肿瘤分子生物学[1]肿瘤的本质课件

XIAN JIAOTONG UNIVERSITYPage1肿瘤细胞生物学肿瘤细胞生物学目的：目的：为生命科学领域研究生开设的，以提供肿瘤生物学为生命科学领域研究生开设的，以提供肿瘤生物学的基本知识（现代概念？）的基本知识（现代概念？）细胞生物学课程中主要介绍了正常细胞的结构、功能、组织、信号转导、实际上肿瘤细胞,免疫细胞,神经细胞,以及干细胞均应在细胞的范畴内。病理学关于肿瘤则主要是从组织形态,临床肿瘤学强调诊断和治疗。而对肿瘤的更深入的了解,从根本上解决诊断治疗,肿瘤细胞生物学的研究应是根本.基本内容：基本内容：肿瘤研究是一个极其宽泛的领域，我们集中于肿瘤研究是一个极其宽泛的领域，我们集中于临床之外，但与临床紧密相关的肿瘤发生、发展、浸润、临床之外，但与临床紧密相关的肿瘤发生、发展、浸润、转移，与宿主的相互作用、转归等行为的生物学机制。转移，与宿主的相互作用、转归等行为的生物学机制。考核：考核：.。Page 1肿瘤细胞生物学目的：肿瘤细胞生物学目的：为生命科学领域研究生开设的为生命科学领域研究生开设的XIAN JIAOTONG UNIVERSITYPage2Page 2XIAN JIAOTONG UNIVERSITYPage3Ultimately，we concluded,cancer immunotherapy passes the test.Page 3Ultimately，we concludedXIAN JIAOTONG UNIVERSITYPage4 It does so because this year,clinical trials have cemented its potential in patients and swayed even the skeptics.The field hums with stories of lives extended:the woman with a grapefruit-size tumor in her lung from melanoma,alive and healthy 13 years later;the 6-year old near death from leukemia,now in third grade and in remission;the man with metastatic kidney cancer whose disease continued fading away even after treatment stopped.As the anecdotes coalesce into data,theres another layer,too,a sense of paradigms shifting.Immunotherapy marks an entirely different way of treating cancerby targeting the immune system,not the tumor itself.20 DECEMBER 2013 VOL 342:1432 SCIENCE www.sciencemag.orgPage 4 It does so because tXIAN JIAOTONG UNIVERSITYPage5Cancer ImmunotherapyTHEWARONCANCERBEGANALITTLEMORETHAN40YEARSAGOASANATIONALRESEARCHPROGRAMto radically improve the survival of patients with cancer,a leading cause of death in the US and worldwide.The main weapons deployed have been surgery,radiation,and chemotherapy,treatments that often carry risks and/or cause adverse side effects.Although some forms of cancer yield to these therapy,not all do,and thus mortality remains high.To that list we now add a fourth weapon,cancer immunotherapy.Constructed over decades,it has begun to demonstrate such promising results in cancer patients that we have selected it as the Breakthrough of the Year for 2013.Page 5Cancer ImmunotherapyXIAN JIAOTONG UNIVERSITYPage6 War on Cancer War on Cancer More Successful Than PerceivedMore Successful Than PerceivedMarch11,2010Overall,theratesofcancer-relatedmortalityhavesubstantiallydeclinedintheUnitedStates.AccordingtotheresultsofanewstudypublishedonlineMarch9inPLoS ONE,cancerdeathrateshavedeclinedinbothmenandwomen,whethertheyaremeasuredagainstbaselineratesin1970/71,whentheNationalCancerActwasinitiated,oragainstthepeakratesseen1990/91.Page 6 War onXIAN JIAOTONG UNIVERSITYPage7 Mortalityrates(per100,000)increasedinmenfrom249.3in1970to279.8in1990,andthendeclinedto221.1in2006.Thisyieldedanetdeclineof21%from1990,apeakyear,andadropof11%since1970,abaselineyearInwomenrosefrom163.0in1970to175.3in1991,andthendecreasedto153.7in2006.Thiswasanetdeclineof12%and6%fromthe1990and1970rates,respectively.Thedeclineincancerdeathratessince1990hasresultedprimarilyfromreductionsintobaccouse,increasedscreeningthatallowsforearlydetectionofseveralcancers,andmodesttolargeimprovementsintreatmentforspecificcancersPage 7 Mortality rates(per 1XIAN JIAOTONG UNIVERSITYPage8FutureTrendsResearchatthemolecularlevelandunderstandingthemoleculardriversandtriggersofcancerisessentialtodevelopingbettertreatments.Wearerecognizingthattreatingalllungcancerinthesamemannerisathingofthepast.Thekeyisnowmoreindividualizedcare,whichisbasedonspecifictypesofbiology.Page 8Future Trends 肿瘤的本质肿瘤的本质 Xian Jiaotong University 2016.2.2016.2.肿瘤的本质肿瘤的本质 Xian Jiaotong XIAN JIAOTONG UNIVERSITYPage10Page 10XIAN JIAOTONG UNIVERSITYPage11Page 11XIAN JIAOTONG UNIVERSITYPage12born Feb.25,1682,Forl,Italy died Dec.5,1771,Padua Italian anatomist and pathologist whose works helped make pathological anatomy an exact science.Page 12born Feb.25,1682,ForXIAN JIAOTONG UNIVERSITYPage13Page 13XIAN JIAOTONG UNIVERSITYPage14Page 14XIAN JIAOTONG UNIVERSITYPage15Page 15XIAN JIAOTONG UNIVERSITYPage16 Hippocrates(460-375 BC),the father of medicine,was the first to divide tumors into two large groups according to their behavior（1）the innocuous tumors,which included swellings and lumps of various kinds(probably both non neoplasitic and neoplastic)（2）the dangerous tumors,which killed the patients (probably representing predominantly malignant neoplasms).肿瘤的概念肿瘤的概念肿瘤的概念肿瘤的概念 Page 16 Hippocrates(460-375 XIAN JIAOTONG UNIVERSITYPage17 Galen(AD 131-201 prominent Greek physician,surgeon and philosopher in the Roman empire）divided tumors into three categories:(1)tumor according to nature,e.g.,pregnancy.(2)tumors exceeding nature e.g.,inflammatory and reparative tumors,callus around a bone fracture;and(3)tumor contrary to nature,e.g.,true neoplasms.Galen was aware of the phenomenon of tumor metastasis.He was also the first to theorize as to the possible cause of cancer,ascribing it to excess of black bile.It is said that he was the one who coined the term sarcoma(Gr.sarx,genitive sarkos,flesh)under which he included various tumors with a fleshy gross appearance.Page 17 Galen(AD 131-201 promXIAN JIAOTONG UNIVERSITYPage18肿瘤的概念肿瘤的概念肿瘤的概念肿瘤的概念 肿瘤是机体在各种致瘤因素的作用下肿瘤是机体在各种致瘤因素的作用下,局部组织的细胞异常增生局部组织的细胞异常增生而形成的新生物而形成的新生物,这种新生物常表现为肿块这种新生物常表现为肿块.肿瘤细胞是从正常细胞转变而来的肿瘤细胞是从正常细胞转变而来的,但当它变为肿瘤细胞后就但当它变为肿瘤细胞后就具有异常的形态、代谢及功能，它生长旺盛，呈相对无止境生长，具有异常的形态、代谢及功能，它生长旺盛，呈相对无止境生长，与整个机体不协调，并在不同程度上失去了发育成熟的能力，有与整个机体不协调，并在不同程度上失去了发育成熟的能力，有些甚至具有接近幼稚的胚胎细胞的表现。一旦形成肿瘤，即便是些甚至具有接近幼稚的胚胎细胞的表现。一旦形成肿瘤，即便是致瘤因子不存在，肿瘤细胞的生长和代谢仍能继续保持下去；当致瘤因子不存在，肿瘤细胞的生长和代谢仍能继续保持下去；当把这种肿瘤细胞接种到体外培养基中培养时这种特征依然存在把这种肿瘤细胞接种到体外培养基中培养时这种特征依然存在（病理学卫生部统编教材第一版1979）。）。Page 18肿瘤的概念肿瘤的概念 肿瘤是机体在各种致肿瘤是机体在各种致XIAN JIAOTONG UNIVERSITYPage19肿瘤概念肿瘤概念 Cancerisageneticdisease,arisingfromanaccumulationofmutationsthatpromoteclonalselectionofcellswithincreasinglyaggressivebehavior.Thevastmajorityofmutationsincanceraresomaticandarefoundonlyinanindividualscancercells.However,about1%ofallcancersariseinindividualswithanunmistakablehereditarycancersyndrome.Theseindividualscarryaparticulargermlinemutationineverycelloftheirbody.Science Vol.278.no.5340,pp.1043 1050,7 November 1997 肿瘤是机体在各种致瘤因素的作用下，局部组织的细胞肿瘤是机体在各种致瘤因素的作用下，局部组织的细胞在在基因水平上失去对其生长的正常调控，基因水平上失去对其生长的正常调控，导致克隆性异常增生而导致克隆性异常增生而形成的新生物形成的新生物（病理学卫生部统编教材第五版2001）。Page 19肿瘤概念肿瘤概念 CancerXIAN JIAOTONG UNIVERSITYPage20 Cancer is a disease of the genome,which is invariably altered at multiple sites in cancer cells.The goal of cancer research is to define these molecular defects and turn these discoveries into effective treatment and prevention regimens.Cancer Cell,Vol 1,37-47,February 2002Page 20 Cancer is a disXIAN JIAOTONG UNIVERSITYPage21 Fundamental to the origin of all neoplasms are the loss of responsiveness to normal growth controls Robinsbasicpathology7thedition.2003 Fundamental to the origin of all neoplasms are heritable(genetic)changes that allow excessive and unregulated proliferation that is independent of physiologic growth-regulatory stimuli.Neoplasms therefore enjoy a certain degree of autonomy and more or less steadily increase in size regardless of their local environment and the nutritional status of the host.Their autonomy is by no means complete,however.Some neoplasms require endocrine support,and such dependencies sometimes can be exploited to the disadvantage of the neoplasm.Robinsbasicpathology8thedition.2007Page 21 Fundamental to the XIAN JIAOTONG UNIVERSITYPage22 In general,neoplasms are irreversible,and their growth is,for the most part,autonomous.Several observations are important:Neoplasms are derived from cells that normally maintain a proliferative capacity.Thus,mature neurons and cardiac myocytes do not give rise to tumors.A tumor may express varying degrees of differentiation,from relatively mature structures that mimic normal tissues to a collection of cells so primitive that the cell of origin cannot be identified.The stimuli responsible for the uncontrolled proliferation may not be identifiable.Neoplasia arises from mutations in genes that regulate cell growth,death or DNA repair.RUBINS PATHOLOGY:Clinicopathologic Foundations of Medicine 6th Edition 2012Page 22 In general,neoplasms XIAN JIAOTONG UNIVERSITYPage23Nocompletelysatisfactorydefinitionofneoplasiaexists，ithasbeensurprisinglydifficulttodevelopanaccuratedefinition.InthePremolecularera,definitionoftheeminentBritishoncologistWillisremainsoneofthemostwidelycitedanduseful:Aneoplasmisanabnormalmassoftissue,thegrowthofwhichexceedsandisuncoordinatedwiththatofthenormaltissuesandpersistsinthesameexcessivemanneraftercessationofthestimuliwhichevokedthechange(WillisB.A.:thespreadofthetumorsinthehumanbody,London,1952.Butterworth&Co.)Page 23 No completely satisXIAN JIAOTONG UNIVERSITYPage24Inthemodernera,aneoplasmcanbedefinedasadisorderofcellgrowththatistriggeredbyaseriesofacquiredmutationsaffectingasinglecellanditsclonalprogeny.Thecausativemutationsgivetheneoplasticcellsasurvivalandgrowthadvantage,resultinginexcessiveproliferationthatisindependentofphysiologicgrowthsignals(Robbins&CotranPathologicBasisofDisease9thEd.2015)Page 24 In the modern era,XIAN JIAOTONG UNIVERSITYPage25肿瘤是一种细胞性病肿瘤是一种细胞性病肿瘤是一种基因病肿瘤是一种基因病(遗传病遗传病)肿瘤是一种组织病肿瘤是一种组织病(肿瘤性复杂组织的组织性疾病肿瘤性复杂组织的组织性疾病)Page 25肿瘤是一种细胞性病肿瘤是一种细胞性病XIAN JIAOTONG UNIVERSITYPage26Tumors and derived xenografted tumor cell linesStromal components of several commonly occurring carcinomaHigh-grade invasive ductal carcinoma of the breastColon cancerLobular carcinoma in situ of the breastAdenocarcinoma of the stomachHodgkins lymphomaPage 26Tumors and derived xenoXIAN JIAOTONG UNIVERSITYPage27Recruitment of endothelial precursor cells by mammary CAFsNormal stroma and desmoplastic stroma Page 27Recruitment of endothelXIAN JIAOTONG UNIVERSITYPage28Page 28XIAN JIAOTONG UNIVERSITYPage29 Tumors arise from normal tissues组织/细胞学证据相似性、异型性（组织病理学)Tumors arise from many specialized cell types throughout the body Epithelia tissues(threeprimitivecelllayers)：Carcinoma(80%cancerdeath)Non-Epithelia tissues(Sarcoma/Hematopoieticmalignancy/Neuroectodermalmalignancy/others)Sometypesoftumorsdonotfitintothemajorclassifications Page 29 Tumors arise from norXIAN JIAOTONG UNIVERSITYPage30Normal vs Hyperplastic epithelium Cancers seem to develop progressivelyMetaplastic conversion of epithelia (metaplastic Barretts epithelium)Dysplastic epitheliumDuctal carcinoma in situInvasive ductal carcinomaPage 30Normal vs HyperplasticXIAN JIAOTONG UNIVERSITYPage31 Thegeneticalterationsofcancercellsareheritable.Asaresult,cellsharboringthesealterationsaresubjecttoDarwinianselection,withcellsbearingmutationsthatprovidethemwithgrowthorsurvivaladvantagesoutcompetingtheirneighborsandthuscomingtodominatethepopulation.Becausetheselectiveadvantagesareconferredonasinglecellthatultimatelygivesrisetothetumor,alltumorsareclonal(i.e.,theprogenyofonecell).肿瘤是单克隆生长肿瘤是单克隆生长Monoclonality vs polyclonality of tumorsPage 31 The genetic alteraXIAN JIAOTONG UNIVERSITYPage32 glucose-6-phosphate dehydrogenase chromasome abrrationTo determine whether all the cells in a tumor mass share a common,highly unique genetic or biochemical marker.Page 32 glucose-6-phosphate deXIAN JIAOTONG UNIVERSITYPage33 Cancer cells exhibit an altered energy metabolismTheenergymetabolismofmostcancercellsdiffersmarkedlyfromthatofnormalcells,firstreportedin1924byOttoWarburgPage 33 Cancer cells exhibit XIAN JIAOTONG UNIVERSITYPage34 Cancers occur with vastly different frequencies in different human populations 日本人胃癌发病是美国人的6-8 倍，第二代则和周围人相类似（环境与生活方式）中国人乳腺癌是美国人的1/6，排除遗传因素，美国人85%的乳腺癌是可以预防的 中国广东的鼻咽癌发病高，即便是移居国外亦是如此 美国一宗教信仰者反对吸烟，酗酒，提倡素食，因肿瘤死亡者是一般人群的1/2 因此，避免明显的环境致癌因素，生活习惯，可以降低50%的肿瘤发生，而肿瘤在人群死亡中所占的比例仅为10%左右。Page 34 Cancers occur with vaXIAN JIAOTONG UNIVERSITYPage35aSeeC.Muir,J.Waterhouse,T.Macketal.,eds.,CancerIncidenceinFiveContinents,vol.5.Lyon:InternationalAgencyforResearchonCancer,1987.ExcerptedbyV.T.DeVita,S.HellmanandS.A.Rosenberg,Cancer:PrinciplesandPracticeofOncology.Philadelphia:Lippincott,1993.Page 35aSee C.Muir,J.WaterhXIAN JIAOTONG UNIVERSITYPage36bRelativerisk:age-adjustedincidenceordeathrateinhighestcountryorarea(H)dividedbyage-adjustedincidenceordeathrateinlowestcountryorarea(L).Thesenumbersrefertoage-adjustedrates,forexample,therelativeriskofa60-year-olddyingfromaspecifictypeoftumorinonecountrycomparedwitha60-year-oldinanothercountry.cSeeP.Pisani,D.M.Parkin,F.BrayandJ.Ferlay,Int.J.Cancer 83:1829,1999.This survey divided the human population into 23 geographic areas andsurveyedtherelativemortalityratesofvariouscancertypesineacharea.Page 36bRelative risk:age-adjXIAN JIAOTONG UNIVERSITYPage37 The risk of cancers often seem to be increased by assignable influences including lifestyle 英国内科医生John Hill,1761年，吸鼻咽者易患鼻癌，14年后，英国外科医生 Percivall Pott 发现扫烟囱者易患阴囊癌，chimney sweeper guild 强制成员每日洗澡，肿瘤发生明显下降。16世纪中期，捷克银矿工人肺癌发生率 1839年意大利医生报道修女乳腺癌发生率高于常人6倍 1949-1950 两组关于吸烟与肺癌的报告，长期大量吸烟者肺癌发生率是常人的20倍Page 37 The risk of cancersXIAN JIAOTONG UNIVERSITYPage38aAdaptedfromAmericanCancerSociety.CancerFacts&Figures1990.Atlanta:AmericanCancerSociety,Inc.bAlargenumberofcancersarethoughttobeprovokedbyadiethighincalories(seeSidebar9.10)actingincombinationwithmanyoftheselifestylefactors.Page 38 aAdapted from AmeriXIAN JIAOTONG UNIVERSITYPage39Relative risk of lung cancer as a function of the number of cigarettessmoked per day Therelativeriskindicatestheriskofcontractinglungcancercomparedwiththatofanonsmoker,whichissetat1.FromR.DollandA.B.Hill,BMJ 2:739748,1950.Page 39Relative risk of lung cXIAN JIAOTONG UNIVERSITYPage40Adapted from S.Wilson,L.Jones,cancer and the environment:Gene-Environment Interaction,Washington DC.National Academy Press,2002Page 40Adapted from S.Wilson,XIAN JIAOTONG UNIVERSITYPage41Examplesofetiologicmysteries:epidemiologiccorrelationsbetweenenvironmental/lifestylefactorsandcancerincidencethatlackaclearexplanationofcausalmechanismPage 41 Examples of etioloXIAN JIAOTONG UNIVERSITYPage42 Specific chemical agents can induce cancer 1915年，日本学者Katsusaburo Yamagiwa 用煤焦油反复涂抹兔子耳朵诱发肿瘤，这是第一次用化学试剂在实验室制造肿瘤模型。1940年，英国化学家从煤焦油中纯化出数种纯品致癌物，如3-methyl-cholanthrene,benzopyrene 等Page 42 Specific chemical ageXIAN JIAOTONG UNIVERSITYPage43 Both physical and chemical carcinogens act as mutagens化学/物理/生物致癌等三大致癌理论1927年Hermann Muller 发现X线能引起果蝇基因组突变，更重要的是，这个发现揭示动物的基因组是可突变的，放射线能够引起正常细胞突变，突变细胞可形成恶性特征。1940年 发现烷化剂是致突变剂，这类物质可以引起实验动物肿瘤，提出致突变剂就是致癌剂Ames 试验用于检测致突变剂Page 43 Both physical andXIAN JIAOTONG UNIVERSITYPage44 Mutagens may be responsible for some human cancers1990年，致突变剂与致癌剂等同的概念已经改变，40%在啮齿类动物致癌的化学物质Ames试验未检测出致突变性。提出有些致癌剂通过突变DNA，而有些可能通过非遗传学机制（如表观遗传学？）哺乳动物肝脏代谢与沙门氏菌不同，代谢后去毒/增毒？Page 44 Mutagens may be respoXIAN JIAOTONG UNIVERSITYPage45肿瘤来源于正常组织肿瘤来源于正常组织/肿瘤分为良性或恶性肿瘤分为良性或恶性肿瘤主要分为上皮肿瘤主要分为上皮/间叶间叶/淋巴造血淋巴造血/神经外胚层四大类神经外胚层四大类身体所有的细胞均可发生肿瘤，最常见的是上皮来源的，身体所有的细胞均可发生肿瘤，最常见的是上皮来源的，鳞状细胞癌鳞状细胞癌/腺癌腺癌非上皮来源恶性肿瘤包括非上皮来源恶性肿瘤包括肿瘤发生是渐进性，肿瘤发生是渐进性，normal/hyperplasia/metaplasia/dysplasia/neoplasiaDysplasia is a transitional state between completely benign and premalignant,adenomatous growths(adenoma,polyps,papilloma/warts)are dysplasitic epithelia tumors that are considered to be benign)Page 45肿瘤来源于正常组织肿瘤来源于正常组织/肿瘤分为良性或恶性肿瘤分为良性或恶性XIAN JIAOTONG UNIVERSITYPage46生化或遗传标志确定肿瘤是单克隆性生化或遗传标志确定肿瘤是单克隆性虽然某些肿瘤全球范围发病率相近（儿童肿瘤，遗传虽然某些肿瘤全球范围发病率相近（儿童肿瘤，遗传/环环境），境），流行病学提示环境因素更重要流行病学提示环境因素更重要实验室结果证实了流行病学研究：化学和物理因素实验室结果证实了流行病学研究：化学和物理因素（Tobacco,coal dust,X-ray)是致癌因素，生物致癌因素亦经是致癌因素，生物致癌因素亦经白血病和鸡肉瘤所证实白血病和鸡肉瘤所证实物理化学因素致癌机理：物理化学因素致癌机理：X-线致果蝇基因突变线致果蝇基因突变（1927），），化学物质致果蝇基因突变，实验室动物致癌化学物质致果蝇基因突变，实验室动物致癌（1950）。）。致癌致癌是通过基因突变所致，致突变剂可能是致癌剂是通过基因突变所致，致突变剂可能是致癌剂 Page 46生化或遗传标志确定肿瘤是单克隆性生化或遗传标志确定肿瘤是单克隆性XIAN JIAOTONG UNIVERSITYPage47 1975年年 Ames试验支持多数致癌剂是致突变剂，试验支持多数致癌剂是致突变剂，研究显示研究显示几乎所有的致突变剂可能是致癌剂，但反之并不亦然几乎所有的致突变剂可能是致癌剂，但反之并不亦然。有些有些致癌剂通过突变致癌剂通过突变DNA机制，而有些是通过非遗传学机制机制，而有些是通过非遗传学机制（nongenetic mechanism)这种非遗传机制性致癌剂称为促癌剂。这种非遗传机制性致癌剂称为促癌剂。Page 47 1975年年 Ames试验支持多数致癌剂是致试验支持多数致癌剂是致