• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Molecular mechanism of tumor invasiveness
 

Molecular mechanism of tumor invasiveness

on

  • 191 views

 

Statistics

Views

Total Views
191
Views on SlideShare
191
Embed Views
0

Actions

Likes
0
Downloads
9
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    Molecular mechanism of tumor invasiveness Molecular mechanism of tumor invasiveness Presentation Transcript

    • 1
    • 2SUMMARIZED INTERACTIONS WITHIN A CELL
    • INTRODUCTIONINVASIVENESS OF CANCER CELLS Tumor invasion is an intrinsic property cancer cellprogression to metastasis after intravasation into the bloodvessels. INVASIVENESS is a phenomenon which involves thedissemination of cancer cells through the destruction of thebasement membrane. Invasion is when the cancer growth goes into a new partwithin an organ, as the tumor gets larger and larger it spreadthrough the organ.3
    •  INVAPODIA or invasive feet are protrusions in the cancer cellmembrane that are rich in actin and extend into theextracellular matrix (ECM). The assembly of actin core structures, followed by theaccumulation of matrix metalloproteinase promote ECMdegradation. These structures are very similar to the PODOSOMES formedby normal cells that need to cross tissue barriers such as MACROPHAGES, MONOCYTES, OSTEOCLASTS that remodel tissue.4
    •  However podosomes are short – lived and do not causemajor degradation of ECM. These assembly of actin core structures in invapodia oftransformed tumor cells are associated with high levels ofproteolysis and cell signalingCOMPONENTS OF INVASIVENESS ACTIN REGULATION: Cofilin, Profilin, Thymosine –β4, Ar2/3, NWASP5
    •  SIGNALLING ADAPTORS:SRC, CDC42, NCK1, P190RhoGAP, PKC, AMAP1 ADHESION:Integrins, Vinculin, Paxillin, Tensin, Immunoglobulin, Selectin, Ephrins, Chemokines PROTEASES:MMPs, Cathepsins, Kallikerins, Plasmin, Elastase6
    • Src (SCHIMIDT RUPPIN A – 2 PROTEIN) c-Src tyrosine kinase also known as proto-oncogene c-Src, isa nonreceptor tyrosine kinase protein that in humans isencoded by the SRC gene. Src is a potent inducer of tumor invasion which wouldeventually progress to metastasis. It includes an SH2 domain, an SH3 domain, and a tyrosinekinase domain.7
    • 8
    •  The binding of Arp2/3 to NWASP recruits CDC42/CIP4 toinduce EGRF which activates the mutated Src through theintegrin homing receptor present on the ECM (ExtracellularMatrix). The assembly of F – Actin is induced by Src. F – Actin recruitsMMPs and proteases leading to tumor cell invasion.9
    •  C – Src is regulated by phosphorylation of tyrosine 527 on itsSH2 domain Mutation of tyrosine 527 by tumor cells converts the proto –oncogen c – Src to Src. Initiate invasion and promotemetastasis. STABILITY OF INVAPODIA: The polymerization of F – Actin byformins and fascin and barbed ends generated by cofilinsstabilizes invapodia and promotes invasion of tumor cells.10
    • 11
    • 12PROPERTIES OF PODOSOMES AND INVAPODIA
    • 13
    • Macrophages in Invasion and Intravasation14PODOSOMES AND INVAPODIA COOPERATING IN INVASION OF TUMOR CELLS.
    • 15
    • 16
    • FAK P190RhoGap PKC AMAP1 PAXILLIN/CORTACTINK – RAS NCK1 EGRF CIP4 CDC42 NWASP Ar2/3RAF INTEGRINVinculin Paxillin Tensin LAMININF – Actin core Dynamin SynatojaninMKP Cortactin ProfillinMTI – MMP EndophilinCofillin ThymosinInvadolysin TPA/UPA MMP – 9, MMP – 2 NWASPPLASMIN CIP417SrcINVASIVENESSMETASTASISALTERED GENE REGULATIONUNCONTROLLED CELL PROLIFERATIONPATHWAY TO INVASIVENESS
    • 18SELCTIN IMMUNOGLOBULINSUPERFAMILY(ICAM, PCAM etc)INTEGRINSEPHRINS CHEMOKINERECEPTORSCD44APNF – KBETSGLIMTAEGRMMPSCATHEPSINSKALLIKERINSPLASMINELASTASEDCC/SEMAPHORINSTIMPSSERPINSCYSTATINSE – CADHERINMAKPAKAPDMBTIKISSBRMSNM23LYMPHOCYTE/MONOCYTEFOS,JUN,MAF,ATFG-PROTEINBIMBCL-2MYOSIN/ACTINSrCF-ACTINENDOPHILININVASIVENESSAPOPTOSISMETASTASISFIBRONECTINTUMOR CELL SURVIVAL PATHWAY LEADING TO METASTASISBCL-2HEDGHOGSMO
    •  mitogen-activated protein kinase(MAPK) A-kinase anchor proteins(AKAP) Kisspeptins(KISS) Breast metastasis suppressor gene 1(BRMS) B-cell lymphoma 2(BCL – 2) Smoothened(SMO) Activating transcription factor(ATF1) Activator protein 1(AP – 1 ) Early growth response protein 1(EGRP) Metastasis-associated(MTA) E-twenty six(ETS) Guanine nucleotide-binding proteins(G – Protein)19ABBREVIATIONS AND THEIR MEANING
    •  Schmidt- Ruppin A-2(c – Src) Epidermal growth factor receptor(EGRF) Cdc42-interacting protein 4(CIP4) Cell division cycle 42(CDC42) Neutral Wiskott-Aldrich syndrome protein(NWASP) Melittin-related peptide (MRP)/(AR2/3) Protein kinase C ALPHA(PKC) Focal adhesion kinase(FAK) Rat sarcoma(RAS) Rapidly accelerated fibrosarcoma(RAF) Mitogen kinase protein(MKP)20ABBREVIATIONS AND THEIR MEANING
    • C – Src (Schimidt Ruppin A – 2 ) NWASP (Wiskott – Aldrich syndromeprotein)21
    • 22
    • PROTEASES INVOLVED IN INVASIVENESS23
    • 24
    •  Malignant tumors secrete proteolytic enzymes to degradebasement membrane thus allowing invasive behavior.CLASSES OF PROTEOLYTIC ENZYMES MATRIX METTALLOPRTEINASES: They are expressed in all forms of cancer and can beclassified according to their structure into eight differentclasses of MMPs.25
    • PROTEINASES OF FIBRINOLYTIC SYSTEM. The components of the fibrinolytic system is zymogeneplasmogen which is secreted in the liver and deposited intumor in response to hyper permeability The conversion of plasminogen to plasmin is regulated by twoplasminogen activators TPA and UPA. Plasmin facilitate tumor cell migration, invasion metastasis bydegrading fibrin and other matrix protein directly byactivating several metalloproteinases that additionallydegrades extracellular matrix .26
    •  Exposure of breast carcinoma cells to estrogens induces upperand uta which is required for the activation of plaminogenwhich is responsible for the degradation of the extracellularmatrix. In ovarian cancer lysophosphatidic acid may induce thesecretion of UPA through EDG (endothelial cell differentiationgene).27
    • Invasion28
    •  Gastric carcinomata also expresses high plasminogen activator The UPA system is also associated with the development ofmelanoma.CATHEPSINS They are all glycoproteins and contain essential cycteineresidue in their active site but they differ in their substratespecifities and PH stability.29
    •  There are 11 cathepsins (B,C,F,H,K,L,O,S,V,W,X) and they aresynthesized as inactive precursors consisting of a signalsequence a pro – peptide and a catalytic active mature region Activation normally occur after cleavage of the aminoterminal region. Cathepsin D is regulated by intracellular growthfactors, hormones and endogenous inhibitors and it isinduced in hepatomata ,thyroid cancer, bladder cancer, gastricand colon carcinomata.30
    •  Cathepsin B (Myeloid precursor protein secretase APPS). It issecreted in an inactive form of 42kD proform. Elevated levelsof cathepsin B is occur ingliomata, lungs, pancreas, prostate, breast, and stomachcarcinomataKALLIKREINS They are a family of several single chain proteases. Theycontain conserved serine proteases. Conserved disulfidebonds The expression of kallikreins is regulated steriod hormones.31
    • ENZYME TARGET STRUCTURALCLASSTUMORMATRIXMETALLOPROTEINASESMMP – 1(INTESTINALCOLLAVGENASES)Collagen type1,2,3,7 and 10Simple hemopexindomainHead and neckcancerMMP – 2 Collagen 4,5,7,9,10 Gelatin binding Skin cancer, coloncancer, stomachcancer, ovariancancerMMP – 7 (Matrilysin,PUMP – 1)Gelatin type1,3,4,5Minimal domain Gastric cancer andcolon cancerMMP – 9 92KDCollagenase type 4.Collagen 4,5,7,9,10 Gelatin binding Skin cancer32
    • ENZYME TARGET STRUCTURALCLASSTUMORMMP – 10SromelysinLaminin,fibronectin,proteoglycan coreproteinSimple hemopexindomainHead and neckcancerFIBRINOLYTICPROTEINASESUrokinase Type Plasminogen Breast cancermelanomaPlasminogenactivator tissuetypePlasminogen Breast cancerPlasminogenactivator plasminLaminin type 4collagenThrombin PAR – 1 Pancreascancer, oral cancer33
    • PROTEASE AND THEIR PRECURSSORS INVOLVED IN INVASION34
    • ENZYME TARGET STRUCTURALCLASSTUMORCATHEPSINSCathepsin D Glioblastoma,hepatoma,melanoma andthyroid cancerCathepsin B Amyloid β pro -UrokinaseGlioblastoma, lungcancerCathepsin K Breast cancer,prostate cancerCathepsin S Elastin Astrocytoma35
    • ENZYME TARGET STRUCTURALCLASSTUMOROTHER PROTEASESElastase Elastin Colorectalcarcinoma, breastcancerPROTEASEINHIBITORSTIMP – 1 92 kD CollagenaseType 4 intestinalcollagenasestromelysinTIMP – 2 72 kD CollagenaseType 4PAI – 1 Plaminogenactivator36
    • SURVIVAL DURING INVASION The binding of integrin (alpha 5,beta 1) to fibronectin inducesthe expression of BCL – 2, which protect cells from apoptosisduring invasion BIM and BMF released from the cytoskeleton of normal cells,through the interaction between myosin and actin on thecontrary inhibits the anti – anoikis properties of BCL – 2 andthis initiates programmed cell death (apoptosis)37
    •  FAK signaling is also implicated in promoting cell survivalthrough its substrate PKB (Phosphtidylinositol 3 – kinase) Cell – cell interaction through cadherin protect from apoptosisthrough a pathway that depends on cytoskeletal integrity.38
    • 39Hanahan & Weinberg 2000
    • 40MOLECULAR BIOLOGY & INFORMATICSBiyoinformatik~30.000 genes~300.000 protein~3.000.000 interaction1 human cell~3.000.000.000 bpDNA
    • 41