have an unlimited life span and will continue to divide for your under appropriate laboratory conditions. Anaplasia is the loss of structural differentiation within a cell or groups of cells. Malignant cells are also Pleomorphic, with marked variability of size and shape. They often have large darkly stained nuclei and mitotic cells are common. Clonal proliferation as a cell accumulates specific mutations; it can acquire, step by step, the charactristics of a cancer cell. Mutant cell may then have a selective advantage over its neighbors; its progeny can accumulate faster than its non-mutant neighbors as this is referred to as clonal proliferation.

Define stem cells, tumor markers and clonal proliferation. o Stem cells are biological cells found in all multicellular organisms that can divide (through mitosis) and differentiate into diverse specialized cell types and can self-renew to produce more stem cells. o A tumor marker is a substance found in the blood, urine, or body tissues that can be elevated in cancer, among other tissue types. Describe how the following mechanisms promote tumor growth: autocrine stimulation, increase in growth factor receptors, mutated cell-surface receptor, mutation in ras intracellular protein, and inactivation of Rb tumor suppressor. o Autocrine stimulation is a process whereby some cancers acquire the ability to secrete their own growth factors to stimulate their own growth. (platelet-derived growth factor [PDGF]). o Increase in growth factor receptors which are often receptor tyrosine kinases. (in some breast cancers the epidermal growth factor (EGF) receptor 2(ERBB2), also known as HER2/neu, is up-regulated and this sends growth signals into the cell even when growth factors are at very low levels). o mutated cell-surface receptor o inactivation of Rb tumor suppressor is part of a common mutation that subvert the antigrowth signal or, conversely, activation of the protein kinases that drive the cell cycle, the cyclin-dependent kinases. o Define and relate angiogenesis to cancer growth. o Angiogenesis the process of forming new blood vessels that occurs in the development of the embryo and fetus, tumor formation, and wound healing. Inflammation can promote the angiogenic response and is noted in such diseases as atherosclerosis, diabetes, arthritis, and cancer. If cancers are to grow larger than a millimeter in diameter, they need their own blood supply to deliver oxygen and nutrient. Describe the role of telomeres and telomerase in tumor development. o Telomeres is a regions of repetitive DNA at the end of a chromosome are shortened during each cycle of DNA replication; this shortening of the telomere is believed to be a component of cellular aging because it deletes vital genetic information over time. Telomeres protect a cell s chromosome form fusing with each other or rearranging and alterations can lead to cancer. Compare and contrast the gene products of proto-oncogenes, oncogenes, and tumor suppressor genes.

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Oncogenes are mutant genes that in their normal nonmutant state direct synthesis of proteins that positively regulate (accelerate) proliferation. o Tumor-suppressor genes encode proteins that is their normal state negatively regulate (halt, or put the brakes on) proliferation. Hence, they also have been referred to as antioncogenes. o In its normal, nonmutant state, an oncogene is referred to as a Proto-oncogenes. Describe how the following genetic events can activate oncogenes: point mutations, chromosome translocations, gene amplification, tumor suppressor gene mutation and loss of heterozygosity. o Oncogene activation mechanisms. Cellular genes may become cancerous oncogenes as a result of o Point mutations that alter one or a few nucleotide base pairs, causing the production of a protein that is activated as a result of the altered sequence (e.g., RAS) o Gene amplification a type of chromosome structural abnormality that can activate oncogenes is gene amplification. Resulting in higher levels of protein expression (e.g., MYCN in neuroblastoma) o Chromosomal translocation that either, lead to the juxtaposition of a strong promoter, causing increased protein expression (MYC in Burkitt lymphoma), or produce a novel fusion protein that is derived from gene fragments normally present on different chromosomes (BCR-ABL in chronic myeloid leukemia). o Tumor-suppressor genes are genes whose major function is to negatively regulate cell growth and prevent mutation. o Loss of heterozygosity for the function of a tumor suppressor to be lost, both chromosomal copies (alleles) of the gene must be inactivated. This is because they act in a recessive manner at the level of the cell. Describe gene silencing. o Silencing tumor-suppressor genes can be deactivated by a variety of mechanism. o First hit is a point mutation in a tumor-suppressor gene, followed by either epigenetic silencing or chromosome loss of the second allele, o Genes can normally be silenced by a variety of interacting processes including DNA methylation, histone modification, necleosomal remodeling, and microRNA changes. A number of cellular enzymes contribute to these modifications, including DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and complex nucleosomal remodeling factors (NURFs). Gene silencing is essential for normal development and differentiation. o Histone modification and promoter methylation regulate gene expression. Genes are transcribed when chromatin is modified by addition of acetyl (Ac) groups to specific lysine groups in histones. Gene expression can be turned off when specific acetyl group are removed (by HDACs) or when the CpG rich promoter regions of genes are modified by direct DNA methylation. o Changes in promoter methylation turn cancer genes off and on. Oncogenes can be turned on by promoter hypomethylation, and tumor-suppressor genes can be turned off by promoter hypermethylation. Each of these changes can produce selective growth and survival advantages of the cancer cell. Describe the role of chronic inflammation and cancer cell development. o Inflammation and cancer have much in common. In both cancer and inflammation (e.g., after injury and during infection), inflammatory cells, including neutrophils, lymphocytes, and macrophages, migrate to the site of injury and release cytokines and growth and o Page 3 of 7

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survival factors that stimulate local cell proliferation and new blood vessel growth to promote wound healing by tissue remodeling. Define mutagen and carcinogen. o The frequency of genetic changes can be increased by exposure to Mutagen, that is, agents causing mutations, and by defects in DNA repair. o A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or the disruption of cellular metabolic processes. Describe bacterial and viral causes of cancer. o Chronic infection with Helicobacter pylori (H. pylori) is an important cause of peptic ulcer disease and is strongly associated with gastric carcinoma, a leading casue of cancer deaths worldwide. o In humans, hepatitis B and C viruses (HBV, HCV), Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV) ( also known as HHV8), and human papillomavirus (HPV) are associated with about 15% of all human cancers worldwide. Describe the mechanisms that favour or inhibit local spread of cancerous cells. o Mechanisms important in local invasion include recruitment of macrophages and other cell typs to the primary tumor, where they promote digestion of connective tissue capsules and other structural barriers by secreted proteases; changes in cell-to-cell adhesion, often by changes in the expression of cell adhesion molecules such as cadherins and integrins, making the cancer cells more slippery and mobile; and increased motility of individual tumor cells. Describe the steps for metastatic spread. o Cancer cells must gain access to blood and lymphatic vessels, survive the trip to distant locations, move back into the tissues, and initiate a new tumor. Because each of these steps is required, the successful metastatic cell is rare compared with the huge numbers of cancer cells at the primary site. Consequently, metastasis usually only occurs late in cancer evolution. Describe the mechanisms of the following environmental factors in cancer development: tobacco use, ionizing radiation, ultraviolet radiation, alcohol consumption, sexual and reproductive behavior, physical activity, occupational hazards and exposure, air pollution, electromagnetic fields, and diet. o Cigarette smoking is carcinogenic and remains the most important cause of cancer. The risk is greatest in those who begin to smoke when young and continue throughout life. o Diet understanding dietary factors that increases the risk for cancer can be difficult. The ways in which diet affects one s likelihood of developing cancer are complicated by the variety of food consumed, the many constituents of foods, the metabolic consequences of eating, and the temporal changes in the patterns of food use. o Sexual and reproductive behavior: sexually transmitted infection with carcinogenic types of human papillomavirus (HPV), referred to as high-risk types of HPV, is required for the development of most cervical cancers. o Ultraviolet radiation sunlight causes basal cell carcinoma and squamous cell carcinoma (i.e., photocarcinogenesis), two common skin cancers found in white individuals. o Alcohol consumption chronic alcohol consumption is a strong risk factor for cancer of the oral cavity, pharynx, hypopharynx, larynx, esophagus, and liver. o Physical activity reduces the risk of breast and colon cancers and may reduce the risk of other cancers. Several biologic mechanisms causing this effect have been proposed and include decreasing insulin and IGF levels; decreasing obesity; increasing free radical Page 4 of 7

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scavenger system; altering inflammatory mediators; decreasing levels of circulating sex hormones and metabolic hormones; improving immune function; enhancing cytochrome. o Electromagnetic radiation; health risks associated with electromagnetic radiation (EMR) are very controversial. Exposure to electric and magnetic fields is widespread. EMRs are a type of nonionizing, low-frequency radiation without enough energy to pull electrons from their orbits around atoms and ionize the atoms. o Occupational hazards and exposure exposure to chemicals occurs every-day-they are present in air, soil, food, water, household products, toys, personal care products, workplaces, and home. o Air pollution; a person inhales about 20,000 L of air every day; thus even modest contamination of the atmosphere can result in inhalation of appreciable doses of pollutants. Describe the common clinical manifestations of cancer: anemia, leucopenia, thrombocytopenia, infection, paraneoplastic syndrome, fatigue, and pain. o Paraneoplastic syndromes are symptom complexes that are triggered by a cancer but are not caused by direct local effects of the tumor mass. A small fraction of carcinoid tumors release hormones, including serotonin, into the bloodstream that cause flushing, diarrhea, wheezing, and rapid heartbeat. o Pain is one of the most feared complications of advanced cancer. Although pain can be one of the presenting symptoms of cancer, most commonly there is little or no pain during the early stages of malignant disease. The diagnosis and treatment of pain is one of the primary responsibilities of the medical team. The individual s perception and, hence, reporting of pain can vary widely and be affected by such factors as age and cultural background. o Fatigue is the most frequently reported symptom of cancer and cancer treatment. The exact mechanisms that produce fatigue are poorly understood. Fatigue is described by individual with cancer as tiredness, weakness, lack of energy, exhaustion, lethargy, inability to concentrate, depression, sleepiness, boredom, lack of motivation, and decreased mental status. o Anemia is commonly associated with malignancy, with 20% of persons diagnosed with cancer having hemoglobin concentration less than 9g/dl. Mechanisms that cause anemia in person with cancer include chronic bleeding, severe malnutrition, cytotoxic chemotherapy, and malignancy in blood-forming organs. o Leukopenia and thrombocytopenia direct tumor invasion of the bone marrow cause both leukopenia (a decreased total white blood cell count) and thrombocytopenia (a decreased number of platelets). Thrombocytopenia is a major cause of hemorrhage in persons with cancer and is often treated with platelet transfusions. Thrombocytopenia also is an accompanying disorder of disseminated intravascular coagulation that occurs in persons with acute promyelocytic leukemia and severe infections. o Infection is the most significant cause of complications and death in persons with malignant disease. Describe the syndrome of cachexia. o The syndrome of cachexia includes a constellation of symptoms including anorexia, early satiety (filling), weight loss, anemia, asthenia (marked weakness), taste alterations, and altered protein, lipid, and carbohydrate metabolism. Cachexia is the most severe form of malnutrition associated with cancer and results in wasting, emaciation, and decreased quality of life. Page 5 of 7

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Compare and contrast the modalities for the treatment of cancer: chemotherapy, surgery, radiation, and immunotherapy. o Chemotherapy can be used for several distinct purposes. Induction chemotherapy seek to cause shrinkage or disappearance of tumors. In Hodgkin disease, chemotherapy alone can be used in some cases to cure the disease. In other setting, chemotherapy may shrink the tumor and improve symptoms without ultimately providing a cure. Adjuvant chemotherapy is given after surgical excision of a cancer with the goal of eliminating micrometasteses. Neoadjuvant chemotherapy is given before localized (surgical or radiation) treatment of a cancer. o Surgery is often the definitive treatment of cancers that do not spread beyond the limits of surgical excision. It is also indicated for the relief of symptoms. o Radiation therapy is used to kill cancer cells while minimizing damage to normal structures. Ionizing radiation damages cells by imparting enough energy to cause molecular damage, especially to DNA. o Describe common side effects associated with cancer treatment in the following systems: GI tract, bone marrow, integument, and reproductive tract. o Bone marrow suppression (a decreased ability of the bone marrow to manufacture blood cells) is a common side effect of chemotherapy. Chemotherapy affects not only cancer cells, but other rapidly dividing cells in the body as well. This includes the cells in the bone marrow that go on to become red blood cells (RBCs), white blood cells (WBCs), and platelets. o The entire GI tract relies on rapidly growing cells to produce an effective barrier to trauma and infection and to provide an absorptive surface for nutrients. Both chemotherapy and radiation therapy may cause a decreased cell turnover, thereby leading to oral ulcers (stomatitis), malabsorption, and diarrhea. o Alopecia (hair loss) results from chemotherarpy effects on hair follicles. Alopecia is usually temporary, although hair may regrow with a different texture initially.

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