L12_Neoplasm and cancer therapy Lecture Notes PDF

SEHH2235 Introduction to Pathophysiology and Pharmacology Lecture 12 Neoplasm and Cancer Therapy 1  Learning outcomes By the end of this lecture, students should be able to identify, describe and differentiate: 1. concept...

SEHH2235 Introduction to Pathophysiology and Pharmacology Lecture 12 Neoplasm and Cancer Therapy 1  Learning outcomes By the end of this lecture, students should be able to identify, describe and differentiate: 1. concepts of cell differentiation and growth 2. cancer and the cell cycle checkpoints, 3. oncogenes and tumor suppressor genes 4. differences of benign and malignant tumor 5. classification of neoplasia 6. etiology of malignant neoplasia 7. clinical manifestation 8. diagnosis and treatment 2  Cancer terminology Term Description Dysplasia 發育異常 abnormal development of tissues Mutant cells 突變細胞 disruption of RNA and DNA within normal cells may produce cells that differ in form, quality and function from the normal cell Neoplasm / tumor 腫瘤 abnormal new growth of cells (not necessary cancer) Benign tumors 良性腫瘤 cells are encapsulated, well differentiated with normal tissue structure, do NOT invade other tissues, may/may not transform to malignancy Malignant tumors 惡性腫瘤 arise from abnormal and uncontrolled cell proliferation, which invade and destroy surrounding tissues Primary tumor 原發腫瘤 the original site where the tumor arises Invasion 入侵 the process in which cancer cells invades surrounding tissues Metastasis 轉移 the process in which cancer cells spread to distant sites via bloodstream or lymph or across body cavities to secondary tumor site Anaplasia 逆行性生長 typical malignant tumor, where cells are poorly differentiated Angiogenesis 血管生成 formation of new blood vessels to supply nutrients for tumor growth Tumorigenesis 腫瘤發生 the process of tumor formation Carcinogenesis 致癌作用 the process in which normal cells transform into cancer cells 3  Proliferation and differentiation Proliferation = the process of increasing cell numbers by mitotic cell division (Mitosis) 有絲分裂 Differentiation = the process whereby proliferating cells become more specialized cell types Apoptosis = a form of programmed cell death that eliminates injured or unwanted cell Mitosis (有絲分裂) 4   The duration of the cell cycle varies between different cell The normal cell cycle types. In most mammalian cells it lasts between 10 and 30 hours. Cells in the first cell cycle phase (G1) do not always M checkpoint continue through the cycle. 有絲分裂期  For all living eukaryotic organisms it is essential that the different phases of the cell cycle are precisely coordinated.  The phases must follow in correct order, and one phase must 相間 be completed before the next phase can begin. Errors in this coordination may lead to chromosomal alterations. G2  Such coordination is determined by both cyclins and cyclin- checkpoint dependent kinases (CDK) within the cell to control the cell cycle by sending signals affecting critical checkpoints, hence determining whether the cell will divide. 相間 Cyclin E Cyclin A Cyclin B DNA複製 Cyclin D 相間 G1 checkpoint https://www.nobelprize.org/prizes/medicine/2001/press-release/ 5  Cellular adaptation  If environmental changes lead to uncoordinated growth and proliferation, cells may limit its effect or may be protected from further injury by using adaptive processes, including: 萎縮 Atrophy 萎縮 – decrease in cell size Hypertrophy 肥大 – increase in cell size Hyperplasia 增生 – increase in cell number 肥大 Metaplasia 化生 - change of cell type Dysplasia 發育不良 增生 – abnormal cell size, shape, appearance & differentiation 化生 Cerebral atrophy Cardiac hypertrophy 發育不良 6  What is cancer? Cancer is characterized by the uncontrolled differentiation and growth, and spread of abnormal cells (normally cell division is precisely controlled). New cells are only formed for growth or to replace dead ones. Cancerous cells do not self-destruct but divide rapidly. Mutated genes have change in DNA sequence, which is mutated from a normal gene  DNA mutation 突變  may result in cancer development Any factors that bring about DNA mutation are called mutagens 誘變劑. Any agent that causes cancer is called a carcinogen 致癌物 and is described as carcinogenic. 致癌的 Some mutagens are carcinogenic. 7 How do normal cells become cancerous? Several mutations need to occur to give rise to cancer. Number of mutation sites Normal Looks Cells proliferate Structural Malignant cell normal too much, change cell otherwise look normal Selection (for survival) within tumor for “most cancerous” cells 8 Oncogenes, Tumor Suppressor Genes and Cancer Mutation inactivates Tumor suppressor gene Proto-oncogenes 原癌基因 are normal genes involved in regulating cell proliferation CELL PROLIFERATE  mutated proto-oncogenes becomes oncogenes 癌基因 which promote uncontrolled cell proliferation and development of cancer  e.g. RAS oncogene (pancreatic, lung, and colorectal cancers) Tumour suppressor genes 抑癌基因 encode proteins that inhibit the Mutation inactivates formation of tumours when DNA is damaged, by DNA repair genes  stop cell division to allow time for DNA repair 原癌基因  induce apoptosis (a programmed cell death) if repair is unsuccessful Mutation of proto-oncogene creates an oncogene 癌基因  mutated tumour suppressor gene lost its ability to prevent cells with DNA damage to divide  unlimited growth of mutated cells Mutation inactivates several more  e.g. Tumor suppressor gene (cervical )  tumor protein (TP53) Tumor suppressor genes Loss of suppression by  more than 50% p53 gene are mutated in human cancer tumor suppressor gene Multiple pathways of carcinogenesis 致癌作用 – Cell mutations occur involving proto-oncogenes, oncogenes, and tumour suppressor genes CANCER 9 Possible types of mutations leading to oncogene activation Abnormal protein Deletion Proto-oncogene gene  oncogene may also occurred in tumor suppressor gene Homologous  abnormal and non-functional tumor protein chromosomes Duplication Excessive amount of protein from duplicated gene Proto-oncogene gene  oncogene Inversion New / abnormal protein synthesis Proto-oncogene gene  oncogene May also in tumor suppressor gene  abnormal and non-functional tumor protein Reciprocal translocation Non-homologous New / abnormal protein synthesis chromosomes Proto-oncogene gene  oncogene May also in tumor suppressor gene  abnormal and non-functional tumor protein 10  Oncogene activation by chromosomal translocation Example: Chronic myelogenous leukemia (CML) Reciprocal translocation occurs at the breaks at the ends of the long arms of chromosomes 9 and 22. This results in formation of Philadelphia chromosome (Ph1), which contains a new fusion gene coding for a hybrid oncogenic protein (bcr–abl), presumably involved in the pathogenesis of chronic myelogenous leukemia. (abnormal) Karyotypes of a patient with CML showing the results of reciprocal translocations between chromosomes 9 and 22. The Philadelphia chromosome is recognized by a smaller-than-normal chromosome 22 (22q-) (abnormal). (abnormal) One chromosome 9 (9q+) (abnormal) is larger than its normal counterpart. From Rubin R., Strayer D. S. (Eds.) (2012). Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 174). Philadelphia, PA: Lippincott Williams & Wilkins. 11 The mutation of tumor suppressor gene Produce normal Cannot produce tumor protein normal tumor protein Able to control Lose ability to cell growth control cell growth Unlimited cell growth in terms Limited cell of both number number and and size size 12  Examples of tumor suppressor genes 1. Retinoblastoma gene (Rb gene) 視網膜母細胞瘤基因  usually prevent cell division  Loss / mutated Rb gene accelerates cell cycle, increased proliferation, as in retinoblastoma 2. Adenomatous polyposis coli (APC gene) 腺瘤性瘜肉抑癌基  Mutation: Familial adenomatous polyps (FAP) 家族性大腸瘜肉症 3. Tumor protein TP53 (p53) gene on chromosome 17q  normally activated in DNA-damaged cells  apoptosis  inactivation  ↑survival of DNA-damaged cells  TP53 gene mutations: associated with carcinogenic lung, breast & colon  Loss of the p53 tumour suppressor gene may facilitate resistance to apoptosis and angiogenesis 13  Genetic events leading to loss of tumor suppressor gene function Normal mutated (1) Loss of heterozygosity silences the normal tumor suppressor gene (TSG)  cancer (eg. Retinoblastoma, Rb) For TSG function to be lost, both chromosomal copies (alleles) of the gene must be inactivated or mutated Germline mutation Germline mutation occurs in gametes (ovum or sperm) and (2) Two-hit hypothesis of carcinogenesis can be passed onto offspring  every cell is affected Cancer develops when sufficient mutations have occurred Normal Normal Mutated Mutated 1 2 1 2 During the lifespan, individual acquires a number of genetic mutations by accumulation over time 1st Somatic 2nd Somatic mutation mutation Non-heritable retinoblastoma  Develop only one tumor in one eye Somatic mutation occurs in a single body cell and cannot be inherited  only tissues derived from mutated cell are affected 14 Hallmarks of cancer 癌症的標誌  During the multistep  避免免疫破壞  development of cancer, the 逃避生長抑製劑 cell acquires 8 essential alterations in cell physiology   that collectively dictate (Slide 17) malignant growth 惡性生長. 維持增殖信號 實現複製永生  Two additional ❷  characteristics enable cancer progression (red 解除細胞能量的調節 腫瘤促進炎症 boxes).   抵抗細胞死亡  ❶ 激活侵襲和轉移 Hallmarks of Cancer 誘導血管生成 (adapted from Hanahan D, Weinberg RA. Cell 2011; 144: 646) 基因組不穩定性（增變表型） 15 Enabling replicative immortality 實現複製永生 (related to Telomere & telomerase) Telomere  repetitive nucleotide sequences 許多重複核酸片段 at each end of a chromosome  protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes Telomeres get shorter and shorter with each division until they are critically short  cell stops dividing Normal cells cannot divide indefinitely as the ends of their chromosomes are capped by telomeres Telomerase  an enzyme for elongation of telomeres  active in stem cells & most cancer cells but normally absent in most somatic cells (normal cells) In cancer cells, the telomerase gene is “switched on”, producing telomerase that rebuilds the telomeres. Thus the cancer cell become immortal and able to divide indefinitely. 16  Risk factors of developing cancer 1) High consumption of certain food substances Radiation exposure – Omega 6-fatty acid – Grilled/preserved food – High calcium > 2000 mg – High-glycemic-Index carbohydrates 2) Ionising radiation 游離輻射– X-ray, UV light 3) Chemicals – tar from cigarettes 游離子 4) Obesity – Multifactorial involving metabolic, endocrine and inflammatory mechanisms 5) Alcohol consumption 活性氧 – Induces generation of reactive oxygen species (ROS) like peroxide, superoxide, hydroxyl radical, singlet oxygen 6) Bacterial and Virus infection – Helicobacter pylori (bacteria) may cause peptic ulcer leading to gastric carcinoma 胃癌 – certain strains of human papilloma virus (HPV) may cause cervical cancer 子宮頸癌 7) Hereditary predisposition – Some families are more susceptible to getting certain cancers (e.g. BRCA1 & BRCA2 for breast cancer) 17 Benign or malignant tumour? Benign tumours 良性腫瘤 do not spread from their site of origin, but can crowd out (squash) surrounding cells eg. brain tumour, warts 繼發性腫瘤 Malignant tumours 惡性腫瘤 can spread from the original sites and cause secondary tumours. This is called metastasis. 轉移 They interfere with neighbouring cells and can block blood vessels, the gut, glands, lungs etc. Why are tumours so bad? – Both types of tumour can tire the body out as they both need a huge amount of nutrients to sustain the rapid growth and division of the cells. 18  Benign vs malignant tumour Features Benign Tumors Malignant Tumors Cell Well differentiated cells (i.e. with functions) Undifferentiated cells, with anaplasia and atypical characteristics structure 未分化細胞，具有發育不全和非典型結構 Rate of growth Progressive and slow, stop growing or The more undifferentiated, the more rapid the regress rate of growth Encapsulated? Usually encapsulated with well defined Not encapsulated 包裹 boundary Mode of Usually encapsulated; By invasion, infiltrate the surrounding tissues growth By expansion without invading surrounded tissue Metastasis No Gain access to blood and lymph channels to other areas of the body Fibroids 肌瘤 are common benign tumor for females, may progress to “transform” & become malignant tumor if not removed. 19 Morphology of cancer cells Anaplasia 逆行性生長 – loss of cell differentiation Pleomorphism 多形性 (cell & nuclei vary in size & shape)  nuclei vary in size, bizarre in shape 形狀怪異.  nucleoli are larger than normal 核仁比正常大  Chromatin or chromosome is coarse and clumped 染色質或染色體粗糙且結塊 Normal epithelial cells Cancerous epithelial cells 異常數量的染色體以雜亂無章的方式排列  Metastasis 轉移  Cancer cells may invade nearby tissues or metastasize 轉移 (spread) to other organs.  They may move to other tissues by any or all of the three routes. 靜脈系統 Superior mesenteric (1) Venous system artery and vein Cancer cells may travel through the veins, Middle colic vein commonly to the liver Transverse colon and the lungs Lymph nodes (2) Lymphatic system 淋巴系統 Ascending colon Cancer cells may move through the lymph vessels from the tissues to lymph nodes and eventually, via the circulatory system, to distant sites in the body Primary cancer (3) Seeding 沿著管道播種 Cancer may penetrate the wall of an organ move into a body cavity, and spread throughout that area. LWW Pathophysiology made Incredibly easy. Ch12 p392, 393 21  Steps by which a malignant tumor penetrates basement membrane and Mechanisms of Tumor Metastasis: then invades the extracellular environment. 原位癌 (1) Carcinoma in situ cells are confined within the basement (3) Proteolytic enzymes membrane are released from the tumor cells (4) The ECM degrades 表面黏附分子  invading cancer cells (2) Surface move through the extracellular adhesion environment and molecules penetrates through to mediate binding blood vessels and components of lymphatics via the the extracellular same mechanisms matrix (ECM) 細胞外基質 (5) Tumor cells metastasize 腫瘤細胞轉移 by way of blood vessels or lymphatics From Rubin R., Strayer D. S. (Eds.) (2012) 22 Diagnosis of cancer 1. Investigation of symptoms depends on location of cancer Loss of normal physiological function Tumor - physical pressure by pressing on nerves 2. Imaging Magnetic resonance imaging (MRI) X-ray, computerized tomography (CT) scan, radio-diagnosis 3. Tumor Markers 癌症腫瘤標記 Substances produced by cancer cells that are found in or on the tumor cells or in blood, spinal fluid or urine Ideal tumor makers should be sensitive and specific, e.g. Cervical cancer by Papanicolaou (PAP) smear, Colorectal cancer by colonoscopy 結腸鏡檢查 柏氏抹片檢查 4. Tumor tissue biopsy for identification of cancer stages (sperm & ovum) neuroendocrine tumor that grows from chromaffin cells 神經母細胞瘤 多發性骨髓瘤 腦下垂體腺腫 23 Manifestations & Prognosis of Cancer  Cachexia 惡病體質: 代表因疾病引起的體重減輕以及肌肉量減少，呈現衰落的狀態 Severe form of malnutrition, anorexia, early satiety, weight loss Present in 80% cancer patients at death Altered protein, lipid, carbohydrate metabolism, taste change  Anemia A decrease of hemoglobin concentration in the blood Chronic bleeding resulting in iron deficiency, severe malnutrition, medical therapies, or malignancy in blood-forming organs  Prognosis associated with cancer origin, tumor size, lymph node involvement and metastasis 4-stage tumor system Stage I: cancer confined to the organ of origin Stage II: cancer is locally invasive Stage III: cancer spread to regional structures (e.g. lymph nodes) Hodgkin disease 霍奇金氏淋巴瘤 is a type of Stage IV: cancer has spread to lymphoma, i.e. a cancer of the lymph system. distant sites 24 Staging of Cancer: TNM system (by American joint Committee on Cancer AJCC) Staging of cancer 4-stage tumor system Determined by size of tumor Stage I: cancer confined to the organ of origin Degree it has locally invaded Stage II: cancer is locally invasive Extent to which it has spread Stage III: cancer spread to regional structures (e.g. Lymph node) Stage IV: cancer has spread to distant sites T – Primary tumor; the number equals to size of tumor and its local extent. T0 – Breast free of tumor T1 – lesion < 2 cm in size T2 – lesion 2 – 5 cm T3 – skin and/or chest wall involved by invasion N – Lymph node involvement; a higher number means more nodes are involved. N0 – no axillary nodes involved 腋下淋巴結 N1 – mobile nodes involved N2 – fixed nodes involved M – Extent of distant metastases M0 – no metastases M1 – demonstrable metastases M2 – suspected metastases 25 Colorectal cancer = Colon and rectal cancers Common cancer in men and women, 90% of colorectal cancers are preventable Risk factors: Age over 50 years old Obese Family history of colon or rectum cancer or polyps Diets high in fats, low in fiber Smoking High alcohol consumption Lack of exercise Treatment: The Government’s Colorectal Cancer Screening radiation, surgery and possible chemotherapy Programme subsidises asymptomatic Hong Kong residents aged between 50 and 75 to receive screening service in private sector for prevention of Prevention: colorectal cancer. regular exercise Participants will first take a Faecal Occult Blood a diet heavy in fruits and plant-origin foods Test (FOBT) that can detect small amounts of blood in stool, even if they are invisible to the naked eye. If a health weight there is blood, colonoscopy will be arranged to remove polyps, if any, to prevent them from moderation in alcohol consumption developing into cancer. 1 standard drink for female and 2 standard drinks for male https://www.colonscreen.gov.hk/mobile/en/public/index.html 27 Four main types of leukemia 血癌 Myeloblast: immature cells of the myeloid cell line 1. Acute Lymphoid Leukaemia (ALL) 急性淋巴性白血病  Cancer of immature lymphocytes (lymphoblasts)  The most common type of leukaemia in children, rare in adults  In children: almost all leukaemia are acute (80% ALL; 20% AML)  Some onset is related to the genetic abnormality “Philadelphia chromosome”  tyrosine kinase  stimulates production of abnormal blood cells by the bone marrow 2. Acute Myeloid Leukaemia (AML) 急性骨髓性白血病  AML is an aggressive form leukaemia, affects the myeloid cells  It forms immature, rapid dividing myeloid cells  More common in adults than in children 3. Chronic Lymphoid Leukaemia (CLL) 慢性淋巴细胞性白血病  CML is a cancer of lymphocytes  Develops more slowly than ALL  Lymphocytes are more mature and divide more slowly  CLL can exist for many years without having symptoms  CLL does not occur in children 4. Chronic Myeloid Leukaemia (CML) 慢性骨髓性白血病  Affects myeloid cells, but slow progression  Can occur at any age but is unusual < 20 years of age MPN: Myeloproliferative neoplasm  Slow chronic stage: can last for 2-3 years  suddenly switch into acute stage like AML 28 Nasopharyngeal Carcinoma (NPC) 鼻咽癌 Gender: Male 2X > Female Diet: Salted cured fish & meat Smoking Viral infection: Epstein-Bar virus (EBV) infection Family history: Inherited genes Living environment factors 29 Breast cancer Estrogen receptor- Estrogen receptor- Incidence of Different Breast Cancers positive breast cancer negative breast cancer Estrogen Tamoxifen Estrogen receptor inhibits Cell proliferation: Estrogen- Human Cell proliferation: receptor / epidermal NOT controlled by estrogen growth controlled by estrogen Progesterone NOT inhibited by tamoxifen -receptor factor inhibited by tamoxifen receptor 2 Breast cancer subtypes Hormone-receptor +ve: +ve for either estrogen or progesterone receptors ~ 80% estrogen-receptor +ve ~ 65% of estrogen-receptor +ve are also progesterone-receptor +ve ~ 13% estrogen-receptor +ve and progesterone-receptor –ve ~ 2% estrogen-receptor -ve and progesterone-receptor +ve Triple negative: ER-ve, PR-ve, HER2-ve (do not response to hormonal therapy) Human epidermal growth factor receptor 2 30  Investigations of Breast cancer Mammogram - breast imaging, looks for tumor mass Biopsy – Fine needle aspirate (FNA) under sonographic guidance looks for infiltrating carcinoma cells Inherited mutation: BRCA1 & 2, HER2 Estrogen receptor: hormonal (anti-estrogen) therapy if ER positive Breast lump detected by mammogram Hormonal therapy for breast cancer For treating estrogen-receptor +ve breast cancers by: lowering the amount of estrogen in the body blocking the action of estrogen in the body 1. Selective estrogen receptor modulators (SERMs) 選擇性雌激素受體調節物 Antagonist of ER  anti-estrogen therapy for ER-positive breast cancer For pre-menopausal women & standard in post-menopausal women Tamoxifen 2. Aromatase inhibitors (AI) Aromatase: the enzyme that synthesizes estrogen Breast cancers require estrogen to grow, so aromatase inhibitor (AI) block production of estrogen Anastrozole (Arimidex ) Exemestane (Aromasin) Letrozole (Femara) 3. Estrogen receptor downregulators (ERDs) 選擇性雌激素受體下調調節物 Fulvestrant (Faslodex) 32  Treatment of breast cancer 乳房腫瘤切除術 乳房切除手術 Surgery Lumpectomy 乳房腫瘤切除術 Quadrantectomy 1/4 乳房切除術 1/4 乳房切除術 Mastectomy 乳房切除手術 Breast conservative surgery 乳房保留手術 Radiation therapy For HER2 +ve breast cancer:  Trastuzumab (Herceptin®)  a monoclonal antibody that interferes with the HER2 +ve receptor  Laptinib (Tyverb®)  a tyrosine kinase inhibitor for advanced HER2 +ve breast cancer that is irresponsive to transtuzumab  Targeted Cancer Therapy Tyrosine Kinase Inhibitor (TKI) Tyrosine kinases are enzymes responsible for activation of many proteins in signal transduction cascades Protein activation by adding a phosphate group (phosphorylation) TKIs work by inhibiting signaling pathways that promote survival and growth of tumour Vascular Endothelial Growth Factor (VEGF) 血管內皮生長因子 signaling & Platelet Derived Growth Factor (PDGF) 血小板衍生生長因子 signaling  stops angiogenesis 停止血管生成 Examples: Glive 1. Imatinib (Gleevec / Glivec) Directly targets and inhibits the fusion proteins BCR-ABL found in chronic myeloid leukemia (CML) 2. Pazopanib (Votrient) PO for late stage renal cancer CML CML apoptosis inhibits tumor growth by restricting angiogenesis proliferation  Programmed Side effects: liver damages cell death 3. Sunitinib (Sutent) PO for late stage renal cancer 34 Other Cancer Treatment  Conventional treatment: the choice of therapy  Depends on staging  More aggressive therapy being delivered to more invasive disease. Surgery Radiation Chemotherapy Combine surgery with radiation or chemotherapy  New possible treatments: Immunotherapy Cancer-fighting vaccines (e.g. Gardasil – HPV vaccine) Stem cell research (e.g. for leukemia) Gene therapy: Introduction of genes into tissues or cells via gene transfer (Purpose: derive therapeutic or preventative benefit from the function of these genes) 35  Notable side effects of 光敏性 chemotherapeutic agents 化療藥物 口炎 不可逆心肌病 肺毒性/肺中毒 肝毒性/肝中毒 潰瘍 Severe Emesis 嚴重嘔吐 Acute Emesis (急性嘔吐)： 在化療後0~24小時內發生的嘔吐 腎毒性/腎中毒 Delayed Emesis (延遲性嘔吐)： 在化療24小時以後發生的嘔吐 神經毒性 出血性膀胱炎 骨髓抑制 無骨髓抑制 延遲性骨髓抑制 36 36  References Hong Kong Cancer Fund http://www.cancer-fund.org/en/ Keogh, J. (2010) Pharmacology Schaum’s Outlines McGrawHill. McCance, K.L. & Huether, S.E. (2019). Pathophysiology: the biology basis for disease in adults and children (8th ed.). St. Louis: Mosby Elsevier. Moreau, D. (2009) Clinical pharmacology made incredibly easy! (3rd ed.).LWW. Norris, T.L. (2019). Porth’s pathophysiology: concepts of altered health states (10th ed.). Philadelphia: Wolters Kluwer. National Cancer Institute (NCI), U.S Department of Health and Human Services. http://www.cancer.gov/cancertopics Rubin’s pathology: Clinicopathologic foundations of medicine (6th ed., p. 193). Philadelphia, PA: Lippincott Williams & Wilkins.) 37