肿瘤的细胞微环境和肿瘤转移ppt课件

1、Basic Clinical Oncology The Cellular Microenviroment and Metastases,Fudan University Cancer Center Prof. Dr. Wentao YANG,Origin and History,The oldest and one of the most prestigious cancer centers in China Founded in 1931 as Sino-Belgium Radium Institute by Kingdom of Belgium Formerly affiliated to

2、 Shanghai Medical University (1954-2000,Sino-Belgium Radium Institute in 1950,Today,1205-bed Cancer Center Outpatients/year: 932,000 Inpatients/year: 40600 Operation/year: 23219 Number of employees: 1300 Affiliated to Fudan University since 2000,Basic Clinic Oncology,Course Objectives: To know the e

3、tiology and biology of cancer and the situation of cancer prevention. To learn the basics of cancer diagnosis, including the clinical, imaging, pathology and the labs To know the principles of cancer therapy, especially the multidisciplinary modalities for a comprehensive cancer patient care To know

4、 the frontiers of basic and clinical researches briefly,Definition of Metastasis,The process whereby malignant tumors spread from their site of origin (the primary tumor) to form tumors at secondary sites (secondary tumor) . Acquisition of the capability for invasion and metastasis is the hallmarks

5、of cancer. Metastasis remains the major driver of mortality in patients with cancer,Bone Metastasis,Lung Metastasis,Brain Metastasis,Soft tissue sarcoma in left leg,alveolar soft part sarcoma in left leg,Lung alveolar soft part sarcoma,Malignant Phyllodes Tumor of the Breast,Malignant Phyllodes Tumo

6、r metastasize to the lung,Metastatic carcinoma of the ovary from the stomach,Classic Type,Tubular Type,Sclerosing Type,Classic Type,Pulmonary blastoma metastasize to right ovary,Metastatic carcinoma of the ovary from the colon,From Blausteins Pathology of the Female Genital Tract,Metastatic carcinom

7、a of the ovary from the appendix,The essential component in providing quality cancer care The staging of cancers is based on the size of the primary lesion, its extent of spread to regional lymph nodes, and metastases. Widely used is a so-called TNM system,T: Primary Tumor T1, T2, T3, or T4, with in

8、creasing size of primary lesion N: regional lymph node involvement No, N1, N2, N3 to indicate progressively advancing nodal disease M: metastases Mo or M, according to whether there are distant metastases,Metastatic cancer is responsible for about 90% of cancer mortality,understanding how cells diss

9、eminate from the primary tumor to invade and successfully colonize distant tissues represents the LEAST understood and the most deadly area of cancer biology,Multistep Process of Metastasis,Metastasis is influenced by the interactions between Tumor cells and host cells Immediate and extended tumor m

10、icroenviroments,Mandi Murph, Research on Melanoma,Multistep processed accomplished by metastasizing cancer,Motility and tissue invasion Intravasation (Alternatively, can enter lymphatic vessels) Survival in the blood stream (trauma, immune cells, oxygen levels, growth factor availability etc.) Arres

11、t at new location Extravasation Attraction/induction of new stromal cells (may occur BEFORE metastasis occurs). Growth and Proliferation. Angiogenesis,Figure 14.4 The Biology of Cancer ( Garland Science 2007) p. 591,Tumor metastasis is a complex, multistep process consisting of a series of discrete

12、biological processes,Invasion and Metastasis,cancer cells proliferate and spread (metastasize) to other parts of the body Invasion - direct migration and penetration into neighboring tissues Metastasis - cancer cells penetrate into lymphatic system and blood vessels,Acquiring Invasiveness,Primary ca

13、rcinoma cell(s) must: Disengage from their neighboring epithelial cells Become motile Degrade the surrounding extracellular matrix,Invasion and Cell Motility,The first step of metastasis. Normal tissue requires proper adhesions with basement membrane and/or neighboring cells. Cells must undergo chan

14、ges in their cell-cell and cell-matrix adhesion interactions to dissociate themselves from the tumor. Tumor cells display diminished cellular adhesion, allowing them to become motile. Tumor cells use their migratory and invasive properties in order to burrow through surrounding extracellular stroma

15、and to gain entry into blood vessels and lymphatics. Cell motility is a critical component of the invasive phenotype,Disruption of the Basement Membrane,A dense meshwork underlying the epithelial cells consisting of collagen, glycoproteins, and proteoglycans. Physical barrier between epithelial cell

16、s and the stroma. Degradation of basement membrane collagen is an early and critical invasion event for epithelial cell invasion,Ductal Carcinoma in situ,Early invasive breast cancer,From Bryson,From Bryson,Intravasation,Intravasation: the entry of tumor cells into the circulation Extravasation: the

17、 exit of tumor cells from the circulation to host tissue,Journal of Carcinogenesis 2012,11:4,Abnormal Vasculature in tumor,Malformed and irregular Possessing breaks in their thin lining that permit the easy access of tumor cells into the circulationdilated, hyperpermeable The vasculature of normal t

18、issue do not have these same features,Survival in the Circulatory System,Out of many thousands of cancer cells that reach the blood circulation, only one survive to form a secondary cancer or metastasis. Immune attack, circulatory forces , apoptosis induced by loss of adhesion Bind to coagulation fa

19、ctors creating emboli, which are more resilient to both circulatory forces and immune attack,Arrest and Extravasation,Extracellular matrix (ECM) components such as fibronectin and laminin enhance tumor cell arrest,Extravasation of tumor cells is more challenging than intravasation since intravasatio

20、n occurs at the primary tumor site where the vasculature is already quite leaky and therefore easy to traverse. Extravasation is facilitated by circulating factors released by the primary tumor itself e.g TGF- and TNF released from primary tumors leads to increased expression of MMPs resulting in hy

21、perpermeability and extravasation,Proliferation,Cell proliferation at the second site Induction of angiogenesis to supply oxygen and nutrients,Angiogenesis- the growth of new capillary blood vessels,Tumors require the continuing formation of new blood vessels,Supply oxygen and nutrients Supply endoc

22、rine and paracrine growth-enabling factors,The process of angiogenesis in tumor,Angiogenic facoractivate endothelial cells Degradation of the wall of the vessel Sprout, proliferation and migration of the endothelial cells Formation of new vessel, and anastomosis,血管检测标记：CD34, CD31, VIII, 微血管密度（MVD,Fi

23、gure 14.42 The Biology of Cancer ( Garland Science 2007,Metastatic seeding patterns of various cancers,Colonization of distant site by metastatic tumor cells,Colonization is an extremely inefficient process that is heavily dependent on the interactions between “seeding” tumor cells and the “soil” mi

24、croenvironment of the secondary site. Many factors including formation of a premetastatic niche and organ specificity determine these patterns of colonization,Organ Tropism A propensity for certain tumors to seed in particular organs,http:/,50,Reason for organ selectivity,Mechanistic theory: determi

25、ned by the pattern of blood flow. “Seed and soil” theory: the provision of a fertile environment in which compatible tumor cells could grow,1889: Stephen Pagets Seed and Soil Hypothesis Tumor Cells = Seed environment = Soil Tumor cells like seeds “are carried in all directions; but they can only liv

26、e and grow if they fall on congenial soil,Figure 20-44 Molecular Biology of the Cell ( Garland Science 2008,Metastasis is a very inefficient process. The majority of tumor cells fail to survive and establish metastatic cascade,Definition of Microenvironment,A network of scaffolding made out of colla

27、gens, glycoproteins, growth factors, and glycans coupled with the cellular component comprising the normal stromal elements: including fribroblasts, endothelial cells, and immune cells into which the tumor cells invade and grow,What is in a Tumor,Cancer cells make up only a portion of a tumor. Other

28、 parts are composed of stromal cells. Large amount of extracellular matrix material (ECM,What other cells are present,Fibroblast make and secrete ECM proteins and growth factors. e.g MMPs. Myofibroblast- derived from fibroblasts but make actin. Endothelial Cells- Growth factors form blood lymphatic

29、function. Pericytes- Near the blood vessels, support blood vessel structure and function by giving them growth factors. Smooth muscle cells- Contractile function. Adiopocytes- storage of fats. Immune Cells,The tumor microenvironment is quite complex,The cells in a tumor talk to each other all the ti

30、me,Normal Stroma,Normal Cells,Basement membrane,ECM,Immune Cells,Fibroblast,Tumor stroma,Cancer Cells,Half of the secrets of the cell are outside the cell. Dr. Mina Bissell. Oct 17, 2007 Erlanger Auditorium,ECM is the matrix laid down by cells upon which they adhere and move. It consists of many com

31、ponents including laminin and fibronectin, which can influence tumor cell behaviour. ECM is also a rich source of growth factors that can be released upon proteolytic degradation and which in many cases increase metastasis,What is extracellular matrix (ECM),Types of ECM Components,Basement membrane

32、(basal lamina) Epithelia, endothelia, muscle, fat, nerves Elastic fibers Skin, lung, large blood vessels Stromal or interstitial matrix Bone, tooth, and cartilage Tendon and ligament,DEFINITION of Epithelial-Mesenchymal Transition (EMT,An orchestrated series of events in which cell-cell and cell-ext

33、racellular matrix (ECM) interactions are altered to release epithelial cells from the surrounding tissue. The cytoskeleton is reorganized to allow movement in 3 dimensions in the ECM and a new transcriptional program is induced to maintain the mesenchymal phenotype,Mesenchyme gives the impression of

34、 much more relaxed organization, and this suggests flexibility, individualism, and motile propensities. Mesenchyme cells form a relatively diffuse tissue network: There is no complete cellular layer, and the cells typically have only points on their surface engaged in adhesion to their neighbors,Dis

35、covery of EMT,First observed and defined by Elizabeth Hay in late 1960s at Harvard First associated with early stages of embryonic development. Process is reversible w/unstable intermediate EMT Metastable MET,Epithelial Mesenchymal Transition (EMT,/dmontell/research,Epitheli

36、al-Mesenchymal Transition (EMT,The number of published reports on EMT and cancer grew 12-fold between 2002 and 2007. EMT “is one of the things that everybodys doing nowadays,” The EMT, which is marked by complex and coordinated set of molecular changes leading to cell behavioral changes, is a portma

37、nteau concept that can be applied to the metastatic behavior of carcinoma cells at a number of junctures,EMT Markers,Proteins that increase in abundance N-cadherin Vimentin Fibronectin Snail1 (Snail) Snail2(Slug) Twist Goosecoid FOXC2 Sox10 MMP-2 MMP-3 MMP9 Integrin v6,Proteins that decrease in abun

38、dance E-cadheren Desmoplakin Cytokeratin Occludin Proteins whose activity increases ILK GSK-3 Rho Proteins that accumulate in the nucleus -catenin Smad-2/3 NF- Snail1 (Snail) Snail2 (Slug) Twist,EMT and Cancer,Occurrence of EMT during tumor progression allows tumors to infiltrate surrounding tissue

39、and ultimately metastasize to distant sites We see EMT stages in pathological staging of tumors,Route of Metastasis,Hematogenous Metastasis Lymphatic Metastasis Implantation metastasis Metastasis through the body wall into pleural, pericardial and peritoneal cavities,Lymphatic Metastasis,This is the

40、 most common pathway for initial dissemination of carcinoma. In solid tumors, the status of the lymph node is the most important prognostic indicator for the clinical outcome of patients,Cancer cells may spread to lymph nodes near the primary tumor, known as the regional lymph nodes. Through the eff

41、erent lymphatic channels tumor may still be carried to distanced lymph rode, and enter the bloodstream by the way of the thoracic duct finally,In lymph nodes, initially tumor cell are confined to the subcapsular sinus; with the time, the architecture of the nodes may be entirely destroyed and replac

42、ed by tumor. Destruction of the capsule or infiltration to neighboring lymph nodes eventually causes these nodes to become firm, enlarged and matted together,Tumor cells form secondary tumors through the circulatory (blood) system which has drained from a tumor. Bone, lung, liver and brain frequentl

43、y multiple, circle, scatter Angiogenesis plays an important role,Hematogenous Metastasis,Tumor cells seed the surface of body cavities, Most often involved is the peritoneal cavity. But also may affect pleural, pericardial, subarachnoid, and joint space,Implantation metastasis,Metastatic carcinoma o

44、f the ovary from the stomach（Krukenberg Tumor,Metastasis through the body wall into pleural, pericardial and peritoneal cavities,Results in a neoplastic effusion (transcoelomic). The fluid contains the neoplastic cells causing the effusion, and cytological examination of the aspirated fluid is very

45、important in diagnosing the cause of effusions into body cavities. The tumor cells often grow as nodules on the mesothelial surface of the cavity,Anti-metastatic therapy,Metastasis Promoting Genes - I,Metastasis Promoting Genes - II,Metastasis Suppressor Genes - I,Metastasis Suppressor Genes - II,正常血管 agiogenesis 抗血管治疗,Anti-angiogenesis Therapy,Normal vessel angiogenesis anti-angiogenesis therapy,Using angiogenesis in