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two types of tumors - benign and Neoplasms malignant (cancer) Terminology Cancer – Pathophysiology – Etiology – Diagnostics – Treatment In order for normal renewal and repair to take place, two processes must occur: 1. Cell Proliferation – new cells r...

two types of tumors - benign and Neoplasms malignant (cancer) Terminology Cancer – Pathophysiology – Etiology – Diagnostics – Treatment In order for normal renewal and repair to take place, two processes must occur: 1. Cell Proliferation – new cells replacing old ones 2. Cell Differentiation – cells acquiring the characteristics of the tissue that they make up In neoplasia, one or both of these characteristics is lost  Neoplasm = new growth = tumor Two types of tumors: 1. Benign Have lost ability to control proliferation, but 1. growth is usually slow and may come to a stop 2. made of fairly well-differentiated cells and well-organized stroma (connective tissue framework) 3. do not invade beyond their capsule 4. no metastasis Generally named for the tissues from which they arise, with the suffix “oma” – e.g., lipoma – benign tumour of fat cells; see Table 8-1 Can still be a problem if the growth interferes with function of surrounding tissue e.g., compression of brain tissue, or inappropriate hormone production Porth p169 2. Malignant More rapid growth rate Loss of differentiation (anaplasia) and tissue organization (a spectrum from low to high grade). Cells are pleomorphic (different sizes and shapes) Lack a capsule and invade nearby blood vessels, lymphatics and surrounding structures Most deadly characteristic: the ability to metastasize (spread far beyond the tissue of origin) Summary: 4 characteristics = loss of control of growth, anaplasia, can invade local tissues, can metastasize (See Table 8.2 for comparison to benign) Malignant tissue is anaplastic and pleomorphic Malignant, cont’d Referred to as “cancer” Many are named for cell type from which they originate with suffix “carcinoma” (from epithelial tissue), or “sarcoma” (from mesenchymal tissue; connective tissue, bone, muscle) – E.g., adenocarcinomas are from glandular tissue. (Table 8.1) Specialized names: “lymphomas” are from lymphatic tissue, and “leukemias” are cancers of blood-forming cells Two categories: – solid tumours (initially confined to specific tissue/organ) – hematologic tumours (cells normally found in blood/lymph) 90% of adult human cancers are carcinomas from malignant transformation of epithelial cells  Poll Question 1 Which of the following is a benign tumour? Response recorded leukemia glioma —- correct answer adenocarcinoma osteosarcoma squamous cell carcinoma glial cells sit around neurons, divide a lot, can become cancerous  Carcinoma In Situ Refers to a growth with malignant characteristics (increased proliferation rate and atypical cells) in epithelial tissue that has not (yet) invaded local tissue (so technically, not malignant) Difficult to decide how to treat, as it may never spread (“wait and see” or remove?) Can remain stable for a long time, become malignant, or even regress Can occur in breast, cervix, skin, stomach Porth p171  Cancer cell characteristics (8) 1. Genetic instability: There is a high frequency of mutations (deletions/insertions/substitutions of bases, loss/gain of whole chromosomes) in cancer cells – normal cells have mechanisms that correct such mutations 2. The cell must become independent of external growth signals: – able to make their own – don’t need any (some breast cancer cells don’t have receptors) – extremely sensitive to growth factors so will respond to extremely low levels (e.g., one type of breast cancer has more receptors on the cell surface, so response to growth factor is increased) (Porth Table 8.3)  3. Loss of contact inhibition: normal cells usually stop growing when they come into contact with each other (E.g. wound Cancer cell healing) but cancer cells keep piling up on top of each other 4. Decrease in cell adhesion: normal cells have membrane structures that allow them to stick together – cancer cells have less of these and can then more easily be shed from a tumour, increasing the possibility of metastasis 5. Loss of anchorage dependence: normal epithelial cells will die if they are not attached to an underlying extracellular matrix Cancer cells can survive and grow under conditions that normal cells can’t (may help in metastasis) 6. Production of unusual antigens: cell surface markers (that are identified as foreign by the immune system), enzymes, or hormones that are not made by the tissue of origin Cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA) ACTH, parathyroid hormone 7. Able to divide without limit (immortal) – how? Telomeres are sections on the end of each chromosome that get shorter with each cell division When they get short enough, the cell can’t divide any more – in the lab, most normal cells can’t divide more than about 50x Cancer cells have a very active enzyme, called makes telomase telomerase, that can lengthen telomere. Therefore, they can divide without limit 8. Altered metabolism; increasing anaerobic respiration ―Why? They divide rapidly, need a lot of building blocks for new cell construction, and often live in anoxic environments ―To facilitate this, cancer cells mainly use anaerobic respiration (glycolysis), even in the presence of oxygen ―This yields much less ATP, but the lactic acid produced can be used to synthesize other molecules needed for rapid growth ―This means that they use much more glucose than regular cells  Geraldine Grows Adorable Corn And Artichokes In Mud This characteristic can be used as a tool for detection: Use a fluorescent compound that is taken up by cells in the same way as glucose, but can’t be metabolized. It accumulates in cells that would take up a lot of glucose (i.e., cancer cells).  Poll Question 2 Contact inhibition describes the property in which normal cells need to attach to a surface to grow Response recorded True False normal cells need to attach to other calls to grow normally would be anchorage dependence and not contact inhibition cancer cells do not stick togetger cancer cells pile on one another, cintact inhibition means when the cells touch another cell and stops growth.  Metastasis A defining characteristic of cancer The spread of cancer cells from the original site to distant organs and tissues Treatment more challenging: cancer that has not metastasized has a much greater chance of being cured with surgery, chemotherapy, and/or radiation Porth p173  Metastasis, cont’d Local spread – helped by enzymes made by the cancer cells that break down cells and connective tissue of surroundings. Growth is via “crablike” extensions sent into surrounding tissue (difficult to remove surgically) – This is different from benign tissue, which pushes on surrounding connective tissue that eventually forms a capsule around the growth (easier to remove surgically) Distant spread - cancer cells must be able to invade lymph and blood vessels (helped by lymphangiogenesis and neoangiogenesis = growth of lymph and blood vessels into the tumour) Carcinomas (epithelial tissue derived) spread through Lymph lymphatic system know the difference!!! Important Sarcomas (fibrous tissue derived) spread through Blood blood stream  If the spread is through the lymph, the tumour cells lodge first in the initial lymph node that drains that area. This node is known as the “sentinel node”. Examination of such nodes can show if metastasis has occurred If spread is though the blood, the organ that is next in the vascular pathway may most likely be affected (e.g., the liver is a common place for metastasis to be successful from tumours in the intestines), or it could be an organ that supplies a similar environment as the tissue containing the original tumour (e.g., same types of growth factors)  Invasion and Metastasis - process Cancer cells: 1. must evolve characteristics needed to metastasize (as outlined previously) 2. initially invade the interstitial spaces of local tissue 3. if carried by lymphatic drainage, go to primary or sentinel lymph node/s 4. enter the venous system as lymph drains into left and right subclavian veins 5. must evade the innate immune system (e.g. NK cells, lymphocytes) by mimicking normal cells (e.g. coating with platelets) 6. secrete proteolytic enzymes in order to penetrate tissues from blood vessels (and vice versa) 7. once “seeded” release cytokines and growth factors that control invaded tissue functions: – to stimulate their growth and proliferation – if cancer tissue grows more than 1 mm in diameter, it requires its own blood supply; cancer must develop ability to perform angiogenesis ****Fewer than 1 in 10,000 cells survives to start a secondary tumour**** (Study of women with malignant ovarian cancer cells) Steps in metastasis:  Poll Question 3 Benign tumours spread into the lymph first and malignant tumours spread directly into blood Response recorded True False because benign tumors dont spread, invade or metastize.  Local effects of tumours (6) Local effects of tumour growth often depend on location: 1. Compression: e.g. brain tumor: headaches, nausea, loss of consciousness, death. Local nerve compression: loss of function, sensation 2. Obstruction: e.g. blockage to airways or gut 3. Infarction: growth of mass can obstruct blood vessels, causing local necrosis of tissues (ulceration and bleeding) (e.g., blood in stool from colorectal cancer) 4. Hemorrhage: damage to blood vessels, e.g., intestine, lungs All of these can cause pain 5. Rupture or perforation e.g. gut, ovary 6. Effusions (inappropriate amounts of fluid) in pleural, pericardial or peritoneal spaces may occur – up to 65% of women with ovarian cancer present with ascites (excess fluid in the peritoneal cavity) Effects are usually combined and relate to symptoms: e.g. cancer of the lung may present with chest pain, shortness of breath and cough, wheezing, blood in sputum  Systemic manifestations of cancer (9) 1. Paraneoplastic syndrome Symptoms triggered by substances released by the cancer cells, but not caused by direct local effects of the tumour mass. E.g., some tumours release hormones that may have systemic effects – small cell carcinoma of the lung releases an ACTH-like substance, causing Cushing syndrome Porth p185 - 187 2. Pain: Little or none in early stages, can be strong in later stages. Can result from pressure, stretching, inflammation. Important to control rapidly and completely 3. Fatigue: Not relieved by sleep or rest. Mechanism not fully understood. May be due to sleep disturbances, various biochemical changes, nutritional status, etc 4. Cachexia: Definition: Loss of body mass due to metabolic disturbances caused by a disease and cannot be reversed nutritionally; even with adequate caloric intake Caused by altered metabolism that leads to inefficient use of energy Compounded by side-effects of the cancer/treatment: depression, anorexia, loss of sense of taste, early satiety 5. Anemia: Caused by chronic bleeding, malnutrition, chemotherapy and malignancy in blood-forming organs 6. Leukopenia and thrombocytopenia: Caused by tumour invasion of bone marrow, chemotherapy, radiation therapy 7. Infection: Most significant cause of complications and death due to loss of immune cells (as described in 6). Causes increased risk from surgery, poor tissue perfusion, indwelling devices (catheters) 8. GI tract: Relies on rapidly multiplying tissue which is the type of tissue affected by chemotherapy and radiation therapy. These treatments can cause oral ulcers, malnutrition and infection Nausea also effect of therapeutic agent on nervous system 9. Hair and skin: Also due to rapidly growing tissue being affected by therapeutic agents Poll Question 4  What causes a cell to become cancerous? A small number of changes in the genetic material of the cell its not just one mutation that cause cancer, its a pile of genetic mutations that causes it. has to be atleast 5. These changes allow that cell to divide with less inhibition – therefore that cell and all of its progeny will divide more than regular tissue uv rays, cancerous cells duh duh duh The rate of cancer increases dramatically with age, due to accumulation of small changes in genetic material (“mutations”) that occur over a lifetime When enough mutations occur, cancer may develop Porth p176-184 age causes cancer! passing of age  Carcinogenesis Initiation Exposure to carcinogenic agent irreversible mutations to genome may be many small doses over time cells in mitosis or meiosis most susceptible Promotion: Cytokines and growth factors begin to induce cell proliferation Progression: Tumour cells eventually acquire all the characteristics needed to invade and metastasize to other tissues  What types of changes in genes actually occur in cancer? 1. Changes in the actual DNA: two types of genes, which if they mutate, can lead to cancer: a. Proto-oncogenes b. Tumour suppressor genes a) Proto-oncogenes Genes that in their normal non-mutant state code for proteins that cause the cell to divide E.g., a growth factor, growth factor receptor, or a protein involved in transmitting the signal from a receptor to the nucleus If these do mutate and become more active, they are called oncogenes and cause cell to divide uncontrollably E.g., the RAS family of proteins that transmit the growth signal from the membrane receptor to the nucleus (involved in 30% all cancers) b) Tumor-suppressor genes (anti-oncogenes) Genes that code for proteins that slow the rate of cell division or stop it when the cell is damaged If one copy of the gene is inactivated, the other copy can still perform the function – Remember, we have 2 copies of each gene: (one maternal, one paternal). Therefore, both copies of the gene must be altered in order for this to have an effect (“recessive in effect”) on cell growth These are usually the type of genes that are involved in cancer that can be inherited – Individuals can inherit a defective allele, but have protection of other allele. However, if the other allele becomes inactivated, then a tumor can develop – E.g. i) BRCA1 gene in breast cancer ii) p53 gene (guardian of genome) - normally stops mitosis of abnormal cells becomes inactivated in >50% cancers Also contributing to the development of cancer: 2. Changes in metabolic pathways inside the cell E.g., loss of DNA repair machinery that could fix an oncogene, loss of ability to perform apoptosis that would normally cause a malfunctioning cell to die, etc. 3. Changes in the control mechanisms that govern which genes are expressed (epigenetics) E.g. you may have normal tumour suppressor genes, but they aren’t active Epigenetics - DNA Sequence remains the same but genes can be switched on / off most important genes to know ARE P-O (growth promoting gene and Tumor suppressor gene (TSG) mutation increases the activity of oncogenes proto oncogenes- helps cell to divide (+) inhibits cell growth (-), decrease activity TSG might cause apoptosis, decreased activity dna repair genes- proof reading the dna and genes and helop repair any changes in DNA. They are genetically unstable. epigenetics- related to our genes, but it is more specific to the molecules  Poll Question 5 Which genetic change (mutation) is most likely to cause cancer? decreased activity in proto-oncogene increased activity in DNA repair gene increased activity in tumour suppressor gene decreased activity in tumour suppressor gene- increased activity in apoptosis gene  -etiology of cancer? getting older Cancer Etiology smoking not protecting yourself from the sun having certain genetic changes being overweight or obese not having a healthy diet not getting enough physical activity Inflammation drinking alcohol coming into contact with harmful chemicals at home or at work increased chronic inflammation may cause cancer having certain types of infections – Chronic inflammation has been recognized for close to 150 years as being an important factor in the development of cancer. – Inflammation and cancer both involve the migration of neutrophils, lymphocytes and macrophages and the release of factors that stimulate the growth of cells and blood vessels. Inflammatory cells also release compounds that can promote mutations (e.g., reactive oxygen species)  Viral A number of viruses have been associated with cancer, through virus alteration of the cell DNA, or through inflammation from the viral disease: Up to 80% of liver cancer cases worldwide are associated with chronic hepatitis (HBV or HCV) Virtually all cervical cancer is caused by infection with specific subtypes of HPV. The viral DNA becomes integrated into the host cell DNA and can activate proto-oncogenes can cause anal cnacer and penal cancer in men EBV virus (infectious mononucleosis) infects B cells and stimulates their growth. If the individual is then immunosuppressed (HIV infection or organ transplant), persistent EBV infection can lead to B cell lymphomas these virus, get into our body and integrate in our DNA and when our cells multily they copy as well and multiply Bacterial Chronic infection with Helicobacter pylori and inflammation has been linked to gastric carcinoma, a leading cause of cancer deaths worldwide Obviously other factors, in addition to the initial infection, are required, since not all people with these infections develop the associated cancer e.g., 90% of population can be infected with EBV, yet relatively few develop EBV-related cancer  Environmental/lifestyle interactions – Supported by epidemiological studies these suggests that the following causes can cause cancer – Include: cigarette smoking, excessive alcohol consumption, poor diet, obesity, lack of exercise, exposure to UV and ionizing radiation, pesticides and other chemicals – May be possible that these are affecting how the genes are expressed, and not the genes, themselves (epigenetics) – Evidence for influence from these sources is strong, but unclear how these factors affect individual resistance to cancer-causing agents (carcinogens)  Population-Based Studies do not memorize Regions of Highest Incidence U.K.: Lung cancer JAPAN: Stomach cancer CANADA: Leukemia lung cancer is more common now U.S.: CHINA: Colon Liver cancer cancer BRAZIL: Cervical AUSTRALIA: cancer Skin cancer  Heredity? Behaviors? Other Factors? Colon Cancer Stomach Cancer (Number of new cases (Number of new cases per 100,000 people) per 100,000 people) 100 100 70 50 5 7 0 0 Japan Japanese U.S. Japan Japanese U.S. families families in U.S. in U.S. Causation is not always clear cut  Diet Correlation Between Meat Consumption and Colon Cancer Rates in Different Countries 40 30 Number of Cases (per 100,000 people) 20 10 0 80 100 200 300 Grams (per person per day)  Heredity and Cancer All Breast Cancer Patients Inherited factors – e.g. BRCA1 / BRCA2 Other factor(s) Only 10 - 20% of all cancers linked to heritable factors  Proportion of women with a TSG BRCA1 or 2 mutation that develop breast cancer by a given age Anglian Breast Cancer Study Group. Br J Cancer. 2000; Easton et al. Am J Hum Genet. 1995; Antoniou et al. Am J Hum Genet. 2003; Antoniou et al. Br J Cancer. 2002; Antoniou et al. Genet Epidemiol. 2000; Brose et al. J Natl Cancer Inst. 2002; Ford et al. Am J Hum Genet. 1998; Schubert et al. Am J Hum Genet. 1997. 46 Heredity Can Affect Many Types of Cancer read this, do not have to memorize it all Inherited Conditions That Increase Risk for Cancer  Chemical read this, do not have to memorize it all Some Carcinogens in the Workplace  smoke ring, whenever you burn anhything you release this. It is a carcinogen Benzopyrene Chemical: Alcohol and Tobacco Combination of Alcohol and Cigarettes Increases Risk for Cancer of the Esophagus 40x 30x Risk Increase 20x 10x Alcoholic Drinks Consumed per Day AND Packs of Cigarettes Consumed per Day  Lag Time 20-Year Lag Time Between Smoking and Lung Cancer Cigarette consumption (men) 4000 150 Lung Cigarettes 3000 cancer Smoked (men) Lung Cancer per Person 100 Deaths (per per Year 2000 100,000 people) 50 1000 1900 1920 1940 1960 1980 Year How does the multi-step process of mutation relate to this?  Low-Strength Radiation High Melbourne Skin Cancer Incidence Pittsburgh Ottawa Low Least Most Annual Sunshine (UV radiation)  High-Strength Radiation High Leukemia Incidence Low Least Most X-ray Dose (atomic radiation)  Diagnostic Methods 1. Tumour markers Substances (hormones, enzymes, antigens, antibodies) produced by both benign and malignant cells that are either present in or on tumour cells, or found in blood, spinal fluid, or urine – E.g. PSA (prostate specific antigen), secreted by prostate tumours into blood Can help to identify high risk people, diagnose the tumour and follow the success of the treatment Must be used with caution, however, as can get false positives and negatives (not the only test used for diagnosis) Best use may be to monitor success of therapy Porth p188-190 2. Cytology/Histology – The Papanicolaou test (“Pap” test): The secretions surrounding a tumour can contain cells of the tumour (as these cells are easily shed). Examination of the secretion can reveal abnormal cells (cervical, pleural, peritoneal secretions, etc.) – Biopsy: removal and examination of tissue sample, (through a needle, an endoscope/laparoscope, or surgically) – Immunohistochemistry: Use of antibodies specific for a particular cell product or surface marker to detect the presence of that product or marker For example, breast cancers can now be sorted into over 4 subclasses based upon the presence of estrogen receptor, HER2/Neu (a gene), and other specific genes and proteins. Such information is extremely important in determining treatment  Immunohistochemistry (IHC) of breast cancer biopsy tissue HER2 neg itive HER2 pos itive human epidermal growth factor receptor cancerous cells https://doi.org/10.1016/j.semcancer.2020.02.016 3. Imaging – endoscopic – ultrasound – standard X-rays – CT (Computerized Tomography): Many x-rays taken from different angles, fed through a computer to produce a 3D image – MRI (Magnetic Resonance Imaging): Uses a magnetic field. Provides more soft tissue detail, but more expensive and time-consuming – PET (Positron Emission Tomography): Like CT, but uses a biologically active molecule attached to a tracer, to show metabolically active tissue Endoscopy - colonoscopy Staging and Grading There are two methods for classifying cancers: grading (according to cellular characteristics) and staging (according to spread) Grading: a portion of the tumour is obtained through a biopsy. The closer the tumour cells resemble normal tissue, the lower the grade.we look to see how abnormal our cells are Porth p190 Staging: Includes size and spread of the disease One common scheme is the 4-stage system: – Stage 1: confined to origin local – Stage 2: local invasive – Stage 3: spread to local lymph nodes – Stage 4: spread to distant sites (e.g., liver cancer to a lung) Another common scheme is the WHO’s TNM system which describes tumour size, lymph node involvement and extent of metastasis The appropriate therapy is then determined. The stage is more influential in deciding on treatment than the grade Staging of colon cancer  Cancer Treatment Three main treatments: 1. Chemotherapy – Targets metabolic pathways – hopefully a cancer cell is more sensitive to a particular chemical. E.g., leukemia is very sensitive to folic acid deficiency, unlike non- malignant cells, so can treat with an antifolate drug – Usually used in combinations to decrease the amount given of any one drug (reducing side effects) to increase attack on cancer cells (some cells in a tumour may be resistant to one drug, but susceptible to another one in the cocktail) – Chemo given alone = induction – Chemo given in combination with surgery: after surgery =adjuvant - to eliminate small metastasized tumours before surgery = neoadjuvant - to minimize removal of normal tissue Porth p191-197 2. Radiation therapy Targeted cells die through molecular damage (particularly to the DNA), caused by the ionizing radiation Most effective on cells that are rapidly renewing Well-suited to localized tissues in areas that are hard to reach surgically (brain and pelvis) Can be through an external beam or by placing small radioactive capsules in the affected area (brachytherapy) – e.g., cervical, prostate, head and neck cancers  3. Surgery Often the definitive treatment for localized tumours May be used prophylactically (women with BRCA1/2 mutations) Precautions include: – Obtaining enough tissue for biopsies, or to ensure all tumour has been removed – Avoiding spread of cancerous cells during operation – Establishing staging information by observing and sampling local lymph tissue  Cancer in children Rare, but still the second leading cause of death in children 1-14 yrs of age Types of cancer are different to adults (epithelial origin: e.g prostate, breast, lung). Children develop leukemia, brain, sarcoma ( e.g., bone); generally fast-growing Childhood cancers usually diagnosed during peak times of physical growth and maturation (first years of life; puberty/adolescence) Causes are largely unknown – some genetic risk factors/congenital conditions have been implicated (e.g., Down syndrome is associated with increased susceptibility to acute lymphoblastic leukemia) – Pre-natal exposure to some drugs or, childhood exposure to ionizing radiation, drugs, electromagnetic fields or viruses More than 70% of children diagnosed with cancer are cured – but early detection is sometimes difficult, as signs and symptoms are often similar to those of common childhood diseases Chemotherapy is more widely used, as children better tolerate side effects and the type of tumours respond better to chemotherapy – Potential benefits of treatment must be balanced against long-term effects, including physical and mental impairments Additionally, there is an increased risk of developing cancer later in life