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Molecular mechanism of tumor invasiveness
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Molecular mechanism of tumor invasiveness

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  • 1. 1
  • 2. 2SUMMARIZED INTERACTIONS WITHIN A CELL
  • 3. 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
  • 4.  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
  • 5.  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
  • 6.  SIGNALLING ADAPTORS:SRC, CDC42, NCK1, P190RhoGAP, PKC, AMAP1 ADHESION:Integrins, Vinculin, Paxillin, Tensin, Immunoglobulin, Selectin, Ephrins, Chemokines PROTEASES:MMPs, Cathepsins, Kallikerins, Plasmin, Elastase6
  • 7. 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. 8
  • 9.  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
  • 10.  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. 11
  • 12. 12PROPERTIES OF PODOSOMES AND INVAPODIA
  • 13. 13
  • 14. Macrophages in Invasion and Intravasation14PODOSOMES AND INVAPODIA COOPERATING IN INVASION OF TUMOR CELLS.
  • 15. 15
  • 16. 16
  • 17. 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
  • 18. 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
  • 19.  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
  • 20.  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
  • 21. C – Src (Schimidt Ruppin A – 2 ) NWASP (Wiskott – Aldrich syndromeprotein)21
  • 22. 22
  • 23. PROTEASES INVOLVED IN INVASIVENESS23
  • 24. 24
  • 25.  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
  • 26. 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
  • 27.  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
  • 28. Invasion28
  • 29.  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
  • 30.  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
  • 31.  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
  • 32. 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
  • 33. 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
  • 34. PROTEASE AND THEIR PRECURSSORS INVOLVED IN INVASION34
  • 35. ENZYME TARGET STRUCTURALCLASSTUMORCATHEPSINSCathepsin D Glioblastoma,hepatoma,melanoma andthyroid cancerCathepsin B Amyloid β pro -UrokinaseGlioblastoma, lungcancerCathepsin K Breast cancer,prostate cancerCathepsin S Elastin Astrocytoma35
  • 36. ENZYME TARGET STRUCTURALCLASSTUMOROTHER PROTEASESElastase Elastin Colorectalcarcinoma, breastcancerPROTEASEINHIBITORSTIMP – 1 92 kD CollagenaseType 4 intestinalcollagenasestromelysinTIMP – 2 72 kD CollagenaseType 4PAI – 1 Plaminogenactivator36
  • 37. 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
  • 38.  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
  • 39. 39Hanahan & Weinberg 2000
  • 40. 40MOLECULAR BIOLOGY & INFORMATICSBiyoinformatik~30.000 genes~300.000 protein~3.000.000 interaction1 human cell~3.000.000.000 bpDNA
  • 41. 41