Trivedi_Intro to cancer_2024.pdf

Introduction to Cancer Meghana V. Trivedi, Pharm.D., Ph.D., BCOP University of Houston, College of Pharmacy [email protected] Integrated Hematology/Oncology Module PHAR 5367 Jan 17, 2024 Learning Objectives 1. 2. Classify different types of cancer, terminology, and nomenclature. Differentia...

Introduction to Cancer Meghana V. Trivedi, Pharm.D., Ph.D., BCOP University of Houston, College of Pharmacy [email protected] Integrated Hematology/Oncology Module PHAR 5367 Jan 17, 2024 Learning Objectives 1. 2. Classify different types of cancer, terminology, and nomenclature. Differentiate between various cancer pathophysiology and common cancer hypotheses. 3. 4. Classify different roles of immune system in prevention of cancer. Identify mechanism of action for monoclonal antibodies, cytokines, cell-based therapies, checkpoint inhibitors, and other immunologic therapies in the treatment of cancer. 2 Cancer: A global problem • Often considered a disease of affluence, but about 70% of cancer deaths occur in low- and middle-income countries. • Global cancer incidence and mortality are rapidly growing. http://globalcancermap.com 3 Cancer: A global problem 2nd leading cause of death 10 million cancer deaths in 2020 1/3rd of cancer deaths are due to 5 modifiable risks: 1. High BMI 2. Low fruit & vegetable diet 3. Lack of physical activity 4. Tobacco 5. Alcohol 1 in 6 deaths is due to cancer Estimated total annual cost of cancer in 2010: $1.16 trillion In low- and middle- income countries: 1. 70% of deaths occur from cancer. 2. Cancer-causing infections (e.g., HBV, HCV, HPV) are responsible for 30% of cancer cases. HBV- hepatitis B, HCV- hepatitis C, HPV- human papilloma virus Many cancers can be cured if detected early and treated effectively. 4 https://www.who.int/news-room/fact-sheets/detail/cancer Cancer: in the United States 2nd leading cause of death 2016: 1.7 million new cases & 600K cancer deaths 2016: Estimated 15.5 million cancer survivors •In the United States, the overall cancer death rate has been steadily decreasing since the 1990s, with the reductions from 1991 to 2017 translating into more than 2.9 million cancer deaths avoided. •The decline in the overall cancer death rate is being fueled in large part by a dramatic decrease in the lung cancer death rate predominantly as a result of reduced smoking rates. 5 https://cancerprogressreport.aacr.org/progress/cpr20-contents/cpr20-cancer-in-2020/ Estimated new cancer cases in the US in 2023 6 https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21763 The lifetime probability of cancer diagnosis 40.1% 38.7% Note: These numbers are average of the entire male and female population and vary for individuals because of genetic and lifestyle factors. 7 https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2020.html Estimated cancer deaths in the US in 2023 8 https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21763 Question Which of the following can reduce the risk of cancer? Mark each choices with Y/N. 1. 2. 3. 4. 5. Increased physical activity Healthy diet rich with fruits and vegetables No use of tobacco Limit alcohol use Low body mass index 9 History of cancer 1. First described by Edwin Smith Papyrus (~1600 BC) – contains a description of cancer and procedure to remove breast cancer. 2. Hippocrates described the term “Karkinos” (carcinos), which is the Greek word for crab or crayfish, as well as carcinoma (ca. 460 – 370 BC). 3. Celsus translated karkinos into cancer, the Latin word for crab or crayfish (ca. 25 BC – 50 AD). 4. Galen used “oncos” (Greek for swelling) to describe all grown masses, reserving carcinos for malignant tumors. He also used the suffix –oma to indicate cancerous lesions (2nd century AD). 5. Insights into cancer after discovery of microscope (17th century), cells (19th century), and genetics (20th century) 10 Terminology Metastasis- Process in which a small group of malignant cells dislodge from original tumor, invade lymphatic or blood vessels, and travel to lymph nodes or other organs where they reside and proliferate. 11 http://pathology.jhu.edu/pc/BasicTypes1.php What is cancer? • Not just one disease but many diseases. • More than 100 different types of cancer. • Typically named for the location/organ or type of cell. Prefix Location Suffix Cell type Adeno Gland Carcinoma Epithelial cells Hepato Liver Leukemia Blood cells Melano Pigment cells Lymphoma Myelo Bone marrow Lymphocytes/ lymph nodes Myo Muscle Sarcoma Fat, Bone, Muscle Osteo Bone E.g. Breast adenocarcinoma- in epithelial cells of glands in the breast Hepatocarcinoma- in epithelial cells of liver Osteosarcoma- bone cancer. 12 Cancer’s warning signs • General signs and symptoms • • • • • Unexplained weight loss Fever Fatigue Pain Skin changes • Specific signs and symptoms to certain cancers • • • • • • • Change in bowel habits or bladder function Sores that do not heal White patches inside the mouth or white spots on the tongue (leukoplakia) Unusual bleeding or discharge Thickening or lump Recent change in a wart or mole or any new skin change Nagging cough or hoarseness 13 https://www.cancer.org/cancer/cancer-basics/signs-and-symptoms-of-cancer.html Question Which of the following is not a general sign/symptom of cancer? A. B. C. D. Unexplained weight loss Fatigue Pain Unusual bleeding/discharge 14 Origin of cancer • Four cellular functions are inappropriately regulated in cancer 1. Ineffective constraint on cell proliferation 2. Distorted cell differentiation [rate or type of progeny] 3. Destabilized chromosomal and genetic organization [variant cells arise with high frequency] 4. Deregulated apoptosis Cell survival Cell proliferation Cell cycle arrest Apoptosis Balance 15 Origin of cancer • Four cellular functions are inappropriately regulated in cancer 1. Ineffective constraint on cell proliferation 2. Distorted cell differentiation [rate or type of progeny] 3. Destabilized chromosomal and genetic organization [variant cells arise with high frequency] 4. Deregulated apoptosis Cell survival Cell proliferation Cell cycle arrest Apoptosis Balance 16 A brief cell biology- cell proliferation vs. differentiation • Proliferation = self renewal • Differentiation = converting to another more-specialized cell type • Various types of cell division dictates whether the cell undergoes cell proliferation or differentiation. • Depending on the need of an organ, any type of division can occur. Stem cells Stem cells Differentiated cells p division r division q division 17 A brief cell biology- types of normal cells Adult Embryonic Type of cells Examples Function Proliferation Differentiation Pluripotent stem Embryonic cells cells Develop into the three Unlimited primary germ cell layers of the early embryo Unlimited Multipotent progenitor cells (organ-specific) Hematopoietic stem cells Maintain tissue regeneration Unlimited Limited (all or most cells of that organ system) Oligo/Unipotent / committed progenitor cells (organ-specific) Committed myeloid progenitors Renew specific cell type(s) within that organ system Unlimited Limited (one or a few cells of that organ system) Differentiating cells Erythroblasts, reticulocytes Differentiate into more functional cells No Limited (one cell type only) Terminallydifferentiated cells Erythrocytes, Maintain function of macrophages etc. the organ No No 18 Hematopoietic stem cell Common lymphoid progenitor cells Common myeloid progenitor cells Megakaryocyte-Erythrocyte progenitor cells Granulocyte-Monocyte progenitor cells Megakaryoblast Pro-erythroblast Promegakaryocyte Erythroblast Megakaryocyte Reticulocyte Thrombocyte (Platelet) Erythrocyte (RBC) Terminally Differentiating cells Differentiated cells Multipotent or Unipotent progenitor cells A brief cell biology- cell proliferation vs. differentiation Macrophages Basophils Dendritic cells Eosinophils Neutrophils Lymphocytes (B and T cells) NK Cells 19 A brief cell biology- cell cycle (= cell division = proliferation = self renewal) Regulated by multiple factors and pathways that are targeted by new anti-cancer drugs Phase Process G0 Resting phase (normal function but no division) G1 Cell enlargement S DNA replication G2 Condensation of chromosomes, Replication of intracellular organelles M Mitosis (division of chromosome, formation of 2 nuclei, cell division Critical juncture: R (restriction) point Transition from G1 to S phase 20 Main points- cell cycle (= cell division = proliferation = self renewal) • Various chemotherapy and targeted therapies have effects on specific phases of cell cycle. • G0 = a phase where cells are not actively proliferating • A cell in prolonged G0 is in the state of quiescence • Initiation of cell cycle occurs when cells enter into G1 phase. • Transition from G1 to S is very critical and is tightly regulated. This is called the restriction point. • Several targeted therapies affect this phase. • Type of cell division dictates cell proliferation vs. differentiation. 21 Cancer Stem Cell (CSC) hypothesis • Hypothesis: There is a small subset of cancer cells that are responsible for tumor initiation and growth. These cells are called cancer stem cells. • Cancer stem cells possess the following properties – • Indefinite self-renewal • Slow replication or quiescence • Differentiate but not into functional cells • Cancer stem cells are thought to arise from malignant transformation of normal stem cells or progenitor cells. 22 http://www.nature.com/labinvest/journal/v86/n12/full/3700488a.html Cancer Stem Cell (CSC) hypothesis Terminally differentiated cells 23 http://www.nature.com/labinvest/journal/v86/n12/full/3700488a.html Cancer stem cells Cancer Adult Embryonic Type of cells Examples Function Proliferation Differentiation Pluripotent stem Embryonic cells cells Develop into the three Unlimited primary germ cell layers of the early embryo Unlimited Multipotent progenitor cells (organ-specific) Hematopoietic stem cells Maintain tissue regeneration Unlimited Limited (all or most cells of that organ system) Oligo/Unipotent / committed progenitor cells (organ-specific) Committed myeloid progenitors Renew specific cell type(s) within that organ system Unlimited Limited (one or a few cells of that organ system) Differentiating cells Erythroblasts, reticulocytes Differentiate into more functional cells No Limited (one cell type only) Terminallydifferentiated cells Erythrocytes, Maintain function of macrophages etc. the organ No No Cancer stem cells Very small portion of cancer Unlimited No No normal function 24 Question Which of the following is a similarity between multipotent normal stem cells and cancer stem cells? Write Y/N for each choices. 1. Both have unlimited potential for proliferation. 2. Both can produce functional cells. 3. Both can give rise to 3 germ cell layers. 25 Therapeutic relevance of CSCs Tumor = cancer stem cells/ progenitor-like cells + differentiated non-functional cells 26 http://www-ncbi-nlm-nih-gov.ezproxyhost.library.tmc.edu/pmc/articles/PMC3657606/ Origin of cancer • Four cellular functions are inappropriately regulated in cancer 1. Ineffective constraint on cell proliferation 2. Distorted cell differentiation [rate or type of progeny] 3. Destabilized chromosomal and genetic organization [variant cells arise with high frequency] 4. Deregulated apoptosis Cell survival Cell proliferation Cell cycle arrest Apoptosis Balance 27 A brief cell biology- cell death (Physical or Chemical) e.g., unfixable problem in DNA Programmed cell death 28 Origin of cancer • Four cellular functions are inappropriately regulated in cancer 1. Ineffective constraint on cell proliferation 2. Distorted cell differentiation [rate or type of progeny] 3. Destabilized chromosomal and genetic organization [variant cells arise with high frequency] 4. Deregulated apoptosis Cell survival Cell proliferation Cell cycle arrest Apoptosis Balance 29 Destabilized chromosomal and genetic organization • Destabilization of chromosomal and genetic organization can cause malignant transformation. • A process where normal cells acquire altered morphology and/or growth pattern • Produces “immortal” cells capable of growing into tumors • Can be triggered by carcinogens • Chemicals (tobacco, formaldehyde, DDT, some pesticides) • Physical agent (asbestos) • Ionizing radiation • Viruses (HTLV-1, HHV-8, HPV, HBV, HCV, EBV) • Genetic alterations (oncogenes vs. tumor suppressors) 30 Chemical carcinogens Drugs or hormones Type of cancer Alkylating agents (e.g. Chlorambucil, mechlorethamine, melphalan, nitrosoureas) Leukemia Anabolic steroids Liver cancer Analgesics containing phenacetin Renal, urinary bladder cancer Anthracyclines (e.g. doxorubicin) Leukemia Antiestrogens (e.g. tamoxifen) Endometrium Coal tar (topical) Skin cancer Nonsteroidal estrogens (diethylstilbesterol) Vaginal or cervical, endometrial, breast, testicular cancer Steroidal estrogens (estrogen replacement therapy, oral contraceptives) Endometrial, breast, liver cancer Epipodophyllotoxins (e.g. etoposide) Leukemia Immunosuppressive drugs (cyclosporine, azathioprine) Lymphoma, skin cancer Oxazaphosphorines (cyclophosphamide, ifosfamide) Urinary bladder cancer, leukemia 31 Infectious carcinogens 32 Viral oncogenes • The viral genes that cause malignant transformation of host cells are called viral oncogenes. • When virus infects human cells, the viral gene(s) integrate into human cell genome and use human cell machinery to make viral proteins and replicate. • The integration of viral oncogenes that code for proteins important in cell cycle can cause transformation. • Some viral genes can disrupt chromosomal DNA leading to transformation. • Not all viruses cause transformation • These viral oncogenes are typically not responsible for viral replication 33 Proto-oncogenes and oncogenes • Proto-oncogenes: Human genes that produce proteins that are critical for cell cycle regulation and control the R or restriction point where the cells make the essential go/no-go decision. • They are normal genes that have the potential to affect cell cycle or any other pathway to increase proliferation or cause abnormal differentiation. • Oncogenes: Proto-oncogenes that are “turned-on” continuously in an abnormal way (usually because of a mutation). 34 Oncogenes * * * * * EGFR/HER1 * * * * * * 35 Tumor suppressor genes • Tumor suppressor genes: Genes that counteract or suppress the R point and are called tumor suppressor genes. • Many tumor suppressor genes are important players in DNA repair mechanisms and inhibit transition of the cell to the Sphase especially when there is DNA damage. 36 Tumor suppressor genes 37 Oncogenes vs. Tumor suppressor genes Oncogenes Dominant – alteration in only one copy is necessary Gain-of-function mutations cause cancer. Somatic Genetic alterations typically lead to structural changes to the encoded proteins making them constitutively active. Genetic mutations (e.g. point mutations, gene amplifications, chromosomal translocation). Tumor suppressor genes Recessive - usually alteration in both copies are necessary Loss of function mutations cause cancer. Germline or somatic Genetic alterations typically lead to loss of protein or nonfunctional protein. genetic mutations or epigenetic silencing (e.g. methylation, histone acetylation). 38 DNA repair genes • Many tumor suppressor genes are DNA repair genes. • DNA damage recruits key players in DNA repair, activating cell cycle checkpoints and cell cycle arrest. • DNA repair can occur at several stages of cell cycle but cells are mostly arrested in the G1/S and G2/M phase. • If DNA damage is not corrected, the errors can cause alterations that can activate oncogenes or inactivate tumor suppressor genes. Abbreviations: MMR: MisMatch Repair, BER: Base Excision Repair, NER: Nucleotide Excision Repair, HR: Homologous 39 Recombination, MMEJ: Microhomology-Mediated End Joining, and NHEJ: Non-Homologous End Joining. Accumulation of genetic alterations • Single genetic alteration is probably insufficient to initiate cancer. • Most cancers acquire multiple, successive genetic alterations. • Types of genetic alterations/driver mutations: • Combination of genetic alterations are required for cancer initiation and progression. Fearson and Vogelstein’s genetic model for colorectal tumorigenesis Abbreviations: APC: adenomatous polyposis coli, DCC- deleted in colorectal cancer. 40 Question Malignant transformation of cells can occur from any of the following except _______. A. B. C. D. Cyclophosphamide treatment Human papilloma viral infection Long-term of tobacco use Loss of one copy of tumor suppressor 41