Lecture 19-20 Metastasis 2.pdf

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1、Metastasis Dr. Ping Pui Wong Lecturer in Cancer Cell Biology Centre for Molecular Oncology, Barts Cancer Institute Barts and The London School of Medicine and Dentistry Email: p.p.wongqmul.ac.ukGlossary for today Dormancy: it is a stage of cancer progression where cancer cells cease dividing but sur

2、vive in a quiescent stage. Invasion: Process by which cancer cells or groups of thereof move from a primary tumour into adjacent normal tissue. In the case of carcinomas, a movement involves breaching of the basement membrane. Intravasation: Process of invading a blood or lymphatic vessels Extravasa

3、tion: Process of leaving a blood or lymphatic vessels Cell polarity refers to spatial differences in the shape, structure, and function of cells. Almost all cell types exhibit some sort of polarity, which enables them to carry out specialized functions Lecture objectives 1. Invasion-metastasis casca

4、de 2. Biological programme of EMT 3. Cancer dispersal: lymphatics and blood 4. Organ specic metastasis Metastasis1. Self-sufficiency in growth signals 2. Insensitivity to anti-growth signals 3. Tissue invasion and metastasis 4. Limitless replicative potential 5. Sustained angiogenesis 6. Evading apo

5、ptosis Tumour invasion and metastasis is one of the hallmarks of cancer What is Metastasis? Important concepts: Metastasis is the spread of tumour cells from a primary site to set up secondary tumours via our body highways- blood and lymphatic vessels Main cause of cancer death (7.6 million people/y

6、ear) Metastases actually have additional genetic transformations that make them uniquely aggressive. The most common sites of cancer metastasis are the bone, liver and lung. This is a fusion image of a CT (computed X-ray tomography) Scan of the bodys tissue (gray, blue) And a PET (positron-emission

7、tomography) scan in which the uptake of radioactively labeled urodoxyglucose (FDG) in various tissue (yellow) has been detected. FDG uptake indicates regions of high glucose uptake associated with aerobic glycolysis. Diagnosis of metastasis It is a multistep process: 1. uncontrolled growth at the pr

8、imary site 2. angiogenesis (= new blood vessel formation) 3. detachment from the primary tumour 4. invasion through tissue stroma 5. migration, entry into the vasculature (= intravasation) 6. survival in the circulation 7. escape from immune surveillance 8. arrest in distant capillary bed; exit from

9、 the vasculature (= extravasation) 9.uncontrolled growth at the secondary site; angiogenesis. Host-tumour (tumour-stromal) interactions are critical the tumour microenvironment. Pagets “Seed and Soil” hypothesis (1889) MetastasisSeed and soils hypothesis In 1889, Paget noticed metastasis was more fr

10、equent in certain organs and proposed it was not random Studies suggest metastasis results from singalling between the cancer cell (seed) and the organ microenvironment at metastatic sites (soil). The microenvirnoment regulates angiogenesis, an important component of metastasis Paget, S. The distrib

11、ution of secondary growths in cancer of the breast. Lancet 1, 571 573 (1889) Hart, I. R. but they can only live and grow if they fall on congenial soil.” -Stephen Paget The origin of metastasis Since 80% of human tumours derive from epithelial cells (giving rise to carcinomas when malignant) we will

12、 mainly consider metastasis of these tumours, but essentially similar steps are involved in the spread of connective tissue tumours (sarcomas) Epithelial cells sit on a basement membrane (basal lamina), with stroma = connective tissue underlying. Stroma includes fibroblasts, blood vessels, immune ef

13、fector cells. Tumour-stromal interactions are of critical importance in metastasis 1. What is invasions and metastasis cascade? Invasions and metastasis cascade (1) (2) (3) (4) (5) (6) The possibility of a single tumor cell to complete the whole cascade is very low! Invasions and metastasis cascade

14、1. The initial step of localized invasiveness enables in situ carcinoma to breach the basement membrane 2. They may then intravasate into either lymphatic or blood microvessels. 3. The latter may transport these cancer cell, via the general circulation to distant anatomical sites, where they may be

15、trapped. 4, 5. They the subsequently extravasate, and form dormant micrometastases. 6. Some of the micrometastases may eventually acquire the ability to colonize the tissue in which they have landed, enabling them to macroscopic metastasis -Colonization. In both situations there is dissolution of ba

16、sement membrane, cell migration and invasion into interstitial stroma. Common features: Changes in adhesion, growth factor regulated, Protease production, regulated by immune system Functional Similarity of Tumour Invasion and Angiogenesis The first of the many steps leading to metastasis- the acqui

17、sition of local invasiveness. The organization of the epithelial cells layers in normal tissues is incompatible with the motility and the invasiveness displayed by malignant carcinoma cells. In order to acquire motility and invasiveness, carcinomas cells must shed many of their epithelial phenotypes

18、, detach from epithelial cell layers, and undergo the epithelial- mesenchymal transition. The epithelial-mesenchymal transition (EMT) and associated loss of E-cadherin expression enable carcinoma cells to become invasive 2. Why is epithelial-mesenchymal transition important for metastasis? Organizat

19、ion of normal epithelium is destroyed during epithelial-mesenchymal transition EMT Connective tissue also called “stroma” Comprised of many cell types and matrix molecules in 3D networks Fibroblasts in collagen matrixDifference between epithelial and meschymal cells apical basalCell-Cell and Cell-EC

20、M Interactions Important factors involved in EMT E-Cadherin = epithelial cell-cell adhesion (adherens junction) Integrins = cell interactions with basement membrane and stromal ECM, and cell-cell too. Ig-like CAMs (cell adhesion molecules) (epithelial cell-cell adhesion) Selectins (epithelial cell-c

21、ell adhesion) functions in homotypic epithelial cell-cell adhesion linking to actin cytoskeleton via catenins ( , , ) Loss of E-cadherin expression from the plasma membrane is a hallmark of EMT , which in turn liberates catenins to migrate to nucleus and turn on expression of genes orchestrating the

22、 EMT program. Cell 1 Cell 2 E-cadherin is essential for epithelial cell-cell interaction Antibodies against E-cadherin will block re-aggregation of normal epithelial cells. Hepatocyte growth factor (a.k.a. scatter factor) is important in epithelial cell migration HGF acts through tyrosine kinase rec

23、eptor Met to trigger epithelial cell migration Mutations in Met are found in many cancers Autocrine production of HGF promotes tumour growth Met activation leads to loss of E-cadherin at adherens junctions and upregulation of integrins that recognize components of stromal matrix Met activation incre

24、ases protease production and stromal invasion .leading to EMT Trusolino and Comoglio Nature Reviews Cancer 2002 The epithelial-mesenchymal transition is used widely in developmental processes and is shared with metastasis During gastrulation cells peel away from the outer layer of ectoderm and migra

25、te inwards to form mesoderm which is the precursor of all mesenchymal tissues (broblasts, muscle, haematopoietic cells etc)EMT involves changes in gene expression proles associated with cell migration and changes in cell shapeTranscription factors such as Twist can induce EMT and are highly expresse

26、d in certain types of cancers Yang et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in metastasis. Cell 117: 927-939 1. Overexpression of Twist (TF) in MDCK kidney cells significantly down-regulate epithelial marker expression such as E- cadherin, catenin and ! cateni

27、n. 2. Mesenchymal markers such as fibronectin and vimentin are up- regulated. Integrins bind to the Basement Membrane Migration through the BM and invasion are part of EMT See Chapter 19, Alberts MBOC Basal lamina = Basement membraneTumour-stromal interaction, via integrins, is important for activat

28、ing the protease cascade leading to MMP activation and ECM destruction Tumours have elevated levels of many proteases, many of which are expressed by host stromal cells. Tumour-stromal interaction activates the protease cascades Leading to MMP activation and ECM destruction Summary: Cell-Cell Intera

29、ctions, ECM and Metastasis Tumour-host stromal interactions are important in tumour formation and metastasis. Epithelial-Mesenchymal Transition (EMT) is important in development and cancer. Multiple adhesive interactions involving Selectins, Cadherins, Integrins and immunoglobulin-like cell adhesion

30、 molecules (Ig- CAMs) are involved. Epithelial cell-cell adhesion involves E-cadherin. Cadherins link to cytoskeleton via catenins. Transcription factors such as Twist control genetic programmes associated with EMT. HGF is an important stroma-derived factor that induces EMT. Integrins mediate “insid

31、e-out” signalling to regulate cytoskeletal organization, cell migration, cell proliferation and survival, and “outside-in” signalling controlling ligand binding activities of integrins. Cell migration involves dynamic changes in integrin- mediated adhesion actin cytoskeleton reorganization. Protease

32、s are important too for focal proteolysis of the ECM. The uPAR/uPA/plasmin system and MMPs are the main extracellular proteases and their activation cascades are interlinked, focussing proteolysis on the cell surface. Summary: Cell-Cell Interactions, ECM and Metastasis 3. How does tumour cells sprea

33、d via the lymphatic or blood vessels? Metastasis can involve spread of tumour cells via the lymphatic or blood vessels Lymphatic dissemination Haematogenous dissemination Lymph node metastasis Secondary distant metastasis Primary distant metastasis Primary tumourWhy do particular cancers metastasize

34、 to particular organs? Primary tumour Common metastasis Prostate carcinoma Bone Breast carcinoma Bone, Brain, adrenal, lung, liver Gastrointestinal carcinoma Liver Melanoma (skin) Liver, brain, bowel Melanoma (eye) Liver One possibility is the “Mechanistic” or “Haemodynamic” theory This argues that

35、organ preference for metastasis may be determined by the site of the primary tumour and the blood ow through that organ where the circulation delivers the tumour cells. The metastasising cell may just become trapped in the narrow capillaries of the rst organ they come to.Eg 1. gastro-intestinal (GI)

36、 tumours, the rst pass liver Eg 2. breast cancer- the ow is to the lungs, and then via the heart to the arteries that lead to the bones, brain and other organs GI tumour Breast tumour A technique called “intra-vital video microscopy” IVVM has shown that most injected tumour cells survive in the circ

37、ulation and arrest in the capillary bed of the rst organ they come to, and then extravasate. It appears from IVVM that it is the subsequent steps ie survival and growth at the secondary site that are critical. This may correspond to Pagets “soil”.Recently, the importance of cells derived from the bo

38、ne marrow - “distant accomplices” - has been recognised. These cells are found to precede the movement of tumour cells to the metastatic site, and are thought to prepare the metastatic nice. They behave as “scout cells” Gupta GP and Massague J (2006) Cancer Metastasis: Building a framework. Cell 127

39、: 679-695Effects of macrophages on invasion and metastasis TAM = Tumour associated macrophage CSF-1 = Colony stimulating factor-1 Cancer cells secrete CSF-1 which acts as a chemoattractant and stimulant for macrophages, which in turn release EGF that stimulates breast cancer cells Tumour Chemokines

40、may be important determinants of growth of metastases at particular sites Chemokines “chemoattractant cytokines” stimulate recruitment of leukocytes (neutrophils, macrophages) to sites of injury or infection. Cancer cells can use the same chemokine signals to drive proliferation and cell migration.

41、Chemokines fall into 4 families based on position of rst two cysteines CC, CXC, C, CX3C. They work through specic G protein coupled receptors (GPCRs) Chemokine-receptor ”match” determines the growth of metastases at particular sites. Breast cancer cell expresses high level of CXCR4 Melanoma cell exp

42、resses high level of CCR10 Summary - key molecular factors involved in metastasis: Adhesion Intercellular adhesion molecule (ICAM), integrins, cadherins, extracellular matrix (ECM) Invasion matrix metalloproteinases (MMPs) and their tissue inhibitors TIMPs; serine proteases (urokinase plasminogen ac

43、tivator/plasminogen/uPAR) and inhibitors Immunity TGF-beta Escape from anoikis (apoptosis due the epithelial cell detachment) Angiogenesis bFGF, VEGF Motility HGF/SF, chemokines Intracellular regulators RhoC, Twist Metastasis requires the ability to penetrate basement membranes. Has led to the conce

44、pt that invasion equates with metastatic ability, but this is too simplistic. Metastasis involves the loss of social organization of cells in tissues.5. How do metastatic cells arise? Is there a small sub-population of cells within tumours that have the ability to metastasize, or acquire this abilit

45、y through genetic changes? Are all cells in a tumour able to metastasize equally well, but with very low efciency? Or both? Metastasis is a complex multistep process and metastases are rare, so. Harts experiment with mouse B16 melanoma cells suggested that there was a small metastatic sub- populatio

46、n of cells in a primary tumour that could be selected for. How do metastatic cells arise? B16F0 = poorly metastatic B16F1 = low metastatic ability B16F2, 3, 4, 5, 6, . B16F10 = highly metastatic Fidler IJ 1973 Nature New Biology 242:148-149. Selection of successive tumour lines for metastasisThere a

47、ppears to be a metastasis signature of genes expressed in the primary tumour in those tumours that will metastasize Ramaswamy S et al. (2003) Nature Genetics 33: 49-54. A molecular signature of metastasis in primary solid tumors Molecular proling has dened metastasis signaturesA molecular signature

48、of metastasis in primary solid tumors Sridhar Ramaswamy, Ken N. Ross, Eric S. Lander A$*#,%.#()*#2*%1)0$A12*%(/2,0#B2C)/#,% 75 89:% ;5 FD% 5 8GH% 5 IGH%!#$%5 8GH% 5 IGH4% 5 IGH7%Recommended General Reading General: Pecorino, Molecular Biology of Cancer Chapter 8; Alberts Chapter 19 Molecular Biology

49、 Of the Cell, Weinberg The Biology of Cancer Chapter 14. Reviews: Gupta GP and Massague J (2006) Cancer Metastasis: Building a framework. Cell 127: 679-695 Chambers AF et al., (2002) Dissemination and growth of cancer cells in metastatic sites. Nature Rev Cancer 2: 563-572. Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57-70. Fidler IJ (2003) Timeline: The


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