Module 8
Learning Objectives
1) Describe the classification of tumors. 2) Define many of the important terms used to describe the biology of cancer. 3) Compare and contrast the characteristics of benign and malignant tumors. 4) Discuss the mechanisms of cell transformation and differentiation. 5) Describe the roles of cancer staging and measurement of tumor markers in the care of individuals with cancer. 6) Discuss the role of genetic mutation, oncogenes, and tumor suppressor genes in the pathogenesis of cancer. 7) Describe the mechanisms by which viruses and bacteria may contribute to the biology of cancer. 8) Discuss some of the frequently used diagnostic modalities for cancer. 9) Discuss the mechanisms of tumor spread into local tissues. 10) Describe the three-step theory of invasion. 11) Describe the clinical manifestations of cancer. 12) Describe the basic concepts of cancer treatment and the selected side effects.
Read Chapters 1, 2 and 4, in your textbook.
1. What are the structure and function of cellular components? Nucleus contains genetic material and is necessary for cell division. Lysosome contains digestive material (Hydrolases). Cell cytoplasm provides enzymes necessary for intermediate metabolism. 2. How do cells proliferate? 3. How do cells adhere to, communicate with, and form tissue? Cell to cell adhesion. Calcium provided a second messenger pathway for cellular communication. Cells can also communicate through protein channels. 4. How are DNA, RNA, and protein structured? 5. How does protein synthesis occur? ribosomes are RNA- protein complexes that provide sites for cellular protein synthesis 6. What are some common chromosome aberrations and associated diseases? Down Syndrome- an autosomal aneuploidy chromosome aberration Hyperplasia- increase in cell number Triploidy- Zygote has three copies of each chromosome Klinefelter Syndrome- a sex chromosome aneuploidy chromosome aberration atrophy-cells decrease in size Metaplasia-reversible replacement of one mature cell type by another less mature cell type. 7. How do cells adapt to their environment to protect themselves from injury?
How is alcohol consumption linked to cancer risk?
According to the International Agency for Cancer Research, alcohol is considered a human carcinogen and contributes to a number of common cancers. Refer to Table 13-5 in the textbook to see the associated risks of different types of cancer and alcohol consumption. Alcohol consumption can also interact with smoking to increase the risk for lung cancer. Proposed mechanisms of alcohol-related carcinogenesis are complex and include: Epigenetic alterations Carcinogenic effects of acetaldehyde Increase in nitrosamines Nutritional deficiencies
What role does angiogenesis play in tumor growth?
Angiogenesis is the process by which cancer cells can stimulate the growth of blood vessels and thus increase nutrient and oxygen delivery to the growing tumor. This neovascularization is stimulated by oncogene production of growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (BFGF). Anti-angiogenic treatments are now available for certain human cancers.
What are the characteristics of benign tumors?
Benign tumors are not cancers. However, it is important to note that the location of a benign tumor can affect an individual's health. Benign tumors share several defining characteristics: Benign tumors usually display slow growth. They are surrounded by a capsule that separates the tumor from the surrounding tissue. The cells in a benign tumor are well differentiated, which means that the cells look relatively mature and resemble the healthy cells from which the tumor first developed. Benign tumors do not invade surrounding tissues (although benign tumor growth may compress nearby healthy tissue). They do not metastasize to lymph nodes or other tissues. A benign tumor is usually named according to the tissue from which it arises and includes the suffix "-oma."
What are the environmental and nutritional needs of cancer cells?
Cancer cells often grow in a hypoxic and acidic environment. Even in the presence of oxygen, cancer cells perform glycolysis. This shift from mitochondrial oxidative phosphorylatin (OXPHOS) allows lactate and its metabolites to be used for the more efficient production of lipids and other molecular building blocks needed for rapid cancer cell growth. In addition, many cancer genes, including receptor tyrosine kinases (for example, MYC) inhibit OXPHOS and promote glycolysis and associated metabolic pathways that support cancer growth. Cancer cells also have different nutritional requirements from normal cells. They behave as parasites and selectively extract nutrients from the bloodstream. The high glucose utilization of cancer can be utilized to detect cancerous tumors. For example, the positron emission tomography (PET scan) is able to detect even small metastatic tumor masses that consume large amounts of glucose.
What are the definitions of the terms carcinoma, sarcoma, lymphoma, and leukemia?
Cancers are named according to the tissues from which they arise. Cell of Origin Type of Cancer Epithelial: Carcinomas Squamous cell carcinoma- Adenocarcinoma- arise from ductal or glandular structures such as breast tissue Connective tissue: Sarcoma such as cancer of skeletal muscle called rhabdomyosarcomas Lymphoid tissue: Lymphoma Blood-forming cells: Leukemia Germ cells: Teratocarcinoma ,Teratoma Refer to Table 12-2 in your textbook to see a classification of selected tumors based on tissue of origin.
What are ways that cancer cells can increase their rate of division?
Carcinogenesis is a process that results from mutations of the genes that control cell division and tissue growth. These mutations lead to an imbalance between pro-growth signals and anti-growth signals. An increase in pro-growth signals derives from mutations of proto-oncogenes into oncogenes that result in several mechanisms that promote cellular replication and tumor growth. Cancers can become addicted to their mutant cancer genes, a phenomenon known as oncogene addiction. A decrease in anti-growth signals (anti-oncogenes) derives from mutations of tumor suppressor genes that result in an inability of the cell to respond to both extracellular and intracellular anti-growth and apoptotic signals. Refer to Table 12-4 to see a comparison of cancer gene types and then view the animation on Six Hallmarks of Cancer to have a better understanding of the different pathways that lead to cancer.
What are telomeres and telomerase, and how do they influence cell death?
Cellular chromosomes are capped with protective ends called Glossary Telomeres. Cell division results in a gradual fragmentation of these telomeres. Once the protective telomeres are lost, the cell's chromosomes begin to disintegrate and the cell dies, thus limiting cell replication. Germ and stem cells have an enzyme called telomerase that rebuilds and maintains the protective telomeres, thus providing these cells with the capacity for unlimited replication. Cancer cells reactivate the genes for telomerase and therefore regain the capacity for unlimited cell divisions. This is why malignant cells are often referred to as "immortal." The capacity for unlimited replication and increased nutrient supply is crucial for clinical tumors to develop. However, it is the ability to invade tissues and to metastasize that makes malignancies so dangerous and difficult to treat. Mutations that result in decreased cell-to-cell adhesion and communication and the ability to secrete digestive enzymes into surrounding tissues are some examples of this kind of pro-growth signal in cancer cells.
Methylation of Histones Another pathway for methylation to affect genetic activity is via histone involvement. Histones are proteins which package and order DNA into structural units. They act as spools around which DNA winds. The configuration of the DNA around the histones determines which part of the DNA is available for transcription and therefore controls cellular activity. Methyl groups can attach to the histones, which leads to DNA unwinding. This can affect how genes are expressed, and potentially contribute to cancer development.
Changes in microRNAs, Oncomirs, and Non-coding RNA's Gene expression networks are regulated by changes in microRNA's (miRNAs or miRs) and other non-coding RNAs (ncRNAs). MicroRNAs are small pieces of RNA derived from genes that were once thought to be nonfunctional. These miRNAs control gene function by forming what are called RNA-induced silencing complexes (RISCs). In some cancers, a deletion of these RISCs results in deregulation of cell division. The miRNAs that lead to cancer development are referred to as oncomirs.
How does inflammation and alterations in the immune system increase the risk of cancer?
Chronic inflammation increases the risk of cancer by increasing cell divisions in an effort to repair damaged tissues. Chronic inflammation is also associated with the release of potentially toxic substances such as oxygen radicals, prostaglandins, and some interleukins. Inhibition of inflammation by some anti-inflammatory medications (e.g., ibuprofen) has been associated with a decreased risk for certain cancers. Individuals with immunosuppression are at higher risk for cancer than those with intact immune systems. Cellular immunity plays a role in detecting and destroying cancer cells. New treatments aimed at restoring the anti-cancer immune responses include infusion of immune cytokines, such as interferon, and the administration of specific immune-stimulants, such as tumor vaccines. Infection Microorganisms can contribute to oncogenesis by two primary mechanisms: Viral replication can damage the host DNA (mutagenesis) Virus- or bacteria-induced inflammation with increased replication of host cells leading to increased likelihood for random mutation (mitogenesis) HPV, Hepatitis B, H. pylori See Tables 12-6 and 12-7 in the textbook to view a list of human viruses, chronic inflammatory conditions, and infectious agents associated with neoplasms.
How do tumor cells lose their normal cell-to-cell adhesion?
Decreased cell to cell adhesion and cancer motility Healthy cells have surface glycoproteins that help them communicate with one another and regulate cell attachment and proliferation. Cancer cells have alterations in these molecules (e.g., fibronectin) that alter their normal adhesion to neighboring cells and allow them to move. Malignant cells can intravasate into blood vessels and then extravasate into secondary sites. One of the factors that has been identified that contributes to cancer cell motility is called autotoxin. This and other motility factors can be released from the cancer cell to stimulate its own (autocrine) receptors and allow it to have the motility necessary for tissue invasion and metastasis.
What is the relationship between in utero and early life conditions and the development of cancer during an individual's lifespan?
Developmental plasticity is the degree to which an organism is dependent upon its environment. It requires stable gene expression that in part appears to be modulated by epigenetic processes such as DNA methylation, histone modification, and micro-RNAs. There is a growing body of knowledge that suggests that events in utero and early in life play a major role in an individual's susceptibility to a variety of disease, including cancer. There may be a long latency period; however, it is increasingly clear that diet and other environmental changes that occur in utero or early childhood may affect the individual later in life. Refer to Tables 13-2 and 13-3 for examples of transgenerational effects related to epigenetic effects that can occur in the developmental environment. Elements of the maternal diet, drugs, or accidentally ingested and/or inhaled toxins can be delivered to the embryo through the placenta. The administration of diethylstilbestrol (DES) between 1938 and 1971 is one of the best examples of how a drug given during pregnancy can lead to future cancer. Click on the link below to learn about DES and cancer.
What are some of the known dietary risk factors for cancer?
Dietary factors affect many pathways to cancer, including inflammation and the immune response, differentiation, carcinogen metabolism, DNA repair, gene silencing, apoptosis and cell cycle control. Many of these processes are most likely determined by DNA methylation, an epigenetic mechanism that affects gene function It is more difficult to directly link diet to cancer risk, but there is good evidence that the following substances are carcinogenic to some cells. Xenobiotics (synthetic chemicals that may be found in foods) Polycyclic aromatic hydrocarbons (organic residue contaminants found in some cooking oils and foods, particularly those that use drying or smoking processes) Nitrosamines (e.g., cured meats) Aflatoxins (from mold contamination, such as Aspergillus species) Humans have several protective enzymes that can detoxify carcinogens, and the incidence of disease may differ in populations with similar diets because of differing genetic abilities to produce these protective substances. It has been suggested that antioxidants are anti-carcinogenic, but clinical trials have been mostly disappointing, and some have even found increased antioxidant intake to be harmful.
What do the terms anaplasia, stem cells, and undifferentiated mean?
Differentiation is the specialized process of a cell acquiring the structure and function necessary to become a normal cell. A cancer cell loses normal differentiation and becomes anaplastic, or without form. The more malignant a tumor, the higher the degree of anaplasia. Other characteristics of a transformed cancer cell include: Autonomy in which growth pattern is independent from normal cellular controls. Loss of contact inhibition where the cancer cells continue to divide and move without any boundaries. Anchorage independent, thus not needing to attach to a firm surface to grow. Immortal in that their life span is unlimited and they multiply for years under the right laboratory conditions. Different environmental and nutritional requirements from normal cells. Pleomorphic, or vary in size and shape. Tissues that require frequent renewal (e.g., skin, intestines, bone marrow) must contain cells capable of rapid proliferation in order to maintain normal tissue function. The cells most capable of rapid proliferation in these tissues are called adult stem cells. Stem cells not only undergo frequent cell division, they are also capable of differentiating into several cell types (multipotent). Furthermore, stem cells can divide asymmetrically (i.e., during division the cytoplasmic contents are unevenly distributed between the daughter cells); they can give rise to another stem cell and one daughter cell that ultimately terminally differentiates into diverse cell types, depending on the needs of the tissue (See image).
Learning Objectives- 8b
Discuss the interaction among genes, lifestyle, the environment and the development of cancer. Identify cancer incidence and mortality trends. Describe epigenetics and genetics in cancer epidemiology. Discuss the role of tobacco use in the development of cancer. Identify how diet influences cancer and cancer growth. Discuss the relationship between alcohol consumption and the development of cancer. Describe the biological mechanisms associated with obesity and cancer. Describe the role of radiation in cancer epidemiology. Identify the factors in sexual and reproductive behavior that are risk factors for cancer. Discuss the role of physical activity in reducing the risk for cancer. Identify occupational hazards that increase the risk for cancer. Discuss how air pollution leads to cancer.
What is epigenetic silencing?
Epigenetics controls gene activity in several different ways. The most important control of gene expression is called DNA methylation. Gene silencing is usually carried out by the binding of a methyl molecule to parts of the DNA that control gene activity. This process of DNA methylation turns off genes that are not needed. Some cancer cells have areas of DNA methylation that extend beyond the normal genes and silence important tumor-suppressor genes. The process by which too many tumor suppressor cells are silenced is called hypermethylation. Although tumor-suppressor gene mutations must be homozygous for the anti-growth signal to be lost, methylation can silence one of the normal alleles, thus unmasking a mutation at the other allele. Alternatively, some cancer cells are characterized by a lack of adequate silencing of growth promoting proto-oncogenes, thus stimulating excess cellular division. The process by which there is inadequate methylation of proto-oncogenes is called hypomethylation.
What types of chemicals and occupational hazards increase the risk of cancer?
Exposure to chemicals occurs daily. These chemicals are present in air, soil, food, water, household products, toys, personal care products, workplaces, and homes. Chemical carcinogenesis involves both genotoxic mechanisms and non-genotoxic effects (epigenetic alterations) on cells. Refer to Table 13-1 in the textbook to see a summary of the chemicals that may be potentially carcinogenic. Occupational exposures are most strongly linked to cancers of the lung, bladder, hematologic system, and peritoneum. Asbestos - Perhaps the best-known occupational hazard is asbestos and its strong link to lung cancer and Glossary mesothelioma. Significant exposure to asbestos plus heavy cigarette smoking has been estimated to increase the risk of lung cancer by as much as 90 times that of the nonsmoking population. Carcinoma of the bladder - It has been linked to dyes, paints, and other industrial compounds such as benzidine. Glossary Leukemia - It has also been linked to many of these same substances. Many other potential carcinogens have been identified in occupational settings. The Occupational Safety and Health Administration (OSHA) works to reduce the risk of harmful exposures in the workplace.
Three Steps of Tumor Invasion
For a tumor cell to invade tissues, it must: Attach to laminin receptors in the basement membrane Clear a path through the surrounding tissues and basement membrane via the production of lytic enzymes such as proteases and collagenases Move into the surrounding tissue
Read Chapter 12, pages 395-398 in your textbook.
How do most chemotherapeutic agents work? Most chemotherapeutic agents target all rapidly dividing cells and therefore have significant toxicity to all tissues, especially healthy tissues that also have high replication rates, such as the gastrointestinal tract, bone marrow, hair, skin, and reproductive tract. Because even healthy, dividing cells are affected by chemotherapeutic agents, normal tissues can be affected by the toxicity of the chemotherapeutic agents.
Read Chapter 12, pages 387-392 in your textbook.
How does cellular multiplication contribute to local tumor spread? Local spread of cancer or invasion is the first step in the progression of cancer. Several mechanisms facilitate the local spread of cancer. These include: Cellular proliferation Release of lytic enzymes with digestion of barriers Decreased cell-to-cell adhesion Increased motility of tumor cells Tumors increase their size when their rate of cellular multiplication exceeds the rate of cell death. As the tumor grows, it exerts mechanical pressure on surrounding tissues. As this pressure increases, the tumor sends projections of tumor cells into the surrounding tissue. The multiple projections arising from the central tumor mass give it a crab-like appearance, which gave rise to the term cancer. Pressure on nearby blood vessels can lead to ischemic necrosis of local tissue, making it easier for the tumor to expand into these tissues.
How is sexual and physical activity associated with cancer risk?
In 2008 infections accounted for 16.1% of diagnosed cancers. The four top infections that contribute to carcinogenesis include HPV, H. pylori, HBV, and HCV. Refer to Table 13-7 for a list of the number of new cancer cases in 2008 attributable to infection. Sexual behavior can contribute to cancer risk through transmission of infectious organisms. One of the most important factors in cervical cancer is the presence of infection by the human papillomavirus (HPV). There are two high-risk types of HPV organisms that are most oncogenic and cause the majority of cancers, HPV-16 and HPV-18. These viruses can also lead to malignancies in the anus and oropharynx. Persistent infection with these high-risk types of HPV can result in cervical intraepithelial neoplasia (CIN), which leads to invasive cervical cancers. The infected cells develop mutations which may eventually form a high-grade lesion and a cancerous tumor. In addition, testing for the presence of HPV during pelvic examination can provide important information about future risk for cancer development. The vaccine for HPV is recommended for all young women to reduce their risk for cervical cancer. It is also approved for boys and men aged 9 through 26 for the prevention of genital warts and oral cancers.
To what tumors has cigarette smoking been linked?
In addition to increasing the risk of lung cancer, cigarette smoke carcinogens are a cause of increased risk for cancer of the bladder, pancreas, kidney, oral cavity, pharynx, larynx, stomach and esophagus and have been implicated in breast, stomach, and liver cancer as well. Persons who start at a young age and who continue to smoke as they age are at the greatest risk of developing cancer and non-cancer related diseases (for example, cardiovascular disease).
What are the risks of passive smoking?
In addition, non-smokers who are exposed to secondhand smoke (environmental tobacco smoke [ETS], passive) also have a greater risk for lung cancer. Cigar or pipe smoking, smoking bidi, or water pipe smoking are other forms of tobacco delivery that can increase the risk of cancer.
What are ways that cancer cells evade anti-growth signals?
In healthy cells, anti-growth signals are controlled by tumor-suppressor genes. Mutations of tumor-suppressor genes are among the most common genetic defects found in human cancers. These mutations cause a loss of the normal anti-growth signals, or cause cancer cells to become insensitive to these signals. Normal anti-growth signals can be divided into: Messages from other cells that inhibit cell replication Gene products from within the cell itself that inhibit the cell cycle The initiation of the self-destruct mechanism called apoptosis
What is the role of infection in cancer?
Infection is common in individuals with cancer, usually because of leukopenia but also as a result of generalized immunosuppression from age, chronic stress, malnutrition, inflammation, and metabolic alterations (see Table 12-12 for a description of factors that predispose individuals with cancer to infection.). In addition, surgery coupled with poor healing can result in formation of abscesses and fistulae. Finally, modern management of cancer frequently includes the use of invasive catheters.
What is the relationship between genetics and cancer-prone families?
Inheritance of a cancer gene means that there was a mutation present in the reproductive cells of one of an individual's parents. As far as we know, oncogenes cannot be carried by germ cells, so the only kinds of mutated genes that can be inherited are tumor-suppressor genes Because loss of heterozygosity is necessary for a tumor-suppressor gene to lose its anti-growth function, cancer inheritance is one of increased risk, but not absolute certainty. It has been postulated that it is possible to inherit vulnerability to mutations without inheriting any measurable specific gene mutation.
How does radiation contribute to cancer development?
Ionizing radiation (IR) at the doses experienced by survivors of atomic bombs clearly causes leukemia and increased risk for thyroid, breast, lung, stomach, colon, esophagus and urinary tract cancers and multiple myeloma. However, ionizing radiation at much lower levels is repetitively experienced by many individuals due to X-rays, radioisotopes, computed tomography (CT) and radiation treatments. The National Council on Radiation Protection and Measurements reported that Americans were exposed to more than seven times as much IR form medical procedures in 2009 as compared to the 1980s. Refer to Table 13-8 for a summary of cancers associated with exposure to ionizing radiation. Initial epidemiologic data from Japanese atomic bomb survivors and from children exposed to radiation for medical purposes indicate that radiation-induced cancers are higher for persons exposed during childhood versus exposure during adulthood. However, even more recent analyses of the Japanese bomb survivors have shown that the excess relative risk (ERR) for cancer induction increases when radiation exposure occurs at older ages. Newer models suggest that IR can act as an initiator of premalignant cells and a promoter of clonal expansion. Subsequently, as people age their lifetime cancer risks secondary to IR exposure becomes greater. Besides potential carcinogenic effects, IR exposure damages the immune system leading to heart disease and brain attacks (stoke) and may contribute to respiratory disease, birth defects, and eye problems.
What are the characteristics of malignant tumors?
Malignant tumors are cancers and share several characteristics that differentiate them from benign tumors: They exhibit rapid growth. They lack a capsule and have a tendency to invade surrounding tissues. They are composed of undifferentiated cells that exhibit irregularities in size and shape of nuclei, frequent mitotic figures (actively dividing cells), and little to no tissue organization (anaplastic). They tend to metastasize to distant tissues and to lymph nodes. Table 12-1 in your textbook provides a quick overview of definitions of benign vs. malignant neoplasms.
What are some of the causes of pain in cancer?
Many individuals with newly diagnosed cancers state that severe and untreatable pain is their biggest fear. The irony of the pain associated with cancer is that it frequently does not occur until late in the progression of the tumor; in fact, the lack of pain makes early diagnosis and effective treatment of the malignancy much more difficult. Even so, the vast majority of malignancies eventually do cause pain. Some of the ways that cancer can cause pain include: Pressure on tissues and nerve endings Invasion of tissues and nerve endings Release of pain-inducing chemicals Obstruction of gastrointestinal or urinary systems Metastases to bone Stretching of viscera Infectious complications, such as mouth ulcers Complications of treatment (surgery, toxic drugs, radiation)
How is obesity linked to cancer risk?
Obesity has been linked to increased cancer risk and increased mortality in persons with cancer. It is a risk factor for cancers of the endometrium, colorectal, kidney, esophagus, breast, and pancreas. Other studies are looking at an association of obesity with cancers of the thyroid, gallbladder, liver, ovary, prostate, and non-Hodgkin lymphoma. Adipose tissue has wide-ranging systemic effects via its role as a storage site for free fatty acids, peptide hormones (leptin, adiponectin, resistin), and steroid hormones. In obesity, the following have all been linked to metabolic changes that can contribute to carcinogenesis: hyperinsulinemia insulin resistance increase insulin-like growth factor 1 decreased adiponectin increased leptin increased levels of estrogens and progestins Warburg Effect and the Reverse Warburg Effect disrupted Circadian rhythms
What are paraneoplastic syndromes?
One group of cancer-related changes results from biologic substances released from the tumor (e.g., hormones) or by an antibody response that attacks the nervous system. In a broad sense, these syndromes are collections of symptoms that result from substances produced by the tumor, and they occur remotely from the tumor itself. The symptoms may be endocrine, neuromuscular or musculoskeletal, cardiovascular, cutaneous, hematologic, gastrointestinal, renal, or miscellaneous in nature. Paraneoplastic syndromes are not common but are significant because they may be the earliest symptoms of undiagnosed cancer and the symptoms can be serious, or irreversible or even life threatening. See Table 12-11 in the textbook to see examples of different types of paraneoplastic syndrome. i.e. cushing's syndrome associated with a tumor
What are the causes and consequences of anemia, leukopenia, and thrombocytopenia in cancer?
One of the most common causes of fatigue in individuals with cancer is anemia . Hemoglobin concentrations of less than 9 g/dL occur in up to 20% of individuals with cancer. This can be the result of: Chemotherapeutic drugs that are toxic to the bone marrow (most common) Chronic bleeding Severe malnutrition Malignant cells in the bone marrow Decreased production of erythropoietin Iron deficiency Iron Deficiency can result from chronic blood loss and from malabsorption of iron, especially in association with cancers of the gastrointestinal tract. Iron utilization by the bone marrow is also abnormal due to increased inflammatory cytokines (e.g., IL-1) and decreased erythropoietin activity. A decrease in white blood cells (leukopenia) and platelets (thrombocytopenia) can result from invasion of the bone marrow by tumor, or from the effects of chemotherapy or radiation. Thrombocytopenia caused by disseminated intravascular coagulation (DIC) can result in life-threatening hemorrhage. Leukopenia usually includes a severe drop in the neutrophil count (neutropenia) and puts the individual at high risk for infections. The diagnosis of Glossary leukopenia and Glossary thrombocytopenia is made by obtaining a complete blood cell count. Management of these symptoms of cancer includes administration of bone marrow-stimulating factors and platelet transfusion.
What are the mechanisms of cachexia in cancer?
One of the questions that is the most important to ask of someone who has cancer is, "Have you lost weight?" Many individuals with cancer will lose significant amounts of muscle mass to the point of wasting (progressive emaciation and weakness); this is called cachexia and is one of the leading causes of death in individuals with cancer. Although anorexia is common in individuals with profound weight loss, it is not the only cause of wasting. In addition to poor dietary intake, there are catabolic factors that tip the balance away from protein synthesis and toward protein degradation. Anorexia results from a constellation of problems, including changes in taste, mouth sores, dysphagia, poor dentition, anxiety, pain, medications, fatigue, dyspnea, nausea, early satiety, unappetizing diets, and social isolation. Inadequate intake of proteins results in loss of muscle mass, hypoalbuminemia, decreased immunity, and weakness. Catabolism results from an increase in basal metabolic rate in individuals with cancer. This increase is caused by cytokines such as TNF-alpha (also called cachectin), IL-1, IL-6, and interferons. In addition, carbohydrate, protein, and fat metabolism is impaired. Protein degradation is increased in skeletal muscle because of the ubiquitin-proteasome protein degradation pathway, which leads to further muscle wasting and weakness. The combination of anorexia and catabolism can lead to a profound decrease in quality of life for individuals with cancer. Non-pharmacologic strategies coupled with appetite stimulants and special nutrition is vital in the care of these individuals.
What sources of ionizing radiation cause exposures in the U.S.? Xray, radio isotopes, CT, and radiation treatments
Researchers hypothesize that there are several biological processes that are responsible for radiation-induced cancer in humans. These processes include: Oncogenes and Tumor Suppressor Genes IR can activate oncogenes and deactivate tumor suppressor genes, resulting in uncontrolled growth. Chromosomal Aberrations IR causes chromosomal abnormalities and gene mutations. The inability to repair an IR induced double-strand break (DSB) leads to significant chromosomal instability. Cell Transformation Radiated cells lose normal homeostatic control. Non-targeted Effects Surrounding cells close to ones directly radiated can have mutations and malignant transformations (bystander effects). Progeny cells from those that were irradiated previously develop genomic instability that can lead to cancer. Acute, Latent, and Microenvironment Effects IR can acutely damage highly proliferative cells (hematopoietic, skin, and gastrointestinal). Several years can pass (5 to 10 or even more) before cancer is diagnosed in individuals exposed to radiation. Non-targeted effects change the tumor microenvironment (See image on screen).
What are tumor suppressor genes, and what role do they play in oncogenesis?
Some examples of commonly-mutated tumor suppressor genes in human cancers include: p53-breast, lung BRCA1-breast, ovary BRCA2-breast (female and male), ovary APC-colon cancer RB-retinoblastoma gene Refer to Table 12-5 in your textbook to see other examples of familial cancer syndromes caused by the loss of the tumor-suppressor gene. The most common mutation found in human cancers is the tumor suppressor gene called Glossary p53. This gene has the capacity to stimulate repair of damaged DNA, or if repair is not possible, it will induce Glossary apoptosis in the injured cell. Mutations of these genes result in the balance tipping toward cell division and tumor growth. These mutations can take several forms including: Point mutations (substitutions) Subtle alterations (deletions or insertions) Chromosomal translocations (aneuploidy and loss of heterozygosity) Gene amplifications Gene silencing Exogenous sequences (tumor viruses)
Clinical manifestations of cancer
Some types of cancer do not cause any clinical manifestations until the disease is very advanced. The location of the cancer can determine symptoms by physical pressure, obstruction, and loss of normal function. A cancer can also create problems far away from its source by pressing on nerves or secreting bioactive compounds or metastasizing to other organs. If cancer is suspected, it is necessary to obtain a tissue biopsy to establish a definitive diagnosis for cancer and to correctly classify the disease. Refer to Table 12-9 in the textbook to see the purpose and different examples of biopsy procedures. In addition, as you go through the next several screens, refer to Box 12-2 for a summary of common clinical manifestations of cancer (and its treatment).
What are the goals of surgery for cancer?
Surgery is used to excise a tumor that has not spread, to relieve symptoms, and in some high-risk cases, to prevent cancer. For example, a colectomy may be performed for persons with familial adenomatous polyposis. Important principles related to cancer surgery include: Obtaining adequate surgical margins to prevent local recurrences Placing needle tracks and biopsy incision scars contaminated with cancer cells so these can be resected in subsequent surgeries Being exact in surgical technique to avoid spreading the cancer Obtaining adequate tissue samples for diagnosis Removal of lymph nodes for staging
What are the major steps in metastasis?
Survival and spread of cancer cells into circulation When healthy cells are separated from their extracellular matrix (ECM), anoikis, a form of cell death, occurs; however, tumor cells can survive and are able to metastasize. Malignant cells can intravasate into blood vessels and then extravasate into secondary tissue. Distant metastasis As described in the previous screens of this module, cancer cells can invade surrounding tissues. The tumor may invade body cavities and spread widely. An example of this process is seen in ovarian cancer. Ovarian malignancies often extend into the surrounding tissues until cancer cells are released into the abdominal cavity. Malignant cells can then travel throughout the abdomen and seed serosal surfaces in distant sites. Most metastases occur by tumor cells penetrating into blood vessels or lymphatics. Single cells or clusters of cells may enter the lymphatics and travel to lymph nodes where they may be killed by the immune system, or they may lodge in the lymph nodes and continue to proliferate. This process gives rise to the critical staging tool of examining lymph nodes for the presence of cancer spread. A good example of this is found with breast cancer in which the number of involved lymph nodes is directly correlated with survival from the cancer. The fact that certain cancer types are more likely to successfully metastasize in certain organs is called organ tropism. See Table 12-8 in the textbook for common sites of metastasis.
Causes of Cancer related fatigue
The National Cancer Institute has established the following list of the major causes of fatigue related to cancer and cancer therapy: Side effects of cancer treatment Anemia Malnutrition (anorexia/cachexia) Metabolic disturbances Hormone changes Chronic stress Sleep disturbances Inactivity Neuromuscular dysfunction Pain At a cellular level, there are two major hypotheses for cancer fatigue: 1) neuromuscular dysfunction and 2) inflammatory mediators. Although the exact mechanisms that produce fatigue are poorly understood, studies suggest that some individuals with cancer lose portions of muscle function needed to perform normal activities. The inflammatory mediators tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), have widespread and complex effects on cellular function, including decreased protein stores in skeletal muscle, which result in poor muscle fiber contractility. Changes in mental status associated with cancer and its treatment can also contribute to lethargy and a sense of exhaustion.
How does radiation work, and what are the goals of radiation therapy for cancer?
The administration of ionizing radiation to a tumor results in damage to and death of the DNA of the cancer cells. Although the beam of radiation can be focused on the tumor by using sophisticated imaging techniques, there is almost always some collateral damage to surrounding healthy tissues. There are few cancers for which radiation is considered curative; it is most often used for adjuvant, neoadjuvant, or palliative purposes. Radiation therapy can be delivered externally or placed into body cavities (brachytherapy). Radiation therapy and chemotherapy can cause a number of side effects including decreased fertility and premature menopause. Individuals should be educated about potential reproductive problems and provided information on sperm and embryo banking.
How does cancer affect the gastrointestinal tract and the skin?
The gastrointestinal (GI) tract is lined with actively dividing cells that are vulnerable to the effects of chemotherapy and radiation. Infections of the mouth, esophagus, and colon can also complicate treatment. Hair and Skin Alopecia (hair loss) and skin changes are common with chemotherapy, and radiation can cause significant burns. Although these side effects cannot always be avoided, proper care can often restore skin health and hair growth once the treatment is over.
What are oncogenes, and how do these mutations occur?
The normal genes that promote cellular division are called proto-oncogenes. These genes and their products stimulate normal cells to replicate when new cells are needed (for example, in wound repair), but their activity is tightly controlled. Mutations of these genes cause them to function as oncogenes whose activity leads to overstimulation of the cellular responses that promote cell division known as pro growth signals. Oncogenes may cause increased cellular replication through a number of mechanisms: Autocrine stimulation- means that a cancer cell develops the ability to secrete growth factors that then act on the cell itself to stimulate cellular replication. Increased growth factor receptors Increased signal transduction Increased transcription and translation Two other oncogene mechanisms that contribute to tumor growth and cancer cell replication are: Angiogenesis Reactivation of telomerase
What is the purpose of adjuvant and neoadjuvant chemotherapy?
There are different delivery modalities for chemotherapy: Induction: used to shrink or eliminate the tumor Adjuvant: given after surgery to eliminate micrometastases Neoadjuvant: administered before surgery or radiation treatment to shrink a cancer in order to spare normal tissue .
How does air pollution cause cancer?
There are numerous substances in polluted air that are potentially carcinogenic, and the link between air pollution and lung cancer is fairly well established. Inhaled pollutants may be directly toxic to airway epithelial cells or may initiate chronic inflammation with its associated generation of toxic oxygen radicals. Air pollution can be considered outdoor or indoor. Outdoor air pollution is caused by damage to the ozone layer from motor vehicle exhausts and industrial emissions. Indoor air pollution is receiving increasing attention with the possibility of exposures to tobacco smoke, radon, and smoke from cooking.
What are electromagnetic fields and how have they been linked to cancer?
There is no consistent evidence linking electromagnetic fields (EMF), a type of non-ionizing and low-frequency radiation, to cancer or any other disease. However, the increasing amount of EMF exposure through cell phones, fluorescent lights, high-voltage power lines, and computers has raised concerns, so in 1998 the National Institute of Environmental Health Sciences designated EMF as a possible carcinogen. Mechanisms of possible carcinogenesis by EMF are also controversial and include thermal injury or the release of toxic radicals.
What are tumor markers, and how can they be used?
Tumor markers are biochemical substances produced by both benign and cancerous cells and can be present in or on tumor cells or measured in the blood, cerebrospinal fluid, or urine. If the tumor marker itself has biologic activity, then it can cause symptoms, a phenomenon known as a paraneoplastic syndrome. For example, benign tumors of the adrenal medulla (pheochromocytoma) can produce catecholamines in large amounts, causing an individual to experience tachycardia, hypertension, diaphoresis, and tremors. Tumor markers include hormones, enzymes, genes, antigens, and antibodies. Examples of types of tumor markers include: Mutated tumor cell proteins (e.g., mucine 1 [MUC1] in breast cancer) Overexpression of normal antigens (e.g., prostate specific antigen [PSA] in prostate cancer) Viral gene expression on surface of cell (e.g., human papilloma virus [HPV] in cervical cancer) Gene products that are produced normally only during fetal development (e.g., alpha fetoprotein [AFP] in testicular cancer and carcinoembryonic antigen [CEA] in colon cancer) See Table 12-3 in the textbook for other examples of tumor markers. When testing large populations, there is a risk of obtaining "false positives" and "false negatives". Some benign tumors can also produce tumor markers; thus, the presence of an elevated tumor marker is not used alone as a definitive diagnose for cancer.
What are some of the lytic enzymes that are involved in tumor spread and how do they function?
Tumors frequently secrete lytic enzymes such as proteases, collagenases, plasminogen activators, and lysosomal enzymes that attack surrounding tissues and provide room for the tumor to expand. Host macrophages also contribute to this process by releasing more proteases. The combined effect of these enzymes is to break down the collagen structure of the tissues surrounding the tumor, help the tumor cells access blood vessels to improve nutrient delivery, and enhance migration of tumor cells. New therapies are aimed at blocking these enzymes, including the blocking of matrix metalloproteinases (MMPs) in breast cancers. In addition, scientists have discovered that an undifferentiated mesenchymal-like phenotype (epithelial-mesenchymal transition [EMT]) is responsible for permitting tumor cells to separate from a primary tumor and be transported to a distant site.
What are the benefits of combination chemotherapy?
Two approaches to effectively treat a cancerous tumor and reduce the toxicity in healthy cells include: Combination chemotherapy that uses combinations of drugs that increase effectiveness without compounding toxicity Targeted therapy to treat cancers in which the molecular target is identified (for example, using imatinib, a competitive inhibitor of BCR-ABL tyrosine kinase, to treat CML and gastrointestinal stromal tumors [GIST])
What kinds of cancers are linked to ultraviolet radiation?
Ultraviolet radiation (UVR) comes primarily from sunlight. It can be categorized by wavelength into two types, ultraviolet A (UVA) or ultraviolet B (UVB). The degree of skin damage depends on the intensity and the wavelength content. This form of radiation causes mutations in the cells of the dermis. Specific gene mutations are: Squamous cell carcinoma (TP53 gene) Basal cell carcinoma (Patched gene) Melanoma (CDKN2A/p16 gene) In addition, ultraviolet radiation produces large amounts of reactive oxygen species (ROS) that lead to oxidative stress, tissue injury, and direct DNA damage. Inflammation can contribute to carcinogenesis by increasing the exposure of cells to toxic oxygen radicals. White individuals in high-intensity sun areas who have fewer Glossary melanocytes in their skin are at highest risk from exposure to UVR for developing both basal cell and squamous cell carcinoma of the skin. These cancers are more commonly seen on sun exposed areas such as the head and neck. Sun exposure also contributes to the risk of melanoma, but the link is complex. The risk for melanoma is likely greatest in sun exposures that are intense and intermittent, as evidenced by a history of sunburns. Genetics and other factors are also important in assessing the overall risk for melanoma, and unlike squamous cell or basal cell carcinomas, malignant melanoma lesions tend to occur in areas of the skin that are not commonly exposed. Thus careful assessment of patients for this type of cancer is essential.
How is physical activity linked to cancer risk?
Unlike the other factors we have discussed so far, physical activity is linked to a decreased risk for many types of cancer. Refer to Table 13-6 in the textbook to see a summary of effects of exercise on cancer risk. The mechanisms responsible for the protective effects of physical activity remain poorly understood, but include: Decreased obesity-related metabolic effects Increased gut motility Decreased endogenous hormones Decreased proinflammatory mediators Improved immune function Enhanced cytochrome P-450 How much and what kind of exercise is optimal for reducing cancer risk continues to be vigorously debated. The only consistent findings are that exercise should be at least moderate in intensity and should be undertaken several times per week. It is safe to say that any amount of exercise is better than no exercise at all.
How is fatigue associated with cancer?
Virtually all individuals with cancer report fatigue as one of the most difficult symptoms with which they must cope. "Fatigue" can be defined as a group of symptoms that cause distress or impair function, which include: Diminished energy Diminished physical or intellectual performance (inability to maintain attention, memory disturbances) Apathy and decreased motivation or enjoyment of activities Lethargy Weakness Disturbed sleep Mood changes These symptoms are also common in depression, which is another complication of cancer and cancer therapy.
Read Chapter 12, pages 372-387 in your textbook.
What is meant by clonal selection, and how does it relate to the growth of tumors? Clonal Selection is a stepwise accumulation of alterations in specific genes is required for the development of cancer. Cancer starts with a mutation in one cell, usually resulting in an increased ability of that cell to divide and survive longer than normal cells. As the progeny of that cell develops further mutations, those mutant cells with the greatest ability to out-compete normal cells for space and nutrients can accumulate faster than the nonmutant cells. This is referred to as clonal proliferation or clonal expansion. Initially, the tumor may be unable to penetrate deeply into surrounding tissues (carcinoma in situ), but further mutations may allow the cancer cells to progress to become invasive tumors and to metastasize. In summary, a clinically significant cancer results from many mutations (multi-hit) until a cellular subclone is created that out-competes all of its neighbor cells through clonal selection and becomes a malignant tumor.
Read Chapter 12, pages 363-372 in your textbook.
What is meant by the term tumor, or neoplasm? A tumor is an abnormal growth secondary to uncontrolled proliferation and serves no physiological function. It is often referred to as a new growth, or neoplasm. Not all neoplasms are cancers.
Read Chapter 13, pages 413-433 in your textbook.
What is the epidemiology of tobacco use in the U.S.? Despite a vigorous public health effort to rid this country of cigarette smoking, it was reported in 2011 that almost 19% of adults in the U.S. continue to smoke. Furthermore, the majority of smokers are between 18 and 44 years of age.
Read Chapter 13, pages 403-409; 410-412 in your textbook.
What is the interaction of epigenetics and genetics and the environment? As we saw in part A of this module, epigenetic factors are not related to changes in the DNA sequence, but rather, changes in gene expression that are perpetuated in cell division. They are related to non-genetic factors that cause the genes to behave differently. Research supports that epigenetic changes collaborate with genetic changes and environmental lifestyle factors to cause the development of cancer. There are three major areas of epigenetics: Methylation Histone modification Micro-ribonucleic factors The interaction between environmental risks such as smoking and diet with changes in DNA and histone methylation is an area of intense research. Most environmental changes in cellular epigenetics occur in somatic cells and are therefore not transgenerational. However, germline methylation changes have been documented and likely confer increased vulnerability to cancers that run in families.The current paradigm shift is from a genetic to an epigenetic model and the development of prevention strategies to alter the course of epigenetic changes that precede and induce cancer causing genetic mutations.
Read Chapter 12, pages 392-395 in your textbook.
What is the primary method used to stage cancers? Once a diagnosis of a malignant tumor is made, further staging of cancer provides information that helps with treatment decisions and allows for the prediction of outcomes (prognosis). The most commonly used cancer staging scheme is the World Health Organization's TNM system, which indicates tumor spread, node involvement, and the presence of distant metastasis. A Stage I tumor generally refers to small tumors that have not spread to lymph nodes or other tissues, whereas Stage IV tumors are generally large and invasive and have metastasized to distant lymph nodes and other organs. The prognosis is generally worse for increasing tumor size, lymph node involvement, and metastasis. Refer to Table 12-10 in the textbook for a comparison of the stages and cancer survival rates for colon and pancreatic cancer and Hodgkin's disease. The following table is an example of the use of the TNM system in staging breast cancer.
What is meant by the term carcinoma in situ?
When malignant cells are confined to the epithelial layer of glandular or squamous cell tissue and have not penetrated the basement membrane, they are called carcinoma in situ (CIS). If these malignant cells are removed at this stage, they cannot invade surrounding tissues or metastasize to distant sites.
