NURS 5315 Module 1 Study Guide Advanced PathophysiologyAltered Cellular Function and Cance, Exams of Nursing

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N5315 Advanced Pathophysiology

Altered Cellular Function and Cancer

Module Core Concepts and Objectives with Advanced Organizers

Cellular Physiology

1. Analyze the steps of the action potential. ● Sodium permeability increases, sodium ions move into the cell increasing positivity, depolarization is occurring, action potential threshold is reached as cell becomes more positive, potassium permeability increases, potassium ions leave the cell, repolarization is occurring, resting membrane potential is reestablished. · The action potential carries signals along the nerve or muscle cell and conveys information from one cell to another. · When a resting cell is stimulated with voltage the membrane becomes permeable to sodium. · Movement of sodium into the cell, the membrane potential decreases, moves to a negative or zero is known as depolarization. Depolarized cells are positively charged. · To generate an action potential and the resulting depolarization is known as threshold potential. It happens when the cell has depolarized by 15-20 millivolts. When the threshold is met the cell continues to depolarize with no further stimulation. This makes the sodium rush out of cell causing the membrane potential to reduce to zero and become positively (depolarization). This rapid reversal in polarity results in action potential. · Repolarization is negative polarity of the resting membrane potential. Membrane permeability to sodium decreases, and potassium increases with outward movement of potassium. This makes the membrane potential more negative. · During most of the action potential the plasma membrane cannot respond to any additional stimulus is known as absolute refractory period. Its related to changes in sodium. · If potassium increases, a stronger stimulus can evoke an action potential is relative refractory period. · A membrane potential more negative than normal, requires a larger stimulus to reach the threshold potential is hyperpolarized (less excitable). occurs when the membrane is repolarizing. · A membrane that is more positive than normal, needs smaller stimuli to reach threshold potential is hypopolarized (more excitable than normal).
2. Discuss how the action potential is altered by calcium and sodium imbalances and the clinical significance · Na has a greater concentration in the ECF. When a neuron is excited by a stimulus, the stimulus-gated Na+ channels open allowing Na+ to move intracellularly. This moves the

resting membrane potential of -70mV more towards 0. Once the threshold potential is reached (-59mV) the voltage gated Na+ channels open allowing for more Na+ to move into the cell and complete the depolarization to a maximum of +30mV. If the depolarization does not reach a minimum of -59mV (threshold potential) the voltage gated Na+ channels will not open and the cell will simply repolarize to -70mV without generating an action potential. · Hyponatremia: Cellular swelling and deficits of intracellular Na alter the ability of cells to depolarize and repolarize normally. Causes neurological changes headaches, lethargy, and seizures. · Hypernatremia: Na is largely in the ECF, increase concentration of Na causes intracellular dehydration and hypervolemia. Causes hypotension, tachycardia, thirst. · Hypercalcemia decreases cell permeability to sodium. This causes the threshold potential to become more positive and is further away from the membrane potential. It takes more of a stimulus to initiate an action potential. The cells are far less excitable and do not initiate action potentials. This leads to weakness, hyporeflexia, fatigue, lethargy, confusion, encephalopathy, a shortened QT segment and depressed widened T waves on EKG. · Hypocalcemia- calcium deficits causes partial depolarization of the nerves and muscle as the threshold potential becomes more negative and approaches resting membrane potential (hypopolarization). A smaller stimulus is needed to start the action potential. This means the cells are more excitable. This results in tetany, hyperreflexia, paresthesias, prolonged QT interval, seizures, muscle spasms, laryngospasm. Topic Describe the Action Potential How is the action potential altered by a potassium imbalance? How is the action potential altered by a calcium imbalance? Action Potential Physiology is the membrane potential of an active neuron. One that is conducting an impulse. The process of conducting an impulse (action potential) involves a stimulus that Hypokalemia causes a more negative resting membrane potential therefore the cell is more difficult to excite. Because potassium contributes to the repolarization phase of the action potential, hypokalemia delays ventricular repolarization and the frequency of action potentials Hypercalcemia causes a higher action potential threshold causing a more difficult excitable action potential. Hypercalcemia decreases the cell permeability to Na+ which makes the threshold potential more positive and further away from the

activates the neuron → the neuron depolarizes → then repolarizes Once the cell is more positively charged, the sodium channels open and sodium flows into the cells. Membrane potential is near zero. The neuron repolarizes (becomes more negatively charged), potassium channels open. Causes: weakness, smooth muscle atony, paresthesias, cardiac dysrhythmias Hyperkalemia affects the resting membrane potential. the resting membrane potential of the cell becomes more positive. A normal RMP of -90mv may now be -80mv. The cell is said to be hypo-polarized. The cells are more excitable and conduct impulses more easily and more quickly.; therefore, the person will have peak T waves on EKG. As potassium rises the resting membrane potential will continue to become more positive and it will eventually become equal to the threshold potential. The threshold potential is the point at which depolarization must reach in order to initiate an action potential (transmit the impulses). If the resting membrane potential equals the threshold potential, an action potential will not be generated and cardiac standstill will occur. Paralysis and membrane potential. Takes a stronger stimulus to initiate the action potential. Cells are less excitable. Causes: weakness, hyporeflexia, fatigue, lethargy, confusion, encephalopathy, shortened QT segment, depressed widened T-waves. When the action potential reaches the axon ending, it causes another ion (calcium, Ca++) to en ter the cell, which in turn causes the vesicles—the tiny bubbles full of neurotransmitters—to release their content into synaptic gap Hypocalcemia : there is an increase in cell permeability to Na+ which causes progressive depolarization. Threshold potential more negative; closer to the resting membrane potential. Cells are more excitable.

paresthesias may also occur. Causes: tetany, seizures, hyperreflexia, dysrhythmias, and circumoral parasthesias Hyperpolarization – requiring a stronger stimulus (decreased excitability) to initiate depolarization and an action potential Cellular Adaptation Patterns

1. Analyze the differences between cellular adaptation patterns. a. Differentiate between the etiology and the pathophysiology of atrophy, hypertrophy, hyperplasia, dysplasia, and metaplasia and identify an example of each. Disease Etiology Pathophysiology Example Atrophy (Adaptive decrease in cell size) Decrease or shrinkage of cell size Can be physiologic – as in early development or pathologic as seen in decrease in workload. Disuse atrophy secondary to immobilization or aging. Decreased protein synthesis, increased protein catabolism. Atrophic muscle cell has less endoplasmic reticulum and fewer myofilaments. Thymus gland decreases in size during childhood, aging brain cells

Hypertrophy (Adaptive increase in cell size) Increase in size of cell and even organs Occurs as an adaptive response in striated muscle cells of both the heart and skeletal muscles. Physiologic: response to heavy work load. Pathologic: associated with pressure or volume overload in disease. Mechanical triggers (stretch) and trophic signals (growth factors and vasoactive agents). The increase in cellular size is associated with an increased accumulation of protein in the cellular components (plasma membrane, endoplasmic reticulum, myofilaments, mitochondria) and not with an increase in the amount of cellular fluid. Hormonal stimulation or increased functional demand Man, who lifts weights regularly develops larger biceps, kidney after transplantation, Cardiac hypertrophy secondary to hypertension, or valvular dysfunction Hyperplasia (Adaptive increase in number of cells) Response to injury occurs when the injury has been severe and prolonged Physiologic: adaptive mechanism that enables certain organs to regenerate. Pathologic hyperplasia: abnormal proliferation of normal cells and can occur as a response to excessive hormonal stimulation or the Increased rate of cellular division in cells capable of mitosis (reproduction). Cells only increase in number; size of the cell remains the same. Compensatory hyperplasia - enables certain cells to regenerate Hormonal - estrogen dependent organs Lining of the uterus thickens after ovulation because of increased amounts of estrogen, liver post transplantation(hep atocytes), bone marrow, callus.

effects of growth factors on target cells Dysplasia (AKA Atypical hyperplasia) Abnormal change in size, shape, and organization of mature tissue cells Strongly associated with common neoplastic growths. Abnormal changes in size, shape, & organization of mature cells. Not a true adaptive process, often called atypical hyperplasia Not considered a true adaptive process. Often found adjacent to cancerous cells Is classified as Mild Moderate Severe Cervical(pap test) and respiratory tract. Atypical hyperplasia is Strong predictor of breast cancer development. Metaplasia (Reversible replacement of one mature cell by another, sometimes less differential, cell type) Results from exposure of cells to chronic stressors, injury or irritations. Thought to develop from a reprogramming of stem cells existing in most epithelia or of undifferentiated mesenchymal cell present in connective tissue Bronchial metaplasia - Columnar epithelium in bronchi of cigarette smoker is replaced by stratified squamous epithelium b. Identify a physiologic and pathophysiologic example for atrophy, hypertrophy, hyperplasia, dysplasia, and metaplasia. Disease Physiologic Example Pathologic Example Atrophy Thymus Gland: shrinks after Disuse muscle atrophy:

puberty, having already produced most of the T-cells needed for a lifetime. It eventually atrophies to nearly nothing, being replaced by adipose tissue. Bed-bound patients, disuse atrophy Hypertrophy Exercising; Changes in uterus during pregnancy Left Ventricular Hypertrophy; Cardiomegaly; Increased workload in hypertensive patients; Hyperplasia Liver regenerates after surgical removal of damaged portion Changes in uterus during pregnancy Endometriosis In the endometrium, which is caused by an imbalance between estrogen and progesterone secretion with over secretion of estrogen, causes excessive menstrual bleeding. Dysplasia Tissue changes in resp tract Cervical Ca or breast Ca Persistent, severe cell injury or irritation. Disordered cell growth. AKA pre-cancer. Epithelial tissue of the cervix and respiratory tract Metaplasia Change from columnar cells to squamous cells of bronchial lining in chronic smokers. New cells don’t secrete mucus or have cilia which causes a loss of a vital protective mechanism. Can be reversed if stimulus (smoking) is removed.

Mechanisms of Cellular Injury

2. Analyze the mechanisms and outcomes of cellular injury. a. Differentiate between the etiology, clinical manifestations and pathophysiology of cellular injuries caused by hypoxia, free radicals, and ethanol. Cellular Injury Etiology Clinical Manifestations Pathophysiology Hypoxic Injury HTN, hyperlipidemia, DM, ischemic heart disease, chronic heart disease, CHF, sleep apnea Lack of sufficient oxygen Lack of O caused by ↓ O in air; loss of hemoglobin or hemoglobin fx; ↓ RBC; cardio dzs; ischemia. From asphyxiation, drowning, Fe def anemia -poisoning of oxidative enzymes Pain, decreased pulses, change in pallor, paresthesia organ injury, cell/organ death Inflammation Anoxia MI Acute CVA Gradual narrowing of arteries, complete blockage, MI, stroke. Lack of O2, insufficient ATP, leads to anaerobic metabolism, which generates ATP from glycogen when tehe runs out, anaerobic metabolism ceases. See page 57 to read this rest!! ↓ O2 → ↓ mitochondrial fx→ ↓ of ATP → Na-K pump disfx → ↑ K out of cell & ↑ Na left in cell also ↑ Ca++ into cell → ↑ H2O coming in cell → swelling → ↓ protein due to ribosomal dilation and malfx

Free Radical and Reactive Oxygen Species (ROS) An atom or group of atoms having an unpaired electron. UV light, x rays, all biologic membranes contain redox systems important for cellular defense, from example inflammation, iron uptake, growth and proliferation, and signal transduction) Molecules are unstable and highly reactive. ROS can be produced as a normal byproduct of ATP production in the mitochondria and by migrating inflammatory cells. A molecule with unpaired electron in outer shell, steals electron from others (usually cell membranes or nucleic acids); from absorption of extremem energy sources (eg uv rays or xrays); reactions such as redox rx, metabolism of chemicals or drugs HTN, hyperlipidemia, DM, ischemic heart disease, chronic heart disease, CHF, sleep apnea Mitochondrial oxidative stress is r/t -Heart disease -Alzheimer’s P-arkinson’s -ALS Cell injury, aging, heart dz, Alzheimer’s dz, Parkinson’s dz, Amyotrophic Lateral Sclerosis, vascular damage, cancer, sterility, GI dysfx, autoimmune dz ROS – adverse cardiovascular events · Vasoconstriction · Vascular smooth muscle proliferation · Hypercoagulability · Thrombosis · HTN · HLD · DM · Ische mic Heart Dz · Chronic HF · Sleep apnea Leads to vascular endothelial injury HTN, hyperlipidemia, DM, ischemic heart disease, chronic heart disease, CHF, sleep apnea. Pg 60 ROS overwhelms endogenous antioxidant systems leading to vascular endothelial injury leading to atherosclerosis. Adverse cardiac events caused by vasoconstriction, proliferation of vascular smooth muscle, hypercoagulability and thrombosis. Overwhelms mitochondria and uses all antiox; destruction of lipids (cell wall permeability); damage proteins (ion pumps and cell transport); fragment DNA; ↓ protein; chromatin destruction and damage mitochondria

Ethanol Rapid loss of the plasma membrane structure, organelle swelling, mitochondrial dysfunction, and the lack of typical features of apoptosis Substance Abuse CNS depression, Wernicke encephalopathy, peripheral neuropathy, Korsakoff psychosis, folic acid deficiency (importance of ETOH and pregnancy). ALD, acute gastritis Liver failure, esophageal tears, Wernicke- Korsakoff syndrome, pancreatitis, Hepatitis and cirrhosis, Fetal alcohol syndrome, withdrawal, vitamin/mineral defic., oral cancer, Affects nutritional status incl. deficiencies of -- Magnesium --Vitamin B --Thiamine --phosphorus -- folic acid – decreases After ingestion, alcohol is absorbed unaltered into the stomach and small intestine and then transported to the liver. It is metabolized into acetaldehyde through the enzyme alcohol dehydrogenase. It is metabolized in the liver. Ethanol is metabolized to acetaldehyde with the ADH (it's an enzyme alcohol dehydrogenase) this causes an Increase in the NADH/NAD+ ratio in liver will: ● Pyruvate converts to lactic acid causing lactic acidosis

intestinal absorption of folate ? sleep apnea hepatic and gastric changes Chronic= ald liver dz Fatty liver? > HCC Cirrhosis > portal HTN & Increased risk of HCC Alc hepatitis Alc cardiomyopathy HTN, regressive change in skeletal muscle In utero exposure = FAS Fetus has very limited ADH causing fetus to be almost completely dependent on maternal ADH. Amniotic fluid holds ETOH --acetylaldehyde can disrupt cell differentiation and growth; DNA and protein synth;modification of carbs, proteins & fats; & flow of nutrition across placenta FAS > growth retardation, Cognitive impairment, facial anomalies and ● Oxaloacetate converts to malate which prevents gluconeogene sis (glucose formation) leads to fasting hypoglycemia ● Triglyceride formation Metabolized by ADH into acetaldehyde → alters NADH/NAD+ ratio causing: pyruvate changes to lactic acid = latic acidosis; oxaloacetate converts to malate preventing gluconeogenesis → hypoglycemia; ↑triglycerides and hepatosteatosis; ↓ citric acid cycle = ketoacidosis and hepatosteatosis

ocular disturbances. ETOH increases apoptotic cell death b. Evaluate the process of necrosis, infarct, and apoptosis and describe the implications for clinical practice. Cell Death Cellular Effect Clinical Implications Necrosis Cellular Effect: Rapid loss of the plasma membrane structure, organelle swelling, mitochondrial dysfunction, and the lack of typical features of apoptosis. Process of cellular self digestion Occurs in the setting of irreversible cellular injury Karolysis- nuclear dissolution & lysis of chromatin from hydrolytic enzymes Pyknosis- nucleus shrinks & becomes small dense mass of genetic material. Mass eventually dissolves via karyolysis Liquefactive brain tissue has + Clinical Implications: Programmed necrosis is associated with development, tissue damage during acute pancreatitis, retinal detachment Provides an innate response to viral infection Coagulative > kidneys, heart, adrenal glands.

• results from hypoxia by ischemia or chemical injury, esp Mercuric chloride. -caused by protein denaturation > protein alb to change from gelatinous to firm, opaque, white -?? Intracellular Ca++ may cause coag necrosis Liquefactive > neurons, glial cells

• digestive hydrolytic enzymes & little connective tissue, walls off and forms cysts -bacterial infections staph, strep, e.coli > hydrolases are released from lysosomes of neutrophils > causes pus Caseous Dead cells disintegrate but debris not completely digested by hydrolases, causing tissue to be soft and granular like lumpy cheese. Granulamatous inflammatory wall encloses area of necrosis Fat cellular destruction by lipases > breakdown trigycerides releasing free fatty acids which combine w/ Ca++, Mag, Na+ creating saponification. Opaque and chalk white. Gangrenous death of tissue from severe hypoxic injury > arteriosclerosis, occlusion of major arteries, esp of lower limbs dry gangrene usually from coagulative necrosis. wet gangrene neutrophils invade site > liquifactive necrosis. gas gangrene invasion of Clostridium bacteria. Produce hydrolytic enzymes and toxins Form cysts as they degrade and liquefy. Caseous Commonly results from TB infection—mycobacterium tuberculosis. Combination of liquitfactive & coagulative necrosis. Fat breast, pancreas, and structures. Gangrenous occlusion of major arteries, esp of lower limbs. May require amputation dry gangrene Skin is dry and shrinks, looks mummified. wet gangrene Very malodorous, +
• pus, can become systemic causing death gas gangrene can be fatal if enzymes lyse RBC membranes destroying O2 carrying capacity.

that destroy connective tissue & cellular membranes causing bubbles of gas Death d/t shock Treated w/ antitoxins and hyperbaric O Infarct Cellular Effect: An infarct is an area of necrosis which results from a sudden insufficiency of arterial blood flow. Ischemic injury. Sudden lack of oxygen to the cell, acute anoxia. Clinical Implications: Example: Myocardial infarction. Obstruction of coronary arteries leads to acute anoxia and cell death if oxygen is not restored soon. Apoptosis Cellular Effect: Cell death that involves orderly dismantling of cell components and packaging the remainder in vesicles. Prevents cellular proliferation that would result in a gigantic body. Prevents abnormal cell changes from being multiplied. Death of lymphocytes after an inflammatory reaction. Involution of lactating breast after weaning (death of hormone- dependent tissue). Involution of lactating breast after

Regulated or programmed cell death and removal of cellular debris/fragments. Normal apoptosis occurs during embryogenesis; involution of hormone dependent tissue after hormone withdrawal. Severe cell injury – injury exceeds cellular repair mechanisms, cell triggers apoptosis Accumulation of misfolded proteins- may result from genetic mutations or free radicals. Infections (esp viral) may be result of virus directly or indirectly by host immune response.

cytotoxic T lymphocytes respond to viral infection inducing apoptosis and eliminating inf. Cells obs in tissue ducts – pancreas, kidney, parotid gland. Dysregulated – excessive or insufficient apoptosis

• may not eliminate lymphocytes that react against host tissue -->
• may increased causing ------> weaning. Cell loss in proliferating cell populations > immature lymphocytes may be self reactive & cause death of cells after useful fxn performed > neutrophils after inflammatory reaction Severe cell injury – DNA damage d/t production of free radicals Accumulation of misfolded proteins- ER stress > linked to degenerative dz of CNS and other organs Infections (esp viral)

  can cause tissue damage rejection of tissue transplants obs in tissue ducts – pathologic atrophy Dysregulated – can cause proliferation of abnormal cells increasing Ca risk. - autoimmune disorders neurodegenerative disorders ischemic injury (MI, CVA) death of virus infected cells Altered Cellular Metabolism

3. Examine the mechanisms and effects of altered cellular metabolism. a. Analyze the steps of ethanol metabolism and describe how it causes hepatocellular damage. · Ethanol is metabolized to acetaldehyde in the cytoplasm of the cell. · The major pathway involves alcohol dehydrogenase, an enzyme located in the cytosol of hepatocytes. The MEOS depends on cytochrome p-450 (CYP2E1) an enzyme for cell oxidation. Activating CYP2E1 is thought to accelerate ethanol metabolism. · After ingestion alcohol goes to stomach and small intestine to go to liver. · Is distributed to tissues and body. · Oxidative stress is associated with cell membrane phospholipid depletion, alters fluidity and functions of cell membrane. · Ethanol increases apoptotic cell death. - The initial liver changes are characterized by accumulation of inflammatory cells and matrix deposition around the portal vein. Reactive oxygen and nitrogen species and dysregulated redox signaling pathways are associated with alcohol consumption b. Analyze the main concepts of ketogenesis and describe the implications for clinical practice. Ketogenesis Concept Role Clinical implications Role of the hepatocytes A protein, hepatocyte growth factor is a mediator in vitro of liver regeneration. Hepatocytes process acetyl- CoA during ketogenesis and transform it into ketone bodies (Acetoacetate, Acetone, and Beta-hydroxybutyrate). Liver regeneration Role of the mitochondria In the liver: ketone body synthesis (produced when glucose is not available as a source of fuel) In mitochondria: Generates ATP by oxidative phosphorylation In the mitochondria: Incr of NADH/NAD+ ratio causes:

• Lactic acidosis
• Hypoglycemia
• Incr triglyceride level & deposits of triglycerides in liver → hepatosteatosis

acetaldehyde is further converted by acetaldehyde dehydrogenase to acetate and further oxidized niacin (NAD+) is reduced to NADH

• Ketoacidosis Triggers for ketogenesis

2. starvation = triggered by the lack of glucose. deficient amounts of glucose may occur from the depletion of carbohydrate stores or may occur because the cell is not able to use glucose but the individual is hyperglycemic. This is what happens in diabetes mellitus type 2 Watch for signs of ketoacidosis in patients predisposed to ‘starvation’.... Uncontrolled Diabetes, anorexia, absorption related diseases (Crohn’s, Ulcerative colitis, etc). Need to either figure out how to get glucose into patient’s blood serum (starvation), or how to get glucose from serum into cells (diabetes) Profound metabolic acidosis Role of Acetyl-CoA Undergoes many metabolic conversions in the citric acid cycle that produces energy ATP Effect on oxaloacetate Needed in order to convert CoA to citric acid cycle to generate energy Also used in gluconeogenesis Without sufficient oxaloacetate to bind to, Acetyl-CoA cannot be converted to citrate. This means there are increased levels of Acetyl-CoA. This leftover Acetyl-CoA is processed into ketone bodies, contributing to ketoacidosis.

Cancer

4. Examine the basic concepts of cancer nomenclature and biology. a. Explain how a cancer cell’s biology differs from a normal cell’s biology. Normal Cell Biology Cancer Cell Biology

• Uniform in size and shape
• Normal cells cease to divide once they fill the space
• Will not grow unless attached to a firm surface
• Limited life span (divide maybe 10 to 50 times in petri dish but then cease growing)
• Use oxidative phosphorylation (OXPHOS) to turn glucose into C and energy in the form of ATP - Anaplasia “without form”, vary in size and shape - Cancer cells lack contact inhibition and continue to crowd, eventually piling up on one another - Anchorage independent, that is; they continue to divide even when suspended in a soft agar gel - Immortal, they seem to have an unlimited life span (can continue to divide for years under appropriate lab conditions) - Cancer cells often show defects in continue the normal process of differentiation, that is the process of acquiring specialized function and organization, such as evolving into a muscle or nerve cell. - Cancer cells take a different approach, even in the presence of oxygen, they don’t use the oxidative phosphorylation. Instead they consume large quantities of glucose to make cellular building blocks, supporting rapid proliferation, A/tP. b. Identify the cancer types which produce the tumor markers alpha fetoprotein, carcinoembryonic antigen, beta human chorionic gonadotropin, and prostate specific antigen. Tumor Marker Origin Alpha Fetoprotein Liver & Germ Cells Carcinoembryonic Antigen Pancreas, GI, Lung, Breast, etc. Beta Human Chorionic gonadotropin Germ Cells Prostate Specific Antigen Prostate

c. Identify the origins of a cancer based on the following cancer nomenclature: Carcino-, sarco-, -oma, -blastoma, and carcinoma in situ. Term Definition Example Carcino- (prefix) Cancer arising from Epithelial tissue Breast, prostate, pancreas, lung & colon Sarco- (prefix) Tissue (connective and supportive) Bone, fat, nerve, muscle and other connective tissues; examples: osteosarcoma (malignancy of bone); liposarcomas (fat), and gastrointestinal stromal tumour -oma (suffix) Benign tumors that are named according to the tissue from which they arise *Tumor or abnormal growth Adenoma (glandular tissue), Fibroma (fibrous tissue), Hemangioma (blood vessel), Myoma (muscle tissue), Lipoma (fat cells), Meningioma (meninges), Neuroma (nerve), Papilloma (epithelial tissue), Osteochondroma (bone) Carcinoma in Situ Preinvasive epithelial malignant tumors of glandular or squamous cell origin Defined as low grade --> high grade Cervix, skin, oral cavity, esophagus, bronchus. In glandular epithelium it occurs in the stomach, endometrium, breast, and large bowel. -blastoma (suffix) Type of cancer, more common in children than adults. Caused by malignancies in precursor cells often called “blasts”. Tumor of primitive incompletely differentiated or precursor cells. Arises in neural or retinal cells Nephroblastoma Medulloblastoma Retinoblastoma

d. Describe the patterns of metastasis of the specified cancers (lung, colorectal, testicular, prostate, breast, head and neck, ovarian, sarcoma, melanoma) and the implications for clinical practice. Primary cancer Sites of Metastasis Clinical Implications Lung Multiple organs, including brain Difficult to treat, need to find primary Colorectal Liver Testicular Lungs, liver, brain Prostate Bones (especially lumbar spine), liver Breast Bones, lung, brain, liver Low stage v. high stage have vastly differing survival Head and Neck Lymphatics, liver, bone Ovarian Peritoneal surfaces, diaphragm, omentum, liver, lungs Sarcoma Lungs Melanoma In transit lymphatics, lung, liver, brain, GI tract e. Evaluate and describe the mechanisms of cancer metastasis and the implications for clinical practice.

1. Invasion or local spread, is a prerequisite for metastatic process. a.Macrophages digest connective tissue capsules by secreted proteases causing the cancer cells to be more slippery and mobile i.Encapsulated tumors must first break down the capsule to spread
2. must be able to Invade local blood & lymphatic vessels by neoangiogenesis and lymphangiogenesis by factors such as VEGF
3. Gene mutation into Oncogenes: a.Point mutations- Ex: Ras gene converts to unregulated oncogene (seen in colorectal and pancreatic cancer) b.Deletions c.Translocations- large changes in chromosomal structure i.Production of proliferation factor- Burkitt lymphomas where MYC protein is found in mature B lymphocytes ii.Production of novel proteins with growth promoting factors –

chronic Myeloid Leukemia (CML) Philadelphia chromosome which promotes myeloid cells 4.Turning off Genes WITHOUT mutation a.Epigenetic silencing- caused by DNA methylation causing whole sections of a chromosome to shut off b.Changes in the miRNA expression- miRs that stimulate cancer development (oncomirs) i.RNA- induced silencing complex (RISC) f. Explain the TNM staging system for cancers and describe its significance for clinical practice. i. T= Tumor (size & local extent)

1. T0- Free of tumor
2. T1- Lesion <2 cm
3. T2- Lesion 2-5 cm
4. T3- Invasion of surrounding area ii. N= Nodes (lymph node involvement)
5. N0- No axillary nodes
6. N1- Mobile node involved
7. N2- Fixed nodes involved iii. M= Metastases (extent of distance)
8. M0- No mets
9. M1- demonstrable mets
10. M2- Suspected mets Staging determines if the spread of cancer. Prognosis worsens with increased tumor size, lymph node involvement, & metastasis. Staging may also alter the choice of therapy, with more aggressive therapy being delivered to more invasive disease. g. Examine the role and function of oncogenes and tumor suppressor genes in a cancer cell. ever, the gene is not completely deactivated because there is still 1 normal. Oncogenes are mutant genes that, in their non mutant state, are responsible for the production of proteins that induce cell proliferation, or rapid growth. Cancer cells are dependent on oncogenes for their survival. If the oncogene were to return to its non mutant self (aka proto-oncogene) the cancer cell would cease to grow and possibly regress. This dependence on oncogenes, or “addiction,” is known as oncogene addiction. But how do proto-oncogenes become oncogenes and how does this affect the cancer cell? Probably the most common way this mutation occurs is through point mutations, a small-scale change in DNA that results in the alteration of one, or a few, nucleotide base pairs thus affecting

functioning of the proteins. This changes regulated cellular proliferation to unregulated proliferation. Gene mutation also occurs on a larger scale through chromosome translocation. In chromosome translocation a piece of one chromosome is translocated to another chromosome. This will activate the oncogene in one of two ways. One way is by changing what part of the chromosome controls the gene. For example, a proto-oncogene that is responsible for cell proliferation, is typically activated at low levels, and only until the cell matures may be translocated to another part of the chromosome and be controlled a gene that is highly active even in mature cells. This causes increased and unregulated proliferation of cells, as is the case in Burkitt lymphoma. Blocking of cell differentiation can also occur, depending on what the gene is programmed to do. Another way mutation occurs is through the fusion of two chromosomes in the middle of two different genes. This leads to the creation of new proteins with growth-promoting properties. In copy number variation large sections of DNA are either gained or destroyed. In cancer this can lead to an increase or decrease in tumor suppressor genes. One final way mutations occur is through gene amplification. Gene amplification is the duplication of a piece of chromosome so that instead of the normal 2 copies there are tens or even hundreds of copies. This leads to increased expression of oncogenes or drug resistance genes. ii. While oncogenes positively regulate cell proliferation, tumor suppression genes negatively regulate cell proliferation. The job of tumor suppression genes is to regulate the cell division by slowing the cell cycle, or stopping it all together when the cell is damaged. Cancers activate oncogenes and deactivate tumor suppression genes. Another way tumor suppression genes differ from oncogenes is that they require 2 events to deactivate both alleles. (This is because tumor suppression genes work in a recessive manner while oncogenes work in a dominant manner.) The first allele is often deactivated by point mutation, just as in the mutation of oncogenes. Wholly functioning allele. The second allele can be inactivated by silencing or by a piece of the chromosome being lost. In silencing a chemical change occurs (methylation (addition of a -methyl group) or acetylation (addition of an acetyl group)) causes one part of the chromosome to shut off. While this is normal in the body, this can advantageous to cancer cells as it allows for the silencing of tumor suppression cells, the expose mutations in genes, and can lead to expression of oncogenes. Discuss the role of BRCA gene in relation to the risk of cancer in men. ● Men who harbored BRCA mutations developed eight times as many cancers as would have been expected in the general population (according to a cohort study) ● Malignancy rates in a screened population of male BRCA mutation carriers were significantly higher than those in the general population ● Findings support the role of comprehensive screening for male BRCA carriers ● BRCA mutations are rare but occur much more commonly in Israel ● It has been recognized that men who harbor BRCA mutations have an increased risk of developing aggressive cancers. ● Cancers include: prostate, melanoma, colon, pancreas and breast

● Data indicates that there should be clinician awareness in that men with BRCA mutations have a high risk of developing prostate cancer and the need to counsel accordingly ● If there is a hx of breast CA or prostate CA they should be screened immediately