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Special approaches of tumor biology and chemotaxis Orsolya Láng 2014.
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TUMOR CELLS AND MIGRATION METASTASISPRIMARY TUMOR Angiogenesis Adhesion
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CELL and CELL CYCLE
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Growth factors Adhesion molecules Chemokines Cell cyle regulatory proteins Apoptotic molecules Oncogenes
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TUMOR CELL
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GENERAL FEATURE OF A TUMOR CELL The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors (Hanahan és Weinberg 2000)
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CELL KINETICS
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Doubling time of the tumor volume (Td) Time of the Cell cycle (Tc): Tc= Ts / Li Ts: S phase Li: labeling index (proportoin of cells in S phase) Growth fraction(GF): GF=P / (P+Q’) P: number of the mitotic cells Q: number of the cells in interphase Rate of the cell loss ( ): = 1-Tpd / Td Tpd= *Ts/Li Tpd: Potential tumor volume doubling time Td: tumor volume doubling time Lymphoma 48 h Lung cancer 108 h Usually 15-125 h Lymphoma 4 weeks Colon adenoma 90 weeks Usually 18-200 days
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Volume of the tumor tissue ~10 divisions =*1000 cell number increase (2 10 =1024) ~20 divisions= 10 6 cells = 1 mg= 1 mm 3 ~30 divisions= 10 9 cells = 1 g= 1 cm 3 ~40 divisions= 10 12 cells = 1 kg 1 tumor cell ~30-33,25 division =1-10 cm 3 Time of the clinical symptomes / diagnosis ~27 division = 0.1cm 3 Earliest time of diagnosis (Visualisation) ~40 division = 10 12 cell Fatal Human total cell number: 3.72 × 10 13 http://www.ncbi.nlm.nih.gov/pubmed/23829164
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BIOLOGY OF THE TUMORPROGRESSION
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Exogen and endogen factors Genom instability Activation of the oncogenes Inactivation of tumorsuppressors Local and systemic factors inhibitionacceleration Growth rate Ectopic survival capacity Invasivity De- d ifferentation Tumorigenesis Epithelial cell Hiperplastic adenoma Displatic Carcinoma in situ Invasive carcinoma Metastasis
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Important steps of tumor progression Transformation of the microenvironment: stromal cells, ECM components, proteolytic degradation Induction of the angiogenesis (w/o max tumor size is 2mm) Escaping from immune-mediated rejection Formation of metastasis
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MICROENVIRONMENT – STROMAL CELLS Cell types: fibroblasts, myofibroblasts, endothelial cells, lymphocytes, macrophages Function: host defence ! MALT - B cell helps to maintain lymphomas ! Growth factors are released by the stromal cells (VEGF - angiogenesis) http://www.nature.com/nrc/journal/v9/n4/fig_tab/nrc2618_F1.html
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Macrophage Cancer cell migration is controlled by paracrine loop THE INVASIVE MICROENVIRONMENT http://www.nature.com/nrc/journal/v9/n4/full/nrc2618.html Macrophage Blood vessel
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ANGIOGENESIS Hypoxia formation of new vessels, proliferation of the endothelial cells Types: vessels arteriovenous shunts „dead end” /lack of smooth muscle, weak vessel wall, irregular shape(insuficient endothelial cell and basement membrane layers)/ sinuses /wall is formed by tumor cells/ Venous circulation VEGF induces angiogenesis increases permeability Lack of lymphatic vessels OEDEMA, decresed blood flow Inhibition of the VEGF pathway is a potential therapeutical tool
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Strategies that tumors use to escape from immune-mediated rejection are: To decrease the antigen expression To inhibit the immune-reactive cells: degrade the chemoattractans decrease their cell adhesion inhibite their phagocytotic activity
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Angiogenesis Local invasion ECM Adhesion Proteolysis Migration Intravasation Extravasationcirculation Metastasis Tumor cell Primary tumor Adhesion Proteolysis Migration Angiogenesis VEGF Angiogenin FGF spreading METASTATIC CASCADE
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INVASION In situ carcinoma DECREASED CELL ADHESION, INCREASED MOTILITY ECM proteolysis
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Angiogenesis Local invasion ECM Adhesion Proteolysis Migration Intravasation Extravasationcirculation Metastasis Tumor cell Primary tumor Adhesion Proteolysis Migration Angiogenesis VEGF Angiogenin FGF spreading METASTATIC CASCADE
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CELL ADHESION Significant change in cell-cell and cell-ECM interactions Molecules: selectins integrins immunoglobulin superfamily cadherins catenins
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SELECTINS Cell-cel junctions Types: E- endothelial cells P- trombocytes L- leukocytes Extracellular C-lectin domain Ca 2+ dependent anchorage It binds Sialyl-Le x carbohydrates „ROLLING” ! Tumor cells express increased amount of sialil-Le x or -Le a
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INTEGRINS Transmembrane receptors Form cell-ECM interaction 8 , 14 subunites ~20 heterodimer Ca 2+, Mg 2+ dependent anchorage „RGD” sequence is the specific substrate Signalling: outside-in – signalling inside-out – adhesion Increased expression of integrins promotes angiogenesis and helps to bind MMPs at the cell surface EXTRAVASATION, ATTACHMENT D G R
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Integrin or celladhesion regulated signalling pathways cellproliferation PTEN RAC PI(3)K CDC42 integrin ECM ILK -catenin Ciklin D1 BAD PKB/AKT FAK RAS RAF MEK MAPK GSK3 motilitygene expressioncellcycleapoptosis SHC GRB2/SOS
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Integrin or celladhesion regulated signalling pathways integrin ECM ILK -katenin Ciklin D1 BAD PKB/AKT FAK cellproliferation RAS RAF MEK MAPK GSK3 motilitygene expressioncellcycleapoptsis SHC GRB2/SOS PTEN RAC PI(3)K CDC42
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Molecular partners of the integrins Cytoskeletal components: actinin, talin,F- actin, filamin Adaptors: rack 1, ICAP-1 Calcium binding proteins: CIB, calreticulin Protein kinases: pp125FAK, p59 ILK Membrane proteins: CD9, CD16,CD47… caveolin, urokinase-plazminogen-activator receptor Ligands in ECM: collagen, laminin, fibronectin, fibrinogen, von Willebrand factor, osteopontin, elastin
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IMMUNGLOBULIN SUPERFAMILY has 5 Ig-like domains at the extracellular region forms cell-cell junction interacts with integrins VCAM - 4 1, PECAM - v 3 takes essential part in extravasation ! ! Over expression of ICAM-1, MUC18 increased inavsion ! ! Down-regulation of VCAM-1 increased metastatic potential (faster detachment)
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CADHERIN Is a transmembrane glycoprotein Forms homophyl cell-cell junctions Ca 2+ dependent anchorage Classical types: E- epithelial P- placenta N- neural, Intracellular part interacts with catenins to connect aktin filaments ! E-cadherin tumorsuppressor ! Increased expression of N-cadherin invasion ! N-cadherin cooperates with the FGF receptor lead to the up- modulation of MMP-9 „Cadherin Switch”
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CATENIN Is an intracellular molecule Fixes cadherins to F-actin ! -catenin binds to the APC gene product ! colon and liver cancer increased cytoplasmic and nuclear localised beta-catenin correlates with invasion and poor prognosis. in melanoma increased cytoplasmic and nuclear beta- catenin is currently emerging as a marker for good prognosis
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Angiogenesis Local invasion ECM Adhesion Proteolysis Migration Intravasation ExtravasationCirculation Metastasis Tumor cell Primary tumor Adhesion Proteolysis Migration Angiogenesis VEGF Angiogenin FGF spreading METASTATIC CASCADE Integrins cadherins Selectins CAM
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PROTEOLYSIS Components of the basement membrane(BM) and ECM: IV collagen, laminin, proteoglycanes Tumorcells (stromal cells) secrete proteases Cathepsin Matrix metalloproteinase (MMP) Plazmin, tPA,Urokinase (plasminogen activator inhibitor 1&2) Tissue inhibitor of metalloproteinases INVASION
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MATRIX METTALLOPROTEINASES (MMP) Zn 2+ dependent endopeptidase (MMP28) ECM degradation – tissue remodelling Interstitial collagenase (MMP2) Stromalysin Gelatinase (MMP9) Membrane type MMP Produces biologically active molecules
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MOLECULAR STRUCTURE OF THE MATRIX METTALLOPROTEINASES SUBSTRATE OF TIMP Nature Reviews Cancer 2, 161-174 (March 2002) http://www.nature.com/nrc/journal/v2/n3/full/nrc745.html
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MMP/TIMP EXPRESSION IN BREAST CANCER Nature Reviews Cancer 2, 161-174 (March 2002)
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MMP – TUMORPROGRESSION ?!? Nature Reviews Cancer 2, 161-174 (March 2002)
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Angiogenesis Local invasion ECM Adhesion Proteolysis Migration Intravasation ExtravasationCirculation Metastasis Tumor cell Primary tumor Adhesion Proteolysis Migration Angiogenesis VEGF Angiogenin FGF spreading METASTATIC CASCADE Integrins cadherins Selectins CAM MMP/TIMP Cathepsin Plasminogen
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MIGRATORY MECHANISMS IN TUMOR Small-cell lung cancer
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FORMS OF MIGRATORY ADAPTATION http://www.nature.com/nrc/journal/v3/n5/full/nrc1075.html
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2D –3D MIGRATIONS http://www.nature.com/nrc/journal/v3/n5/full/nrc1075.html
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STEPS OF 3D MIGRATION 1. Pseudopod protrusion 2. Formation of focal contact 3. Focal ECM proteolysis 4. Actomyosin contraction 5. Detachment
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Cell-cell interactions visualized in tumorigenesis
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Angiogenesis Local invasion ECM Adhesion Proteolysis Migration Intravasation ExtravasationCirculation Metastasis Tumor cell Primary tumor Adhesion Proteolysis Migration Angiogenesis VEGF Angiogenin FGF spreading METASTATIC CASCADE Integrins cadherins Selectins CAM MMP/TIMP Cathepsin Plasminogen AMF/gp78 Autotaxin HGF/c-MET
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!! Tumor markers e.g. cytokeratin, mucin HEMATOGENIC DISSEMINATION http://www.nature.com/nrc/journal/v4/n6/fig_tab/nrc1370_F3.html
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Blood flow patterns can predict the specific regions of metastases in approximately two-thirds of cancers TYPICAL SITE OF METASTASIS
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LOCALISATION OF THE METASTASIS
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CHEMOKINES – TISSUE SPECIFIC LOCALISATION http://www.readcube.com/articles/10.1038/nrc865
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adhesion motility ?
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EXTRAVASATION ? Attachment Migration
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http://www.nature.com/nrc/journal/v12/n1/fig_tab/nrc3180_F2.html#figure-title
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