Week 11 Neoplasia F24 Student PDF

PATH 1017 Neoplasia PATH 1017 2024-2025 1  Outline Review cell cycle – Role of growth factors, tumor suppressor proteins, checkpoints Oncogenesis – Differentiation and cell mutation Etiological factors Benign tumors vs. Malignant tumors Metast...

PATH 1017 Neoplasia PATH 1017 2024-2025 1  Outline Review cell cycle – Role of growth factors, tumor suppressor proteins, checkpoints Oncogenesis – Differentiation and cell mutation Etiological factors Benign tumors vs. Malignant tumors Metastasis Manifestations of cancer Diagnosis and Treatment PATH 1017 2024-2025 2  Let’s review… Can you define these terms? – Proliferation – Differentiation – Apoptosis PATH 1017 2024-2025 3  The Cell Cycle Why is it important to understan d the cell cycle when learning about neoplasia ? PATH 1017 2024-2025 4  Cell proliferation Normally, after a cell has divided, it becomes either a permanent cell or a stable cell What is the difference between a permanent cell, stable cell and labile cell? PATH 1017 2024-2025 5  The cell cycle Normally, the number of cells produced = the number of cells that die The total number of cells in the body remains constant PATH 1017 2024-2025 6  Growth factors Cells divide only when they are told to do so by growth factors These cause stable cells to enter the cell cycle PATH 1017 2024-2025 7 and divide  Cells check themselves… Within the cell cycle, there are checkpoints where the cell will stop cell division if certain parts are not completed There are also checkpoints for DNA damage, where the DNA can be repaired. If it cannot be repaired, the cell is dies by apoptosis. The checkpoints usually stop the division of mutated cells They keep most mutations from developing into cancer PATH 1017 2024-2025 8  Tumor suppressor proteins The proteins that control the checkpoints are called tumor suppressor proteins If the genes for these proteins were mutated, you might get many more cancers PATH 1017 2024-2025 9 Cell Division Requires Duplicating the DNA Telomeres: DNA sequences at the ends of the chromosomes – The enzymes that duplicate DNA attach here – The end of the telomere does not get duplicated What will happen to the telomere as the cell continues dividing? PATH 1017 2024-2025 10  Differentiation “Grown-up” cells are called differentiated because they look different from one another You can tell a liver cell from a skin cell PATH 1017 2024-2025 11  Think about it… What is needed for a cell to develop into a neoplasm? What protective mechanisms fail? PATH 1017 2024-2025 12  Neoplasia Neoplasms proliferate to They often do form new tissue not mature They do not normally die off They do not (differentiate) (apoptosis) to wait for to do the keep the signals from “job” the number of the body tissue is total cells that the new supposed to constant tissue is needed do They ignore signals to stop dividing PATH 1017 2024-2025 13 Oncogenesis Initiation initial mutation occurs Promotion mutated cells are stimulated to divide Progression: tumor cells compete with one another and develop more mutations, which makes them more aggressive PATH 1017 2024-2025 14  Cell Mutation When undifferentiat When ed, rapidly differentiat dividing cells ed, mutate, they “working” form rapidly cells dividing mutate, tumors— they form malignant differentiat tumors ed “working” tumors— benign tumors PATH 1017 2024-2025 15 Comparison of Normal and Cancer Cells What are the differences between normal cells and tumor cells? PATH 1017 2024-2025 16  Tumor cell characteristics Differentiation and anaplasia Genetic instability – Chromosomal abnormalities Growth properties – Altered proliferation – Growth factor – Contact inhibition – Immortality PATH 1017 2024-2025 17  Etiology of cancer Molecular basis of Host/Environment cancer factors Overactive Heredity genes Hormones – Oncogenes Immunologic Underactive mechanisms genes Chemical – Tumor suppressing carcinogens genes – Apoptosis genes Radiation – DNA repair genes Viral agents PATH 1017 2024-2025 18 Molecular Basis of Cancer Cancer growth & replication is controlled by: DNA repair genes: genes that regulate the repair of damaged DNA Proto-oncogenes- genes that promote growth Tumor suppressor genes- genes that are growth inhibiting Apoptosis genes- genes that control programmed cell death PATH 1017 2024-2025 19  Proto-oncogenes The normal genes that code for normal proteins used in cell division – Growth factors – Growth factor receptors – G proteins – Enzymes that produce second messengers – Genes that turn the production of these proteins on and off With alteration (mutation), gene becomes an oncogene. PATH 1017 2024-2025 20  Oncogenes Oncogenes are But they might mutated proto- produce: oncogenes – Too much of the protein Promote autonomous – An abnormal protein cell growth in cancer – Protein that turns on cells in absence of all by itself normal cell growth – Protein that is made promoting signals when it is not needed – Protein that cannot turn cell division off They still code for the – Protein that should be proteins needed for made by a different cell division cell PATH 1017 2024-2025 21  Loss of tumor-suppressor gene function When these genes are not activated, the signals that If there is normally inhibit cell loss of p53 proliferation is lost  leads gene, why to unregulated growth would the person be Example: p53 gene (the more at risk guardian genome) of metastasis? PATH 1017 2024-2025 22  Host & Environmental Factors Heredity – Factor in 50 different types of cancer – Inheritance of gene mutations Examples? Hormonal Factors – Role in cancers of reproductive system – Mechanism unclear – Theory: hormones have role in promoting reproduction of malignant cells – Both endogenous and exogenous hormones play a role PATH 1017 2024-2025 23  Host & Environmental Factors Immunologic Mechanisms 1. Immune system surveillance hypothesis: Normally, the immune system plays a role in resistance to development and progression of cancer 2. Cancer may be associated with impairment or decline in immune function Who is at risk? Why? 3. Tumour antigens – Proteins on tumour cells recognized by immune T- cells or by antibodies – May trigger various immune system cells to attack cancer cell PATH 1017 2024-2025 24  Host & Environmental Factors Chemical Carcinogens Can you – Agent capable of causing identify cancer examples of – Direct or indirect effect on life-style metabolism (procarcinogens) – Typically cause mutation in associated genes, RNA, DNA or cellular carcinogens? proteins – Promoters- can cause normally non-carcinogenic substances to become carcinogenic – Dose-dependant PATH 1017 2024-2025 25  Host & Environmental Factors Radiation – Ionizing radiation linked to cancer development – Exposure during warfare; medical treatment; occupation – Onset of cancer and type will depend on age at exposure, dose and duration – Ultraviolet radiation – Exposure to sun or UV light from other sources – Cumulative effect PATH 1017 2024-2025 26  Host & Environmental Causes Oncogenic Viruses – Virus that can induce cancer There are a few virus that can cause cancer in humans by inserting their DNA into cells – Examples? – There are other viruses strongly linked to cancer – Research to develop vaccines (i.e. HPV) PATH 1017 2024-2025 27  Naming Tumors Benign tumors: tissue name + “-oma” Malignant tumors (cancers) – Epithelial tissue: tissue name + “carcinoma” – Mesenchymal tissue: tissue name + “sarcoma” – Example: osteoma, osteosarcoma PATH 1017 2024-2025 28  Benign Tumors Contain cells that look like normal tissue cells May perform the normal function of the tissue (like secreting hormones) Usually have a capsule around them Usually do not invade neighboring tissues But they can damage nearby organs by compressing them PATH 1017 2024-2025 29  Malignant Tumors Contain cells that do not look like normal adult cells These cells divide rapidly, so: – Tumors grow quickly – Cells mutate faster and can change type The tumor does not have clear boundaries and sends “legs” out into surrounding tissue Do not perform the normal functions of the organ – May secrete hormones associated with other tissues Can compress and/or destroy the surrounding tissues PATH 1017 2024-2025 30  Benign vs. Malignant What are the key differences between benign and malignant tumors? – Level of differentiation – Rate of growth – Local invasion – Capacity for metastasis PATH 1017 2024-2025 31 Metastasis Cells in a primary tumor develop the ability to escape and travel in the blood (or lymph) Imagine you were a cancer cell. What abilities would you need to survive in the tumor? What abilities would you need to metastasize? PATH 1017 2024-2025 32 Space for Additional Metastasis Notes PATH 1017 2024-2025 33  Manifestations related to metastasis When cancer metastasizes, what manifestations might one observe? To brain? To lungs? To liver? To bones? PATH 1017 2024-2025 34  Manifestations & complications of cancer Changes in organ function Local effects of tumors Ectopic hormones secreted by tumor cells – paraneoplastic disorders Nonspecific signs of tissue breakdown – protein wasting, bone breakdown PATH 1017 2024-2025 35  Changes in organ function Organ failure Benign tumors may cause overproduction of normal organ secretions Malignant tumors may occasionally cause overproduction (as in thyroid cancer), but more commonly decrease production of normal organ secretions PATH 1017 2024-2025 36  Local Effects of Tumor Growth Bleeding Compression of blood vessels – Superior vena cava syndrome – Portal hypertension Compression of lymph vessels – Edema, ascites, effusion Compression of hollow organs Compression of nerves – Pain, paralysis PATH 1017 2024-2025 37  Paraneoplastic Syndromes Endocrine 1. Cancer cells – ADH leads to produce hormones syndrome of or hormone-like inappropriate proteins ADH (SIADH) 2. Cancer cells – ACTH leads to produce proteins Cushing that affect clotting syndrome 3. Paraneoplastic – PTH-related neurologic disorders protein hypercalcemia Associated with lung, PATH 1017 2024-2025 38  Cancer anorexia-cachexia syndrome Manifestations: What is the cause – Weight loss (pathophysiology) of – Muscle wasting this syndrome? – Weakness – Anorexia – Anemia PATH 1017 2024-2025 39  Diagnostics Specimens: Method depends on – Urine/stool tests location & type of – Cytology tests cancer suspected – X-rays – Histology tests – Endoscopy/ – Blood tests for colonoscopy/ tumour markers bronchoscopy etc. – Bone marrow aspiration – Ultrasound – CT – MRI PATH 1017 2024-2025 40  Diagnostics: Biopsy Specimen obtained by various methods: Needle aspiration (percutaneous) Endoscopy methods Laparoscopy or surgical Types of biopsies: needle, excision, wedge Removal of tissue specimen for microscopic study Crucial in determining treatment PATH 1017 2024-2025 41  Diagnostics: Tumor Markers Antigens found on Common Tumour the surface of tumour Markers: cells or on the Human chorionic surface of normal gonadotrophin (hCG) cells when neoplasm CA-125 present – Typically hormones, Prostate specific enzymes/proteins that antigen (PSA) are normally produced but become over Alpha-fetoprotein produced in neoplasia (AFP) – Proteins produced in Carcinoembryonic fetal development may antigen (CEA) reappear in neoplasia These tumor markers correlate to which PATH 1017 2024-2025 42  Diagnostic: Tumor Markers Tumour markers are NOT used a routine screening test because: – May be elevated in non-neoplastic conditions – Often not elevated in early stages of neoplasia – Cost of test typically not covered However, if significantly elevated, it is useful in: – – – PATH 1017 2024-2025 43  Staging and Grading of Tumours Grading Staging Based on – Extent and clinical histological/cellular spread of the characteristics of the disease tumour under a – Surgery may be microscope Looks at the needed to properly determine stage differentiation of cells and number – Two current of mitoses methods of staging Graded as I, II, III, TMN (UICC) IV Stages 0 to IV (AJC) PATH 1017 2024-2025 44 TNM Classification System Component T N M (Union International Centre le Cancer) PATH 1017 2024-2025 45 Cancer Treatment Cure Control Palliati on PATH 1017 2024-2025 46  Treatments Surgery used for: – Diagnosis and staging (i.e.. obtain specimens) – Tumour removal – In combination with chemotherapy or radiation – Control of oncology emergencies (i.e.. hemorrhage) – Palliation (symptom relief) May not be possible to remove entire tumour Considerations: – location & structure involved; invasiveness of tumour; health ofPATH patient; post-op quality of life 1017 2024-2025 47  Treatments Radiation Therapy: – May used alone or in conjunction with chemotherapy or surgery – Used for: Palliation (symptom relief) Treatment of oncology emergencies (examples?) – Typically delivered as smaller multiple does of radiation- why? PATH 1017 2024-2025 48  Treatments – Radiation Therapy Ionizing radiation delivered (directly or indirectly) using x- rays or gamma rays Causes cells to give-up energy and electrons Electrons produce free radicals that cause DNA damage in cells Cell dies after replication PATH 1017 2024-2025 49  Treatment Radiation kills or injures rapidly dividing cancer cells Radiation may also affect normal cells Rapidly reproducing cells of bone marrow, mucosal ling of GI tract often affected This leads to adverse effects of radiation such as: – Infection; bleeding; anemia; N &V PATH 1017 2024-2025 50  Chemotherapy Systemic treatment Drug reaches tumour and distant sites Toxic to rapidly dividing cancer cells May used alone in combination with other treatments – Radiation and surgery may used to induce the tumour into entering a cycle of very rapid growth phase of the cell cycle because chemotherapy is most effective at this phase PATH 1017 2024-2025 51  Chemotherapy Kill cell hypothesis: Relationship between tumour cells and chemotherapy dose are related and proportional (exponential killing) Because the kill is proportional to the dose, multiple doses are needed to eradicate the disease PATH 1017 2024-2025 52  Chemotherapy Types: – cell cycle specific- action occurs during a specific phase of cell cycle – cell cycle non-specific- act throughout the cell cycle on all phases – Combination of both types often used together and is more effective – Route of delivery varies to promote greatest effect of drug PATH 1017 2024-2025 53  Chemotherapy Chemotherapy is toxic to all cells and also affects normal cells (in particular rapidly dividing cells) – Mutagenic, carcinogen and tetragenic Special handling, storage and training is required when working with these drugs (i.e.. protective equipment, special disposal) PATH 1017 2024-2025 54  Chemotherapy This leads to side-effects are often related to effects on rapidly proliferating normal cells: – Bone marrow suppression  anemia, neutropenia, thrombocytopenia – Anorexia, N&V – Stomatitis and GI mucosal problems – Fatigue – Hair loss – Reproductive system- menstrual changes or amenorrhea; decreased or absent sperm count; – Birth defects if during chemo given pregnancy PATH 1017 2024-2025 55  Cancer Treatment Other treatments: – Hormonal therapy – Biotherapy – Bone marrow transplant (leukemia) – Stem cell transplant (leukemia) Investigational: – Gene therapy PATH 1017 2024-2025 56