Fall 2018 Dr. Chundong Yu cdyu@xmu.edu.cn, D220 15960836828 Cancer Biology Fall 2018 Dr. Chundong Yu cdyu@xmu.edu.cn, D220 15960836828

炎症与肝病学课题组长：俞春东 教授 研究方向与成果： 研究转录辅激活因子在肝癌、结肠癌等消化系统肿瘤中的作用及分子机理。 1989-1993 年 学士 中山大学生物学系 1993-1996 年 硕士 厦门大学生物学系 1998-2002 年 博士 University of Texas-Houston 2002-2006 年 博士后 Baylor College of Medicine 2006 ---至今 教授 厦门大学生命科学学院 研究方向与成果： 研究转录辅激活因子在肝癌、结肠癌等消化系统肿瘤中的作用及分子机理。 研究转录辅激活因子在炎症和感染相关疾病中的作用及分子机理。 至今在Molecular Cell, Hepatology, Journal of Hepatology, Oncogene, Journal of Biological Chemistry等杂志上发表研究论文40多篇。

课程目标 掌握肿瘤学中的基本概念 了解肿瘤发生的病因 了解肿瘤学科研究的概况 学会阅读和总结文献

课程内容与成绩要求 总成绩： 出勤20%+期中30%+演讲20%+期末30% 课后作业：阅读5篇论文 主要内容： 1.癌症学说及癌症分类 2.癌症发生发展-正常细胞的恶性转化 3.癌症诱因-病毒/环境 4. 病毒诱发癌症发生的机制 5. 抑癌基因 6. 癌基因 7. 期中考试 (11月12日) 8.细胞周期调控与肿瘤发生 9. 基因组稳定性与肿瘤发生 10.肿瘤代谢 11.肿瘤微环境 12.肿瘤免疫 13.肿瘤干细胞与异质性 14. 学生专题汇报 1 15.学生专题汇报 2 16. 期末考试 总成绩： 出勤20%+期中30%+演讲20%+期末30% 课后作业：阅读5篇论文

Robert A. Weinberg 第一个抑癌基因Rb 人类的第一个原癌基因Kras 参考书和文献

文 献 1.Hallmarks of cancer （肿瘤综述） 2. Oncogene （癌基因） 文 献 1.Hallmarks of cancer （肿瘤综述） Cell. 2011;144(5):646-74. Hallmarks of cancer: the next generation. Hanahan D(1), Weinberg RA. 2. Oncogene （癌基因） Nature Reviews Cancer 3, 459-465. RAS oncogenes: the first 30 years 3.Tumor suppressor（抑癌基因） Nature Reviews Cancer 9, 749-758 (October 2009) The first 30 years of p53: growing ever more complex 4.Tumor immunity （肿瘤免疫） Cancer Cell, 2015, 27(4 ) Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy 5. Hippo and cancer （器官生长与肿瘤） Br J Cancer. 2011;104(1):24-32. Mst1/2 signalling to Yap: gatekeeper for liver size and tumour development

Cancer Biology 第一讲：癌症学说及癌症分类

由此可见，癌症是本世纪人类的第一杀手，并成为全世界的公共卫生问题。 癌症概况 世界范围 根据《世界癌症报告》，2012年癌症新发病例达1409万，死亡820万，现有癌症患者3254.5万，分别比2000年的1000万、620万、2240万增加40.9%、32.3%、45.3%。 世界卫生组织预测2025年全球人口83亿，癌症新发病例将达到2000万，死亡病例达到1140万。 中国 我国流行情况亦如此，根据1990—1992年和2004—2008年次全国死亡原因调查，15年间癌症死亡率上升25.5%，占总死因构成比由17.94%上升至22.32%。2012年中国癌症新病例达312万，每分钟就有6人患上癌症；癌症死亡220万，占全球癌症死亡26.9%。到2020年将达276万。 由此可见，癌症是本世纪人类的第一杀手，并成为全世界的公共卫生问题。

Estimated New Cancer Cases and Deaths Worldwide CA CANCER J CLIN 2015;65:87-108

Introduction What is cancer? What causes cancer? How do we prevent cancer? How do we treat cancer?

What is cancer? A foreign body? A parasite? Produced by “evil” force? Neoplasma: “Neo”=New “Plasma”= formation; Tumor: Solid mass, tumor means a neoplasm that has formed a lump

History of cancer The earliest known descriptions of cancer, as well as a procedure to remove breast tumours by cauterization appear in several papyri from Ancient Egypt (1600 B.C). Hippocrates: Greek physician (460-370 B.C) “father of medicine”. He described several kinds of cancer, referring to them by the term karkinos (carcinos), the Greek word for crab or crayfish, as well as carcinoma. Body was composed of four fluids: blood, phlegm, yellow bile and black bile. Excess of black bile  cancer. Celsus ( 25 BC - 50 AD) translated karkinos into cancer, the Latin word for crab or crayfish.

New Technology： Microscope 1590：Dutch（荷兰） eye glass makers, Zaccharias Janssen and son Hans Janssen：multiple lenses placed in a tube: forerunner of the compound microscope and telescope. 1665, Robert Hooke (1635-1703), English microscopist, cork --empty small compartments. The “cell” was discovered! Latin, cellula ; i.e., small compartment 1676, Anton van Leeuwenhoek, using a simple microscope, was the first to observe microorganisms 1700, first description of the nucleus by Leeuwenhoek.

New Theory： Cell 1838 Matthias Schleiden (1804-1881) German botanist Thousands of plant specimens  all the vegetables are made of cells. 1839, Theodor Schwann (1810-1882) German zoologist and physiologist  all living beings were composed of cells.

施莱登 1838 Matthias Schleiden

Cell theory All living beings are composed of cells. The living beings may grow and reproduce themselves because the cells may in turn multiply. The new cells are formed from other pre-existing ones.

Histology 组织学 1852: first textbook of Histology ： Marie François Bichat, French pathologist (1771-1802) A texture was a “tissue” by its macroscopic physical properties. tissu = to weave (ancient French) in 1819, A. Mayer -Histology. histos = tissue logos = study 1852: first textbook of Histology ： Rudolph von Kölliker (1817-1905) Swiss professor of Anatomy <<Handbuch der Gewebelehre>> (i.e., The book for teaching tissues)

Histology of Tumor A foreign body? A parasite? Produced by “evil” force? Tumor under microscope: Mass of cells Similarity to surrounding tissue Less organized  Tumors arise from self

Carcinoid Tumor of the Ileum 大肠 小肠 http://www.pathology.vcu.edu/education/gi/lab2.h.html a slow-growing type of neuroendocrine tumor 小肠： 十二指肠(Duodenum), 空肠(Jejunum), 回肠(Ileum).

submucosal carcinoid tumor of illeum http://www.pathology.vcu.edu/education/gi/lab2.h.html

closely packed, uniform round cells with small, central nuclei

Classification of tumors Based on clinical effect on patients Based on location/tissue of origin Based on microscopic features Stages of tumor

Based on clinical effect on patients Benign: Grows locally Without invading of adjacent tissues Malignant Invade nearby tissues Spawned metastasis

Clinical effect of Benign tumor Secrete high levels of hormones Grow only in one place, cannot spread or invade other parts Be dangerous if they press on vital organs

Guinness World Records 2.47 m Sultan Kosen, from Turkey

2009 World’s tallest man pituitary gigantism （垂体性巨人症）

World’s tallest woman 姚德芬 2.33m July 15, 1972 (age 37) 安徽

Pituitary tumor （Benign) Because she is illiterate, since 1992 Yao Defen has been forced to earn a living by traveling with her father and performing.

Acromegaly（肢端肥大症）

Clinical effect of Malignant tumor 90% cancer deaths are due to metastasis Once metastatic cells are attached to the basement membrane (a physical barrier that seperates tissue components), they break through with the help of an enzyme called type IV collagenase. Cancer cells then move through the blood stream enabling them to spread to other parts of the body. A secondary tumor may form at another site in the body. This is a file from the Wikimedia Commons

Classification based on tissues

asweknowit.net/images_edu/ dwa5%20tissues.jpg

Knowing Cancer Origin Informs Therapy Target-specific Drugs: Prostate 33% Lung & bronchus 13% Colon & rectum 11% Urinary bladder 6% Melanoma of skin 4% Non-Hodgkin lymphoma 4% Kidney 3% Oral Cavity 3% Leukemia 3% Pancreas 2% All Other Sites 18% HERCEPTIN TARCEVA AVASTIN, ERBITUX RITUXAN SUTENT GLEEVEC 32% Breast 12% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Ovary 4% Non-Hodgkin lymphoma 4% Melanoma of skin 3% Thyroid 2% Urinary bladder 2% Pancreas 20% All Other Sites Total Women: 668,470 Total Men: 699,560 Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2004.

全国肿瘤登记中心发布的《2012中国肿瘤登记年报》 更令人关注的是，2012年中国新增癌症病例高居世界第一位，肝癌和食管癌患者约占全球一半，死亡分别占全球的51%和49%；胃癌症例和死亡均占全球40%；鼻咽癌80%发生在中国。 全国肿瘤登记中心发布的《2012中国肿瘤登记年报》

Cancer Cell types Most adult cancers are carcinomas Epithelial origin In contrast, most childhood cancers are: Leukemias/lymphomas Blastomas → Embryonal cells Sarcomas → Mesenchymal origin Source:http://www.ncbi.nlm.nih.gov/About/primer/genetics_cell.html

Based on tissue/cell of origin Carcinomas = epithelia derived >80% of all human cancer-related deaths 1. Adenocarcinoma  gland epithelia 2. Squamous cell carcinoma  Seal, protective layers 3. Other

Classification of Epithelium Simple: One cell layer Stratified: two or more cell layers Squamous: wildth>height Columnar: Height> wildth Cuboidal:wildth=height=depth

The Morphology of an Epithelium often Correlates with Its Function 1.Simple: One cell layer Epithelia involved in secretion or absorption Transepithelial transport 2.Stratified: two or more cell layers Transepithelial impermeability 3.Psedostratified: Maintain a stable population of cells to balance cell turnover

1. Adenocarcinoma  gland epithelia Lung Stomach Pancreas Small intestine Colon Breast Uterus (Endometrium) Ovary

Colon

Colon Polyps

Colon cancer

Colon polyps/cancer

Stomach www.gihealth.com/images/imgStomachCancer.gif

Colon Cancer spread to liver

Breast Adenocarcinoma http://www.microscopyu.com/galleries/pathology/images/adenocarcinomaofbreast40x05.jpg

2. Squamous cell carcinoma  Seal, protective layers Skin Esophagus(食道) Nasal cavity Larynx(喉) Cervix(宫颈)

Squamous cell carcinoma NCI VisualsOnline

Squamous Cell Carcinoma http://www.microscopyu.com/staticgallery/pathology/all40x04.html

3. Other types of carcinoma Small cell lung carcinoma Large cell lung carcinoma Hepatocellular carcinoma (Liver cancer) Renal cell carcinoma (Kidney cancer) Transitional cell carcinoma (Urothelial carcinoma (UCC))

II. Sarcomas Derived from mesenchymal cells of connective tissues 1% cancer death

Types of Sarcomas Fibrosarcoma  fibroblasts Liposarcoma adipocytes Osteosarcoma  Osteoblasts Leiomyosarcoma  Smooth muscle Rhabdomyosarcoma  Striated skeleton muscle Angiosarcoma  precusors of endothelial cells

Uterine Sarcoma  http://www.microscopyu.com/galleries/pathology/images/sarcomaofuterus20x02.jpg

Uterine Sarcoma 

III. Leukemia & lymphoma Lymphoma = Solid mass in lymph nodes Hodgkin’s lymphoma Non-Hodgkin’s lymphoma=lymphocytic lymphoma 15-20 subtypes Leukemia=cancer cells in blood （from bone marrow)

2. Leukemia: cancer cells in blood Acute lymphocytic leukemia (ALL) - 80% from B cells, 20% from T cells - Distinguished by cell surface markers Chronic lymphocytic leukemia Acute myelogenous leukemia (AML) - Small rim of cytosol, large nucleus - Pre-granulocytes (precursors of monocyte/macrophage) Chronic myelogenous leukemia - Bone marrow derived Multiple myeloma  Plasma cell derived

Normal blood http://www.medicalhistology.us/twiki/pub/Main/ChapterTenSlides/a100_11_blood_smear_40x_wright_labeled.jpg

Acute lymphocytic leukemia (ALL) http://spittoon.23andme.com/wp-content/uploads/2009/08/Acute_leukemia-ALL.jpg http://www.pharmacy-and-drugs.com/illnessessimages/acute-lymphoblastic-leukemia1.jpg

Acute Myelomonocytic Leukemia-AML http://www.microscopyu.com/staticgallery/pathology/images/all40x04.jpg

Granulocytic Leukemia

Lymphoma http://www.ispub.com/ispub/ijs/volume_9_number_2/primary_non_hodgkin_lymphoma_of_the_breast/lymphoma-fig3.jpg

T cell Lymphoma http://webpathology.com/slides/slides/LymphNode_LymphoblasticLymphoma3.jpg

IV. Neuroectodermal tumors CNS (central nervous system) PNS (Peripheral nervous system) 1.3% diagnosed cancer2.5% cancer death Glioma（胶质瘤） Glioblastoma（胶质母细胞瘤） Neuroblastoma（神经母细胞瘤） Schwannoma （神经鞘瘤 ） Medulloblastoma(髓母细胞瘤)

http://www.uthsc.edu/pathology/Brain/brain.5.jpg

Brain Imaging

V. Other tumors Melanoma  melanocytes Tumors of unknown origin

Moles and melanoma

Melanomas melanoma.at/images/ melanoma_1.jpg I

Stages of tumor Contemporary practice is to assign a number from I to IV to a cancer, with I being an isolated cancer and IV being a cancer which has spread to the limit of what the assessment measures. The stage generally takes into account the size of a tumor, whether it has invaded adjacent organs, how many regional (nearby) lymph nodes it has spread to (if any), and whether it has appeared in more distant locations (metastasized). The most clinically useful staging system is the tumor, node, and metastasis (TNM) staging system developed by the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC), herein referred to as the AJCC TNM staging system. The AJCC TNM system classifies cancers by the size and extent of the primary tumor (T), involvement of regional lymph nodes (N), and the presence or absence of distant metastases (M).

The stage of colorectal cancer