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* EUGENE PARDI, DO ESTRELLA MOUNTAIN COMMUNITY COLLEGE * Cancer is a leading disease, cause of death, and source of morbidity of adults in the Western world. * Incidence of cancer increases with advancing age. * Strongly affected by gender, lifestyle, ethnicity, infection, and genetics. * Cancer is a collection of many different diseases caused by an accumulation of genetic and epigenetic alterations. * Environment, heredity, and behavior interact to modify the risk of developing cancer and the response to treatment. * EUGENE PARDI, DO 2 2/26/2011 *1922 definition of cancer: *The most generally accepted definition of a tumor is that it is a tissue overgrowth which is independent of the laws governing the remainder of the body. It is usual to add as a qualifying phrase to separate tumors from reparative processes, such as bone callus, that the neoplasm overgrowth serves no useful purpose to the organism. * EUGENE PARDI, DO 3 2/26/2011 * CANCER: derives from the Greek word for crab, karkinoma, which was used by Hippocrates to describe the appendage – like projections extending from tumors. * TUMOR: generally reserved for describing a new growth, or NEOPLASM. * Not all tumors or neoplasm are cancer. * CANCER refers to a MALIGNANT tumor and is not used to refer to BENIGN growths or hypertrophy of an organ. * EUGENE PARDI, DO 4 2/26/2011 * Cancer classification starts with knowing the site of origin and microscopic appearance of the lesion. * Can extend to a detailed description of critical genetic changes in the cancer. * BENIGN TUMORS are usually encapsulated and well differentiated. * Retain some normal tissue structure. * Do not invade the capsule surrounding them or spread to regional lymph nodes or distant locations. * Generally named according to the tissue of origin and include the suffix “ – oma”. * i.e. lipoma, leiomyoma, etc. * EUGENE PARDI, DO 5 2/26/2011 *MALIGNANT TUMORS: tumors initially described as benign that have progressed to cancer. *Distinguished from benign tumors by their more rapid growth rates and specific microscopic alterations. *Loss of differentiation and absence of normal tissue organization. * EUGENE PARDI, DO 6 2/26/2011 * ANAPLASIA: one of the hallmarks of cancer cells as seen under the microscope. * The loss of cellular differentiation, irregularities in the size and shape of the nucleus, and loss of normal tissue structure. * Malignant tumors lack a capsule and grow to invade nearby blood vessels, lymphatics, and surrounding structures. * The most important and deadly characteristic of malignant tumors is their ability to METASTASIZE. * Spread far beyond the tissue of origin. * EUGENE PARDI, DO 7 2/26/2011 EUGENE PARDI, DO 8 2/26/2011 EUGENE PARDI, DO 9 2/26/2011 EUGENE PARDI, DO 10 2/26/2011 * Cancers are named according to the cell type from which they originate. * CARCINOMAS: cancers arising in epithelial tissue. * If they arise from or form ductal or glandular structures are named ADENOCARCINOMAS. * SARCOMAS: cancers arising from connective tissue. * LYMPHOMAS: cancers of lymphatic tissue. * LEUKEMIAS: cancers of blood forming cells. * Many cancers are named for historical reasons that do not follow this naming convention. * Hodgin’s disease; Ewing sarcoma. * EUGENE PARDI, DO 11 2/26/2011 *CARCINOMA IN SITU (CIS): preinvasive epithelial malignant tumors of glandular or squamous cell origin. *Are localized to the epithelium and have not broken through the local basement membrane or invaded the surrounding stroma. *Recognized in the cervix, skin, oral cavity, esophagus, and bronchus. * EUGENE PARDI, DO 12 2/26/2011 EUGENE PARDI, DO 13 2/26/2011 *In glandular epithelium, in situ lesions occur in the stomach, endometrium, breast, and large bowel. *In the breast, ductal carcinoma in situ (DCIS) fills the mammary ducts but has not progressed to local tissue invasion. *The time that such preinvasive lesions remain in situ before becoming invasive is unknown. * EUGENE PARDI, DO 14 2/26/2011 There are three grades of DCIS: low or Grade I; moderate or Grade II; and high or Grade III. The lower the grade, the more closely the cancer cells resemble normal breast cells and the more slowly they grow. Sometimes it's difficult to figure out where the cells are on in the range from normal to abnormal. If the cells are in between grades, they may be called "borderline." EUGENE PARDI, DO 15 2/26/2011 Normal breast with non–invasive ductal carcinoma in situ (DCIS) in an enlarged cross–section of the duct. Breast profile: A ducts B lobules C dilated section of duct to hold milk D nipple E fat F pectoralis major muscle G chest wall/rib cage Enlargement: A normal duct cells B ductal cancer cells C basement membrane D lumen (center of duct) EUGENE PARDI, DO 16 2/26/2011 Irregular clustered microcalcifications of ductal carcinoma in situ. EUGENE PARDI, DO 17 2/26/2011 EUGENE PARDI, DO Ductal carcinoma in-situ (solid-type). Histologic section. 18 Hematoxylin and Eosin stain. 2/26/2011 * The classification of cancers was originally based on gross and light microscopic appearance. * Now aided by additional immunohistochemical analysis of protein expression. * Is also sometimes supplemented by extensive molecular analysis of the tumors. * This detailed analysis of each tumor is a form of PERSONALIZED MEDICINE offering therapy based on a very detailed knowledge of individuals’ characteristics and their specific cancer. * EUGENE PARDI, DO 19 2/26/2011 *TRANSFORMATION: the process by which a normal cell becomes a cancer cell. *AUTONOMY: refers to the cancer cell’s independence from normal cellular controls. *Part of the transformational process. * EUGENE PARDI, DO 20 2/26/2011 * The cellular mechanisms that regulate cell birth, growth, and cell death are referred to as SOCIAL CONTROLS and require SOCIAL CONTROL GENES. * Transformed cells lack many of the normal social controls seen in nontransformed cells * Normal cells cease to divide when they fill a Petri (or tissue culture) dish. * Transformed cells continue to crowd and eventually pile up on each other. * EUGENE PARDI, DO 21 2/26/2011 EUGENE PARDI, DO 22 2/26/2011 * Normal cells usually will not grow unless they are attached to a firm surface. * Cancer cells are often ANCHORAGE INDEPENDENT. * Continue to divide even when suspended in a soft agar gel. * Normal cells will not grow when injected into a special type of mouse. * Cancerous cells from humans can continue to grow and even metastasize in these mice. * EUGENE PARDI, DO 23 2/26/2011 EUGENE PARDI, DO 24 2/26/2011 *Normal cells have a limited life span in the laboratory. *Cancer cells usually are IMMORTAL. *They seem to have an unlimited life span and will continue to divide for years under appropriate laboratory conditions. * EUGENE PARDI, DO 25 2/26/2011 * Normal cells are uniform in size and shape within a tissue. * Cancer cells often show defects in the normal process of differentiation. * ANAPLASIA is the absence of differentiation. * Is recognized by a loss of organization and a marked increase in nuclear size with evidence of ongoing proliferation. * Anaplastic cells are of variable size and shape, or PLEOMORPHIC. * The most malignant tumors tend to have the most anaplasia and be the least differentiated. * EUGENE PARDI, DO 26 2/26/2011 Normal skeletal muscle cell EUGENE PARDI, DO Anaplastic skeletal muscle cell 27 2/26/2011 * The ongoing proliferation of tissues with a high turnover rate depends on their regeneration from a small fraction of cells know as ADULT STEM CELLS. * Adult stem cells have two essential characteristics: * They self – renew. * They are MULTIPOTENT, or, have the ability to differentiate into multiple different cell types. * EUGENE PARDI, DO 28 2/26/2011 * A key feature of stem cells is that they can divide asymmetrically. * 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. * Multipotent bone marrow stem cells can self – renew and differentiate into all types of bone marrow – derived cells, such as red cells, lymphocytes, and neutrophils. * EUGENE PARDI, DO 29 2/26/2011 EUGENE PARDI, DO 30 2/26/2011 * Just as normal tissues in adults can arise from a rare tissue stem cell, cancers may arise from cancer stem cells. * Rare cells capable of transmitting the cancer have been demonstrated in many other cancers as well. * Only a small subset of cancer cells have the ability to divide indefinitely and give rise to full blown cancer. * EUGENE PARDI, DO 31 2/26/2011 EUGENE PARDI, DO 32 2/26/2011 EUGENE PARDI, DO 33 2/26/2011 * In some, but not all tumors, greater than 99% of the cells in the cancer are not capable of propagating the cancer. * The most important cell in the cancer may be a rare “tumor initiating cell” or “cancer stem cell”. * Current treatments that effectively shrink tumors by killing 99% of cancer cells appear ineffective at killing the cancer stem cells. * Therapies may shrink cancers but when the cancer stem cell is not killed, the cancer can grow back. * EUGENE PARDI, DO 34 2/26/2011 EUGENE PARDI, DO 35 2/26/2011 EUGENE PARDI, DO 36 2/26/2011 * TUMOR MARKERS (biologic markers) are substances produced by cancer cells that are found either in or on the tumor cells or in the blood, spinal fluid, or urine. * Markers include hormones, enzymes, genes, antigens, and antibodies. * Markers can be used in three ways: * To screen and identify individuals at high risk for cancer. * To help diagnose the specific type of tumor in individuals with clinical manifestations relating to cancer. * To follow the clinical course of cancer. * EUGENE PARDI, DO 37 2/26/2011 EUGENE PARDI, DO 38 2/26/2011 *Nonmalignant conditions also can produce tumor markers. *E.g. PSA is elevated in both BPH and prostate cancer. *The presence of an elevated tumor marker therefore may suggest a specific diagnosis, but it is not used alone as a definitive diagnostic test. * EUGENE PARDI, DO 39 2/26/2011 * Changes in the genes of the cancer cell cause the cell to become cancerous. * Heritable changes in cells that can contribute to cancer include: * DNA mutations. * Changes in DNA and histone chemical modification (epigenetic changes). * Changes in micro – ribonucleic aid (miRNA) expression. * A MUTATION can refer to heritable changes in gene expression (EPIGENETICS) that do not involve changes in DNA sequence. * EUGENE PARDI, DO 40 2/26/2011 * Cancer is predominantly a disease of aging. * The fraction of individuals in each age group who develop cancer increases dramatically with age. * Each individual acquires a number of genetic “hits” or mutations over time. * When sufficient mutations have occurred, cancer develops. * Four to seven specific hits are required to cause a full – blown cancer. * EUGENE PARDI, DO 41 2/26/2011 EUGENE PARDI, DO 42 2/26/2011 * As a cell accumulates specific mutations, it can acquire, step by step, the characteristics of a cancer cell. * The mutant cell may have a selective advantage over its neighbors and its progeny can accumulate faster than its nonmutant neighbors. * CLONAL PROLIFERATION or CLONAL EXPANSION. * As a clone with a mutation proliferates, it may become an early stage tumor. * EUGENE PARDI, DO 43 2/26/2011 *Additional heritable changes can occur in these early lesions that permit progression to more advanced tumors. *The progressive accumulation of distinct advantageous mutations leads from normal cells to fully malignant cancers. *It is the STEPWISE ACCUMULATION of alterations in specific genes that is required for the development of cancer. * EUGENE PARDI, DO 44 2/26/2011 EUGENE PARDI, DO 45 2/26/2011 * Multiple genetic hits are required for the evolution of full – blown cancer. * Six specific pathways that must be misregulated for cancer to develop. * Cancer cells must have mutations that enable them to proliferate in the absence of external growth signals. * AUTOCRINE STIMULATION: the ability of some cancer cells to secrete growth factors that simulate their own growth. * EUGENE PARDI, DO 46 2/26/2011 EUGENE PARDI, DO 47 2/26/2011 * Other cancers have an increase in growth factor receptors. * The signal cascade from the cell surface receptor to the nucleus may be mutated in the “on “ position. * 1/3 of all cancers have an activating mutation in the gene for an intracellular signaling protein called RAS. * Stimulates cell growth even when growth factors are missing. * EUGENE PARDI, DO 48 2/26/2011 EUGENE PARDI, DO 49 2/26/2011 EUGENE PARDI, DO 50 2/26/2011 *Cells also receive “antigrowth” signals from their normal milieu. *Contact with other cells, with basement membranes, and with soluble factors all normally signal cells to stop proliferating. *Can put a halt to unregulated cell growth. * EUGENE PARDI, DO 51 2/26/2011 *This normal antigrowth signal must be inactivated or ignored. *Common mutations that subvert the antigrowth signal include inactivation of the tumor suppressor RETINOBLASTOMA or, activation of the protein kinases that drive the cell cycle, the CYCLIN DEPENDENT KINASES. * EUGENE PARDI, DO 52 2/26/2011 Molecular control of the cell cycle. Increasing levels of cyclin E in conjunction with the cyclin-dependent kinase-2 (cdk2) leads to the phosphorylation of the retinoblastoma gene product (Rb). Phosphorylated Rb releases the transcription factor E2-F, allowing PARDI, 2/26/2011 E2-F EUGENE to bind toDODNA and in conjunction with 53 RNA polymerase initiate the transcription of S phase–specific genes and entry into S phase. EUGENE PARDI, DO 54 2/26/2011 * Cells have a mechanism that causes them to self – destruct when growth is excessive and cell cycle checkpoints have been ignored. * Called APOPTOSIS. * Triggered by diverse stimuli, including normal development and normal growth. * The pathway to apoptosis is disabled in advanced cancers. * The most common mutations conferring resistance to apoptosis occur in the TP53 gene. * EUGENE PARDI, DO 55 2/26/2011 EUGENE PARDI, DO 56 2/26/2011 EUGENE PARDI, DO 57 2/26/2011 *In adults, new blood vessel growth is normally limited to areas of wound healing and to the uterus during the proliferative phase of the menstrual cycle. *More advanced cancers can secrete multiple factors that stimulate new blood vessel growth. *Called NEOVASCULARIZATION or ANGIOGENESIS. * EUGENE PARDI, DO 58 2/26/2011 * ANGIOGENIC FACTORS include: * Vascular endothelial growth factor (VEGF). * Platelet – derived growth factor (PDGF) * Basic fibroblast growth factor (bFGF) * Recruit new vascular endothelial cells and initiate the proliferation of existing blood vessel cells, allow small cancers to become large cancers. * Therapies directed against new vessel growth are in clinical use. * EUGENE PARDI, DO 59 2/26/2011 EUGENE PARDI, DO 60 2/26/2011 * A hallmark of cancer cell is their immortality. * Most cells in the body can divide only a limited number of times (HAYFLICK LIMIT) before they cease dividing. * One major block to unlimited cell division is the TELOMERE. * Protective end or cap on each chromosome that are placed and maintained by a specialized enzyme called TELOMERASE. * EUGENE PARDI, DO 61 2/26/2011 EUGENE PARDI, DO 62 2/26/2011 *Telomerase is usually active only in germ cells and in stem cells. *All other cells in the body lack telomerase. *When nongerm cells begin to proliferate abnormally, there telomere caps become smaller and smaller with each cell division. *Short telomere caps signal the cell to cease cell division. * EUGENE PARDI, DO 63 2/26/2011 EUGENE PARDI, DO 64 2/26/2011 EUGENE PARDI, DO 65 2/26/2011 * If the telomeres become critically small, the chromosomes become unstable and fragment, and then the cells die. * Cancer cells, when they reach a critical age, activate telomerase in order to restore and maintain their telomeres and thereby make it possible to divide over and over again. * Telomerase becomes an attractive therapeutic target. * EUGENE PARDI, DO 66 2/26/2011 EUGENE PARDI, DO 67 2/26/2011 *Genetic differences exist between cells that metastasize and those that do not. *Specific genes regulate the ability to metastasize. *Decreased cell – to – cell adhesion, the secretion of various proteases that digest surrounding barriers, and the ability to grow in new locations, all contribute to successful metastasis. * EUGENE PARDI, DO 68 2/26/2011 *ONCOGENES are mutant genes that in their normal non – mutant state direct synthesis of proteins that positively regulate (accelerate) proliferation. *TUMOR – SUPPRESSOR GENES encode proteins that in their normal state negatively regulate (halt, or “put the brakes on”) proliferation. *Also called ANTI – ONCOGENES. * EUGENE PARDI, DO 69 2/26/2011 EUGENE PARDI, DO 70 2/26/2011 EUGENE PARDI, DO 71 2/26/2011 EUGENE PARDI, DO 72 2/26/2011 EUGENE PARDI, DO 73 2/26/2011 * In its normal, nonmutant state, an oncogene is referred to as a PROTO – ONCOGENE. * Example of a proto – oncogene: EPIDERMAL GROWTH FACTOR, or EPIDERMAL GROWTH FACTOR RECEPTOR. * Other positive regulators of proliferation: signal transduction pathway that transmits the signal from the growth factor receptor to the cell nucleus. * RAS is a proto – oncogene. * EUGENE PARDI, DO 74 2/26/2011 * POINT MUTATIONS: the alteration of one or a few nucleotide base pairs. * A point mutation in the RAS gene converts it from a regulated proto – oncogene to an unregulated oncogene, an accelerator of cellular proliferation. * Found in many cancers, especially pancreatic and colorectal cancer. * Can be detected by direct DNA sequencing in clinical samples. * EUGENE PARDI, DO 75 2/26/2011 EUGENE PARDI, DO 76 2/26/2011 EUGENE PARDI, DO 77 2/26/2011 EUGENE PARDI, DO 78 2/26/2011 *CHROMOSOME TRANSLOCATIONS, in which a piece of one chromosome is translocated to another chromosome, can activate oncogenes by way of either two distinct mechanisms. *A translocation can cause excess and inappropriate production of a proliferation factor. * EUGENE PARDI, DO 79 2/26/2011 * Best example: t(8;14) translocation found in many Burkitt lymphomas. * An aggressive cancer of B lymphocytes. * The myc proto – oncogene found on chromosome 8 is normally turn on at low levels in proliferating lymphocytes and turned off in mature lymphs. * The t(8;14) alters the control of myc and production of the MYC protein, which is part of the positive signal for cell proliferation. * MYC, when inappropriately high, drives proliferation and block differentiation. * Hence, the t(8;14) translocation causes cancer of maturing B cells. * EUGENE PARDI, DO 80 2/26/2011 EUGENE PARDI, DO 81 2/26/2011 Fig. 9B —45-year-old man with Burkitt's lymphoma. Photograph of gross pathologic specimen shows polypoid mass in gallbladder. EUGENE PARDI, DO 82 2/26/2011 * Chromosome translocations also can lead to production of novel proteins with growth – promoting properties. * E.g. CML and the Philadelphia chromosome. * Translocation t(9;22), fuses two chromosomes right in the middle of two genes, bcr on chromosome 9 and abl on chromosome 22. * Results in production of a BCR-ABL protein that promotes growth of myeloid cells. * EUGENE PARDI, DO 83 2/26/2011 * Imatinib is a drug that specifically targets this protein and is the first successful chemotherapy targeted against the product of a specific oncogenic mutation. * Lack toxic side effects noted with nonspecific anticancer drugs. * Not effective in those who do not have this translocation or related mutations. * EUGENE PARDI, DO 84 2/26/2011 EUGENE PARDI, DO 85 2/26/2011 EUGENE PARDI, DO 86 2/26/2011 EUGENE PARDI, DO 87 2/26/2011 *Amplifications are the result of duplication of a small piece of a chromosome over and over again, so that instead of the normal two copies of a gene, tens or even hundreds of copies are present. *Results in the increased expression of an oncogene, or, in some cases, drug resistance genes. * EUGENE PARDI, DO 88 2/26/2011 *The N-myc oncogene is amplified in 25% of childhood neuroblastoma cases and confers a poor prognosis. *The epidermal growth factor receptor erbB2 is amplified in 20% of breast cancers. *Individuals whose cancers have erbB2 amplification respond well to drugs specifically targeted to this oncogene. * EUGENE PARDI, DO 89 2/26/2011 *Tumor suppressor genes are genes whose major function is to negatively regulate cell growth and prevent mutations. *May normally slow the cell cycle, inhibit proliferation resulting from growth signals, or stop cell division when cells are damaged. * EUGENE PARDI, DO 90 2/26/2011 *One of the first discovered tumor suppressor genes, the RETINOBLASTOMA (Rb) GENE, normally strongly inhibits the cell division cycle. *When it is inactivated, the cell division cycle can proceed unchecked. *Rb is mutated in childhood retinoblastoma, and in many lung, breast, and bone cancers as well. * EUGENE PARDI, DO 91 2/26/2011 EUGENE PARDI, DO 92 2/26/2011 * Tumor suppressors must be inactivated to allow cancer to occur. * A single genetic event can activate an oncogene because it can act in a dominant manner in the cell. * It takes two hits, though, to inactivate the two alleles of a tumor – suppressor gene. * They act in a recessive manner at the level of the cell. * If one allele is functional, then appropriate control of cell division can be maintained. * EUGENE PARDI, DO 93 2/26/2011 * For the function of a tumor suppressor to be lost, both chromosomal copies (alleles) of the gene must be inactivated. * They act in a recessive manner at the level of the cell. * Usually, the first allele is inactivated by simple mutation. * The second allele is usually lost when entire regions of the chromosome are epigenetically silenced or a piece of the chromosome is simply lost. * EUGENE PARDI, DO 94 2/26/2011 EUGENE PARDI, DO 95 2/26/2011 *Because you have two chromosomes, one from each parent, you can be heterozygous for nearby genetic markers. *Loss of a chromosome region in a tumor is referred to as LOSS OF HETEROZYGOSITY, or, LOH. *LOH, like silencing, unmasks inactivating mutations in recessive tumor suppressor genes. * EUGENE PARDI, DO 96 2/26/2011 * Gene expression can be regulated in a heritable manner by an “epigenetic” mechanism called SILENCING that is passed from mother to daughter cells during cell division and does not require mutations or changes in DNA sequence. * The same DNA sequence can produce different phenotypes depending on chemical modifications that alter the expression of genes. * EUGENE PARDI, DO 97 2/26/2011 EUGENE PARDI, DO 98 2/26/2011 * Epigenetic silencing is caused by reversible chemical modification of histones and related chromatin components, as well as methylation of cytosine residues in DNA known as DNA METHYLATION. * METHYLATION: addition of methyl group. * ACETYLATION: addition of acetyl group. * Whole regions of chromosomes are normally shut off by silencing, so that the pattern of gene expression is different than in other cells with the same genes. * GLOBAL changes in epigenetic silencing can turn these cells back into stem cells. * EUGENE PARDI, DO 99 2/26/2011 EUGENE PARDI, DO 100 2/26/2011 EUGENE PARDI, DO 101 2/26/2011 EUGENE PARDI, DO 102 2/26/2011 * Silencing can shut off critical tumor suppressor genes in the absence of mutations in the gene. * These changes in gene expression can lead to a selective advantage for affected cells , leading to their immortalization and clonal expansion. * Silencing of tumor suppressors may be a faster way to create cancer cells than mutational or genetic loss of tumor suppressors. * EUGENE PARDI, DO 103 2/26/2011 *Conversely, loss of silencing can contribute to inappropriate expression of oncogenes. *Chemotherapeutic drugs that can regulate gene silencing have proven effective in reactivating silenced tumor – suppressor genes in the treatment of selected cancers. * EUGENE PARDI, DO 104 2/26/2011 EUGENE PARDI, DO 105 2/26/2011 *The integrity of genetic information can be compromised at several points: *During each round of DNA synthesis. *During each mitosis when chromosomes are segregated to daughter cells. *When external mutagens (chemicals and radiation) alter or disrupt DNA. * EUGENE PARDI, DO 106 2/26/2011 * Multiple mechanisms have evolved to protect and repair the genome. * Repair mechanisms are directed by CARETAKER GENES. * Genes that are responsible for the maintenance of genomic integrity. * Encode proteins that are involved in repairing damaged DNA. * Loss of function of caretaker genes leads to increased mutation rates. * If DNA damage is severe, the cell undergoes apoptosis. * EUGENE PARDI, DO 107 2/26/2011 * Inherited mutations can disrupt the caretaker genes that protect the integrity of the genome. * Xeroderma pigmentosum (XP) defects in the repair of ultraviolet light – induced DNA damage. * Have a high incidence of skin cancer. * Hereditary nonpolyposis colorectal cancer (HNPCC) defects in repairing DNA base pair mismatches that occur from time to time during DNA replication. * High rate of colon and other cancers. * EUGENE PARDI, DO 108 2/26/2011 * Most of the genetic and epigenetic alterations that cause cancer occur during the lifetime of the individual within the somatic tissues. * The frequency of genetic changes can be increased by exposure to MUTAGENS. * Agents that cause mutations and by defects in DNA repair. * These genetic events occur in somatic cells and are not transmitted to future generations. * EUGENE PARDI, DO 109 2/26/2011 * Mutations present in germline cells result in the transmission of cancer – causing genes from one generation to the next, producing families with a high incidence of specific cancers. * Inherited mutations that predispose to cancer are almost invariably found in tumor – suppressor genes. * Inheritance of one mutant allele predisposes a person to a specific form of cancer. * Individuals who inherit the germline mutant allele will inevitably suffer loss of the normal allele by LOH or EPIGENETIC SILENCING. * EUGENE PARDI, DO 110 2/26/2011 EUGENE PARDI, DO 111 2/26/2011 * Examples of inherited cancers are: * Retinoblastoma: germline mutations in one allele of the Rb gene. * Wilms tumor: childhood cancer of the kidney. * Neurofibromatosis. * Inherited breast cancer. * Familial polyposis coli or adenomas of the colon. * A specific tumor – suppressor gene has been found in each of these cancers. * EUGENE PARDI, DO 112 2/26/2011 * Characterization of cancer – causing genes and other genetic factors helps identify individuals prone to developing cancer. * Contributes to our understanding of sporadic cancers. * Individuals known to carry mutations in tumor – suppressor genes are offered targeted cancer screening to facilitate early cancer detection and therapy. * EUGENE PARDI, DO 113 2/26/2011 A familial colon cancer pedigree. Darkened symbols represent individuals diagnosed with colon cancer. One of the individuals in the first generation Must have carried a mutation in the APC gene. EUGENE PARDI, DO 114 2/26/2011 * Chronic inflammation has been recognized for close to 150 years as being an important factor in the development of cancer. * The active immune response in chronic inflammation predisposes to cancer. * Ulcerative colitis 30 fold increase in the risk of developing colon cancer. * Hepatitis B (HBV) or hepatitis C (HBC) increased risk of liver cancer. * 66% increase in risk of lung cancer among women with chronic asthma. * EUGENE PARDI, DO 115 2/26/2011 * After injury and during an infection, inflammatory cells release cytokines and growth and survival factors that stimulate local cell proliferation and new blood vessel growth to promote wound healing by tissue remodeling. * In addition, inflammatory cells release compounds such as reactive oxygen species (ROS), and other reactive molecules that can promote mutations and block the cellular response to DNA damage. * Increased COX – 2 increased PGs associated with colon and other cancers. * NSAIDS, which inhibit COX – 2, reduce the risk of colon cancer by as much as 20%. * EUGENE PARDI, DO 116 2/26/2011 * The immune system is important in protecting us against cancers caused by specific viral infection. * It does NOT protect us against most common cancers. * Individuals on immunosuppressive drugs have a 10 fold increased risk of non – Hodgkin lymphoma (Epstein – Barr virus) * Up to 1000 – fold increased risk of developing Kaposi sarcoma (human herpesvirus 8). * EUGENE PARDI, DO 117 2/26/2011 * There are many complex interactions between elements of the immune system and tumors. * Tumors activate surrounding stromal and inflammatory cells to secrete cytokines that support tumor growth and spread. * Various cells of the immune system can exert antitumor effects by secretion of different factors. * Immune cells both promote and inhibit proliferation. * Hard to harness the immune system to fight cancer. * EUGENE PARDI, DO 118 2/26/2011 EUGENE PARDI, DO 119 2/26/2011 * A number of viruses have been associated with human cancers. * hepatitis B and C viruses (HBV, HCV). * Epstein Barr virus (EBV) * Kaposi sarcoma herpesvirus (HHV8) * Human papillomavirus (HPV). * Above viruses are associated with about 15% of all human cancers worldwide. * Cancer of the cervix and hepatocellular carcinoma account for about 80% of all virus – linked cancers. * EUGENE PARDI, DO 120 2/26/2011 * Chronic hepatitis B infections confer up to a 200 – fold increased risk of developing liver cancer. * Up to 80% of liver cancer worldwide is associated with chronic hepatitis caused by either NBV or HCV. * A lifetime of chronic lifer inflammation predisposes to the development of hepatocellular carcinoma. * The initial acute disease does not increase the risk. * Widespread use of the vaccine should decrease both the risk of infection and cancer. * EUGENE PARDI, DO 121 2/26/2011 EUGENE PARDI, DO 122 2/26/2011 EUGENE PARDI, DO 123 2/26/2011 *Virtually all cervical cancer is caused by infection with specific subtypes of HPV. *Infects basal skin cells and commonly causes genital warts. *100 HPV subtypes. *Only a few (HPV16, 18, 31, 45, and a few others) are associated with cancer. * EUGENE PARDI, DO 124 2/26/2011 *HPV causes cancer when the viral DNA is integrated in to the DNA of the infected cell and directs the persistent production of viral oncogenes. *Can be detected by the Pap smear. *Early detection of cellular atypia is seen. *Vaccine now available. * EUGENE PARDI, DO 125 2/26/2011 EUGENE PARDI, DO 126 2/26/2011 EUGENE PARDI, DO 127 2/26/2011