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1、,Basic Clinical OncologyThe Cellular Microenviroment and Metastases,Fudan University Cancer CenterProf. Dr. Wentao YANG,Origin and History,The oldest and one of the most prestigious cancer centers in ChinaFounded in 1931 as Sino-Belgium Radium Institute by Kingdom of BelgiumFormerly affiliated to Sh
2、anghai Medical University (1954-2000),Sino-Belgium Radium Institute in 1950,Today,1205-bed Cancer CenterOutpatients/year: 932,000Inpatients/year: 40600Operation/year: 23219Number of employees: 1300Affiliated to Fudan University since 2000,Basic Clinic Oncology,Course Objectives:To know the etiology
3、and biology of cancer and the situation of cancer prevention. To learn the basics of cancer diagnosis, including the clinical, imaging, pathology and the labsTo know the principles of cancer therapy, especially the multidisciplinary modalities for a comprehensive cancer patient careTo know the front
4、iers 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 of cancer.M
5、etastasis 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 Tumor metastasi
6、ze 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 carcinoma of the ov
7、ary from the appendix,The essential component in providing quality cancer careThe 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 TumorT1, T2, T3, or T4, with increasing siz
8、e of primary lesionN: regional lymph node involvementNo, N1, N2, N3 to indicate progressively advancing nodal diseaseM: metastasesMo or M, according to whether there are distant metastases.,Metastatic cancer is responsible for about 90% of cancer mortality.,-understanding how cells disseminate from
9、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 betweenTumor cells and host cellsImmediate and extended tumor microenviroment
10、s,Mandi Murph, Research on Melanoma,Multistep processed accomplished by metastasizing cancer,Motility and tissue invasionIntravasation (Alternatively, can enter lymphatic vessels)Survival in the blood stream (trauma, immune cells, oxygen levels, growth factor availability etc.)Arrest at new location
11、ExtravasationAttraction/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 biological processes
12、.,Invasion and Metastasis,cancer cells proliferate and spread (metastasize) to other parts of the bodyInvasion - direct migration and penetration into neighboring tissues Metastasis - cancer cells penetrate into lymphatic system and blood vessels,Acquiring Invasiveness,Primary carcinoma cell(s) must
13、:Disengage from their neighboring epithelial cellsBecome motileDegrade 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 changes in their cell-cell
14、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 and to gain entry into
15、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 cells and the stroma. Degra
16、dation 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 circulationExtravasation: the exit of tumor cells fr
17、om the circulation to host tissue,Journal of Carcinogenesis 2012,11:4,Abnormal Vasculature in tumor,Malformed and irregularPossessing breaks in their thin lining that permit the easy access of tumor cells into the circulationdilated, hyperpermeable The vasculature of normal tissue do not have these
18、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 adhesionBind to coagulation factors creating emboli, wh
19、ich 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 intravasation occurs at the primary
20、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 hyperpermeability and extr
21、avasation.,Proliferation,Cell proliferation at the second siteInduction 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 nutrientsSupply endocrine and paracrine growth
22、-enabling factors,The process of angiogenesis in tumor,Angiogenic facoractivate endothelial cellsDegradation of the wall of the vessel Sprout, proliferation and migration of the endothelial cellsFormation of new vessel, and anastomosis,血管检测标记：CD34, CD31, VIII, 微血管密度（MVD),Figure 14.42 The Biology of
23、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” microenvironment of the sec
24、ondary 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:/,Reason for organ selectivity,Mechanistic theory: determined by the pattern of bloo
25、d flow.“Seed and soil” theory: the provision of a fertile environment in which compatible tumor cells could grow.,50,1889: Stephen Pagets Seed and Soil Hypothesis Tumor Cells = Seed environment = SoilTumor cells like seeds “are carried in all directions; but they can only live and grow if they fall
26、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 collagens, glycoproteins,
27、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 parts are composed
28、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 function.Pericytes-
29、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 time.,Normal Stroma,Norma
30、l Cells,Basement membrane,ECM,Immune Cells,Fibroblast,Tumorstroma,Cancer Cells,Half of the secrets of the cell are outside the cell. Dr. Mina Bissell. Oct 17, 2007Erlanger Auditorium,ECM is the matrix laid down by cells upon which they adhere and move. It consists of many components including lamini
31、n 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 (basal lamina)Epitheli
32、a, endothelia, muscle, fat, nervesElastic fibersSkin, lung, large blood vesselsStromal or interstitial matrixBone, tooth, and cartilageTendon and ligament,DEFINITION of Epithelial-Mesenchymal Transition (EMT),An orchestrated series of events in which cell-cell and cell-extracellular matrix (ECM) int
33、eractions 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 much more relaxed organizat
34、ion, 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.,Discovery of EMT,First observe
35、d and defined by Elizabeth Hay in late 1960s at HarvardFirst associated with early stages of embryonic development.Process is reversible w/unstable intermediateEMT Metastable MET,Epithelial Mesenchymal Transition (EMT),http:/esgweb1.nts.jhu.edu/dmontell/research/,Epithelial-Mesenchymal Transition (E
36、MT),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 portmanteau concept that can be a
37、pplied to the metastatic behavior of carcinoma cells at a number of junctures.,EMT Markers,Proteins that increase in abundanceN-cadherinVimentinFibronectinSnail1 (Snail)Snail2(Slug)TwistGoosecoidFOXC2Sox10MMP-2MMP-3MMP9Integrin v6,Proteins that decrease in abundanceE-cadherenDesmoplakinCytokeratinOc
38、cludinProteins whose activity increasesILKGSK-3RhoProteins that accumulate in the nucleus-cateninSmad-2/3NF- Snail1 (Snail)Snail2 (Slug)Twist,EMT and Cancer,Occurrence of EMT during tumor progression allows tumors to infiltrate surrounding tissue and ultimately metastasize to distant sitesWe see EMT
39、 stages in pathological staging of tumors,Route of Metastasis,Hematogenous MetastasisLymphatic MetastasisImplantation metastasisMetastasis through the body wall into pleural, pericardial and peritoneal cavities,Lymphatic Metastasis,This is the most common pathway for initial dissemination of carcino
40、ma. 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 efferent lymphatic channels tumor may still be carried to d
41、istanced 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 replaced by tumor.Destruction of the capsule or infiltration
42、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 frequently multiple, circle, scatter Angiogenesis plays an impor
43、tant 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 of the ovary from the stomach（Krukenberg Tumor）,Metasta
44、sis 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 important in diagnosing the cause of effusions into b
45、ody 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,Norma
46、l vessel angiogenesis anti-angiogenesis therapy,Using angiogenesis inhibitors to block the protein carrying the growth signals. By preventing blood vessels from forming, the tumor starves and can not grow.,Angiogenesis Inhibitors Angiogenesis inhibitors have been found in nature-in green tea, soy pr
47、oducts, fungi, mushrooms, Chinese cabbage, tree bark, shark tissues, snake venom, red wine, and many other substances.Other angiogenesis inhibitors have been manufactured synthetically in the laboratory.Some FDA-approved medicines have also been “re-discovered” to have anti-angiogenic properties.,Sp
48、ecific Angiogenic Inhibitors,AngiostatinAvastinCelebrexEndostatinMetaret (Suramin)Thalidomide,The advantage of anti-angiogenesis therapy,Can be used invarious tumors,Do not develop resistance,easier to tolerate, so can be given for long time,managed in combination with chemotherapy and radiation,Adv
49、antage,Summary,Definition of metastasisDefinition of microenvironmentMultistep process of metastasisRoute of metastasis,The “Metastatic Cascade”,Route of Metastasis,Hematogenous MetastasisLymphatic MetastasisImplantation metastasisMetastasis through the body wall into pleural, pericardial and perito
50、neal cavities,Recommended Reading,Basic Clinical Oncology (2012)Abeloffs Clinical Oncology, 4th ed (2008)DeVita, Hellman, and Rosenbergs Cancer: Principle & Practice of Oncology (2008)Clinical Oncology Fourth Edition: Basic Principles and Practice (2009)Manual of Clinical Oncology (2012)If you have
