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1、1889 种子与土壤假说 1909 免疫监视 1910 病毒与肿瘤 1915 激素与癌症 1937 肿瘤干细胞 1939 血管再生术 1950 吸烟与肿瘤 1953 二次突变假说 1960 染色体易位 1971 肿瘤抑制基因 细胞凋亡与肿瘤 1975 肿瘤微环境 1976 克隆演变&多步骤肿瘤发生,1976 病毒癌基因的细胞同系物 1978 癌基因编码 蛋白调控细胞生长 1979 第一个人类癌基因 1983 癌基因互作 、肿瘤表观遗传学 1989 细胞周期和DNA损伤检查 1990 肿瘤易感性的遗传基础 肿瘤遗传不稳定性的机制 1999 肿瘤谱 2001 肿瘤靶向治疗,肿瘤研究百年大事记,（N
2、ature Milestones in Cancer, milestones of timelines),1889 种子与土壤假说 (Seed and Soil Hypothesis),Stephen Paget (assistant surgeon to the West London hospital),By analyzing 735 case histories of fatal breast cancer, he found that metastasis formed in the liver far moreeven those such as the spleen that c
3、ould be considered to have the same exposure to the cancer cells because of similar blood flows.,（Nature, milestones of timelines),Question: “what is it that decides what organ shall suffer a case of disseminated cancer”,Conclusion: Cancer cells require some “nourishment nourishment” from the enviro
4、nment to develop.,Molecular mechanism (until today),?,1975 肿瘤微环境 (Tumor Microenvironment),Beatricemintz and Karl Illmensee,They took the tetracarcinoma cells from embryoid bodies in vivo, and injected them into developing mouse blastocysts. Surprisingly, normal mice were born with no evidence of tum
5、ors. They found that tumor-derived cells were present in large numbers and contributed to several unrelated tissues, the most notable being functional spermatozoa. They concluded tumor cells were developmental totipotent and could revert to normal behavior in the appropriate environment.,（Nature, mi
6、lestones of timelines),1984 肿瘤微环境 (Tumor Microenvironment),Mina Bissell,Context is everything,People and idea, JCB, 2009,The tumor-inducing behavior of Rous sarcoma virus (RSV) when injected into the wings of newly hatched chicks was already known, and the viral gene v-src had been identified as the
7、 sole culprit. What Bissell found was that if RSV was injected into 4-day-old embryo, no tumor were produced, despite the spread of RSV infection and active v-src expression.,Other contributions :,The wounding is important for tumorigenesis,Blocking integrin function is sufficient to revert the magl
8、ignant phenotype of human breast cancer.,General concept of tumor microenvironment,Tumor microenvironment refers to the unique properties of tissue microenvironment conferred by abnormal interactions between tumor and host cells. Tumor microenvironment is often characterized by hypoxia, nutrient dep
9、rivation, acidosis, and aberrant stroma.,Highly variable, with differences seen between patients and often in different areas of the same tumor. The tumor microenvironment is often altered as the diseases progresses; even the percentage of a tumor made up of cancer cells may change.,基本定义:,主要特征:,Tumo
10、r microenvironment,Tumor cell,Tumor-associated stromal cells （fibroblast，endothelial cell, Immune cell）,Extracellular Matrix Proteins （structural and non-structural),Acidic,Cytokines,Neurotransmitters,Hypoxia,Growth factors,MMPs, ADAMs, other secreted proteins and their receptors,Hormone,Chemokines,
11、Tumor-associated stromal cells,Activated fibroblast ( hepatic stellate cell),Immune cell,Endothelial cell,Pericyte,Adipocyte,Glial cell,Tumor associated fibroblast,Characteristics of normal fibroblast,Activated fibroblast in the tumor microenvironment,Origin of activated fibroblasts in the tumor str
12、oma,Interaction between tumor cells and activated fibroblasts,The role of activated fibroblast in cancer development,Cross-talk between activated fibroblasts and other tumor-associated host cell,Characteristics of normal fibroblast,Basic component of connective tissue and contribute to structural in
13、tegrity,Main resource of ECM and regulation of ECM turnover,Low proliferate index and minimum metabolic capacity,Main resource of growth factors and cytokines,Activated fibroblast in the tumor microenvironment,Similar phenotype as fibroblasts in inflammation and wound healing,Indented nuclei, stress
14、 fibers and well-developed cell-matrix interaction,Markers: Fibroblast activation protein (FAP), a-smooth muscle actin (aSMA), r-smooth muscle actin (gSMA), Prolyl-4-hydroxylase (P4H, for collagen synthesis),Identification: a-SMA in combination with at least 3 other markers (e.g., positive for a-SMA
15、, vimentin and P4H and negative for cytokeratin),基本特征：,如何鉴定：,Origin of activated fibroblasts in the tumor stroma,Surrounding resting fibroblasts after their activation and recruitment to the tumor tissue, Bone marrow stem cell, pericytes, via epithelial or endothelial to mesenchymal transition.,Xour
16、i, et .al. 2010, seminars in cell and developmental biology,Interaction between tumor cells and activated fibroblasts,Tumor,Activated fibroblasts,TGF-b, PDGF, LL-37, LPA,All the stages of tumor development,The role of activated fibroblast in cancer development,Initiation of tumor,Kuperwasser, et al.
17、, 2004, PNAS,Bhnowmick, et al., 2004, Science,Progression of tumor,Bhnowmick, et al., 2004, Science,Metastasis of tumor,Grugan , et al., 2010, PNAS,Duda, et al., 2010, PNAS,TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Bhowmick NA, Chytil A, Plieth D, Gor
18、ska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL. Science. 2004 Feb 6;303(5659):848-51.,Conditional knock-out TGF-beta type II receptor,Fibroblasts,Abundance of stromal cells,Intraepithelial neoplasia in prostate （5-7 weeks）,Invasive squamous cell carcinoma of the forestomach （7-wee
19、k-old）,Paracrine HGF signaling,（FSP1 promotor）,3 weeks,Initiation of tumor,Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion. Grugan KD, Miller CG, Yao Y, Michaylira CZ, Ohashi S, Klein-Szanto AJ, Diehl JA, Herlyn M, Han M, Nakagawa H
20、, Rustgi AK. Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11026-31. Epub 2010 Jun 1.,HGF/MET signaling,Invasion of tumor,Malignant cells facilitate lung metastasis by bringing their own soil Duda DG, Duyverman AM, Kohno M, Snuderl M, Steller EJ, Fukumura D, Jain RK Proc Natl Acad Sci U S A. 2010 De
21、c 14;107(50):21677-82,Metastasis of tumor,Cross-talk between myofibroblasts and other tumor-associated host cell,Wever et al. 2008, Int.J.Cancer,Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L
22、, Jones JO, Gopinathan A, Tuveson DA, Fearon DT. Science. 2010 Nov 5;330(6005):827-30.,Transgenic mouse,FAP (fibroblast activation protein-a) promotor,Expressing Primate diphtheria toxin receptor,Endothelial cells and tumor,Tumor angiogenesis: Therapeutic implication. N. Engl. J. Med.,1971 Judah Fol
23、kman,In 1939, Gordon Ide and colleagues,In 1945, Glenn Algire and colleagues,In 1968, Melvin Greenblatt and Philippe Shubik,He proposed that tumour cells secrete a soluble factor that stimulates the proliferation of endothelial cells, that these in turn control tumour expansion and, in the absence o
24、f new vessel growth, that tumours do not increase beyond 23 mm in size, entering instead a state of dormancy.,Stromal endothelial cells directly influence cancer progression. Franses JW, Baker AB, Chitalia VC, Edelman ER. Sci Transl Med. 2011 Jan 19;3(66):66ra5,Secretions from quiescent endothelial
25、cell,(EC-conditioned medium),Breast and lung carcinoma proliferation and invasiveness,Knockdown of perlecan,Eliminates EC ability to suppress cancer invasiveness,Inhibit,Tumor microenvironment,Tumor cell,Tumor-associated stromal cells （fibroblast，endothelial cell, Immune cell）,Extracellular Matrix P
26、roteins （structural and non-structural),PH,Cytokines,Neurotransmitters ？,Hypoxia,Growth factors,MMPs, ADAMs, other secreted proteins and their receptors,Extracelluar Matrix,The extracellular matrix (ECM) the extracellular part of animal tissue that usually provides structural support to the animal c
27、ells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.,Extracellular matrix includes the interstitial matrix and the basement membrane.,Interstitial matrix: present between various animal cells,Basement memb
28、rane: sheet-like depositions of ECM on which various epithelial cells rest,Composition of ECM,Proteins,Collagens,Laminins,-G-X-Y-,a, b, g subunit,Fibronectin,Elastins,Proteoglycans (蛋白聚糖）,Syndecan (硫酸乙酰肝素蛋白聚糖),1. Classical extracellular matrix,2. Matricellular proteins,Osteopontin (OPN), Osteonectin
29、 (SPARC), thrombospondins, tenascin, CCNs,Biology of Collagens,Structure (Triple helix),Basic Composition,-Glycine-Proline-Hydroxyproline (hydroxylysine)-,Types of Collagen,29 types of collagens have been found,Collagens is the most abundant protein in mammals, making up about 25% to 35% of the whol
30、e-body protein content,Usage,Cosmetic, Medical,Laminins: ubiquitous proteins of basement membranes,Epithelia,Vasculature,Laminins: a family of proteins,Specific spatio-temporal expression 111 embryonic 211, 221 mainly muscles 411, 421 mainly endothelium 332 mainly epithelium 511, 512 more ubiquitous
31、,Aumailley et al., A simplified laminin nomenclature Matrix Biol., 2005, 24, 326-332,5 a, 3 b, 3 g subunits, 16 laminins,Subunits of laminins,LAMA1: 3075 amino acids, 337084 Da; 17 EGF-like domain, 5 LamG domain; 1 LamNT domain, 2 LamB domain.,a subunit,LAMB1: 1786 amino acids, 198066 Da ; 13 EGF-li
32、ke domain, 1 LamNT domain, 1 PDB domain (Protein Data Bank, chemotaxis).,b subunit,LAMC1: 1609 amino acids, 177603 Da ; 10 EGF-like domain, 1 LamNT domain, 1 LamB domain, 1 Scop domain (Structural Classification of Proteins, Apolipophorin-III).,g subunit,Roles of ECM in Biology,Providing support and
33、 anchorage for cells,Segregating tissues from one another,Regulating intercellular communication,Reservoir of growth factors,ECM and ECM fragments can function as growth factor,ECM in pathological processes,Wound healing,Fibrosis,Cancer Biology,Invasion,Metastasis,Tumor Progression,Inflammation,Extr
34、acelluar Matrix, A Matter of Life and Death ,Anoikis is a form of programmed cell death which is induced by anchorage-dependent cells detaching from the surrounding extracellular matrix (ECM).,Anoikis and cancer,Metastatic tumor cells,Escape from anoikis and invade other organs,Cancer stem cell,Extr
35、acelluar Matrix, A Matter of Life and Death ,Pro SURVIVAL ECM,Fibronectin prosurival,2386 amino acids; 262625 Da,FNI domain, FNII domain, FNIII domain,15 FNIII domain, RGD motif for integrins and other protein interaction,Confer resistance to apoptosis; activates ERK1/2, ROCK and PI3K/AKT pathway,Pr
36、o SURVIVAL ECM,Fibronectin prosurival,Fibronectin,a5b1 integrin,FAK,ERK,RhoA,Cell survival,Pro SURVIVAL ECM,Rescues cells from apoptosis by protein kinase B/AKT activation,Laminin 10/11,a5b1g1, a5b2g1,Laminin 10/11,a3b1 integrin,p130cas,PI3K/AKT,Rac1,Cell survival,Extracelluar Matrix, A Matter of Li
37、fe and Death ,ECM stiffness (Physical properties),Leads to integrin clusterization and triggers mitogenic signals,Physico-mechanical aspects of extracellular matrix influences on tumorigenic behaviors. Cukierman E, Bassi DE. Semin Cancer Biol. 2010 Jun;20(3):139-45.,ECM stiffness influence tumor ini
38、tiation, progression and metastasis,From fibrosis to cancer,Roles of ECM in cancer,Matrix crosslinking forces tumor progression by enhancing integrin signaling,Levental et al., 2009, Cell,This article offer a new paradigm for understanding why tumor incidence so dramatically with aging.,ECM stiffnes
39、s on celluar behaviors,Extracelluar Matrix, A Matter of Life and Death ,Pro APOPTOTIC ECM,CCN1,Induces apoptosis through a6b1 integrin and syndecan-4 binding,CCN family (6 members): cysteine-rich protein 61 (Cyr61 or CCN1) connective tissue growth factor (CTGF or CCN2) nephroblastoma (肾母细胞瘤 ) overex
40、pressed protein (Nov or CCN3) Wnt-inducible secreted protein-1 (WISP-1 or CCN4) WISP-2 (CCN5) WISP-3 (CCN6),SPARC,Induces apoptosis through a yet unknown mechanism,Decorin,Induces apoptosis through activation of caspase-3 by an unknown mechanism,EMILIN2,Induces apoptosis through death receptors DR4
41、and DR5 direct binding,Pro APOPTOTIC ECM,Endostatin,Induces apoptosis through downregulation of apoptosis inhibitors,EMILIN2 (Elastin Microfibril Interface Located Protein 2),Matricellular Proteins,At the crossroad of infalmmation and cancer,Matricellular proteins are a class of non-structural ECM p
42、rotein exerting regulative functions likely through a direct binding to specific surface receptors, to growth factors and cytokines, to other matrix proteins.,Matricellular Proteins,At the crossroad of infalmmation and cancer,OPN (Osteopontin),Wound healing,Affected phases during healing,Healing rat
43、e,Matrix deposition and contraction,Accelerated,Inflammation,Role in inflammation,Leukocyte function,Pro-inflammatory Th1 committing,Pro-survival of lymphocytes, monocytes and neutrophils,Tumorigenesis,Role in tumor-host interaction,Effect on tumor growth,Pro-angiogenic,Involved in tumor progression
44、 and angiogenesis. Level of expression correlated with stages of disease (breast and prostate),Matricellular Proteins,At the crossroad of infalmmation and cancer,TSP-1,Wound healing,Affected phases during healing,Healing rate,TGFb activation inflammation,In transgenic mice overexpression TSP-1,Infla
45、mmation,Role in inflammation,Leukocyte function,Resolving inflammation,Recruits monocyte and neutrophils Negative regulator of DC and Th1 effectors activation neutrophils chearance,Tumorigenesis,Role in tumor-host interaction,Effect on tumor growth,Stromal TSP-1 is anti-angiogenic,Tumor growth, Angi
46、ogenesis and activates TGFb,Healing in also in TSP-1 KO mice,Matricellular Proteins,At the crossroad of infalmmation and cancer,TSP-2,Wound healing,Affected phases during healing,Healing rate,Collagen deposition,Accelerated,Inflammation,Role in inflammation,Leukocyte function,Inflammation and angiog
47、enesis in TSP-2 KO mice,Tumorigenesis,Role in tumor-host interaction,Effect on tumor growth,Stromal TSP-2 is anti-angiogenic,TSP-2 deficiency susceptibility to skin carcinogenesis and tumor formation,Roles of ECM in cancer,Desmoplasia,Appears at relatively early-stage lesions and disappears in highl
48、y invasive, advanced tumor,It could be a host defense reaction designed to confine the developing tumor by tumor associated with stromal cells,Fragments of ECM in Angiogenesis,Roles of ECM in Angiogenesis,Collagen XVIII,inhibits angiogenesis,C-terminal fragment, Endostatin,Trimeric NC1 domain,promot
49、es angiogenesis,1 NC domain, 1 FRI (Frizzled ) domain, 1 LamG, 6 Collagen doamains, 1 Endostatin,Roles of Endostatin in Cancer,Perlecan,Promote tumor growth angiogenesis,endorepellin,C-terminal fragment from domain V of Perlecan,inhibits angiogenesis,Roles of ECM in Angiogenesis,Roles of ECM in cancer invasion and metastasis,Roles of ECM in cancer invasion and metastasis,Laminin 332,Laminin 332 g2 chain has been found at leading edge of invading carcinomas,Bladder, Breast