ECM

ECM

1. cells must digest through to migrate

2. extracellular peptidases

   • metalloproteases
     • require Zn2+ or Ca2+
     • MMP1: collagenase
       • cleaves many more forms of collagen
     • MMP3: stromelysin
       • cleaves laminin, proteoglycans, fibronectin, and collagens
     • serine proteases: plasmin
       • SERPINS: inhibit
       • plasminogen: inactive, cleaved to form
         • u-PA cleaves plasminogen
           • activated by binding to u-PA receptor
     • Tissue specific inhibitors of metalloproteases (TIMPS)
     • start cascade of protease activation

3. cells depend on interactions from to organize/grow/differentiate

4. cancer cells must change interaction w/ to metastasize

5. bc of this tumors in culture are different than in body

6. heterogeneous

7. cells in contact produce and interact w/

8. includes basal lamina, loose connective tissue, hard connective tissue

9. Functions

   • cell adhesion cues
   • cues for cell structure/function
   • cell morphology cues
   • cues for cell proliferation/differentiation
   • cues for cell migration

10. main components

    • carbohydrate
      • glycosaminoglycans: GAGs
        • repeating disaccharide units
        • negative
        • high hydrostatic pressure
        • form loose hydrated gels like jello
        • ex: heparin
      • GAG + protein = proteoglycan
        • acts as a core protein
    • fibrous proteins
      • collagens
        • provide strength
        • 3 alpha chains forms triple helical fiber
        • 4 major types
          • I, II, III: fibrillar collagens in loose CT
          • IV: forms sheets in basal lamina
        • every 3rd aa is glycine
      • laminins
        • found in basal lamina
        • chains can each bind other components of ECM to form final sheetlike structure of basal lamina
    • adhesive glycoproteins
      • ex: fibronectin: bridge between cell and ECM
        • only one gene but multiple types from alternative pre-mRNA splicing
      • link cells to ECM
      • protein w/ 2 subunits, each monomer binds to matrix molecules
        • each subunit also binds a receptor protein on the cell surface: integrin
          • transmembrane heterodimers
            • 1 alpha subunit
            • 1 beta subunit
            • 24 distinct alpha/beta heterodimers are known
              • different combos have different binding specificity for different attachment factors
          • different cells make different integrins
          • link cytoskeleton to ECM
          • important for adhesion, cell movement, morphology
            • focal contact: site of interaction between microfilaments and ECM
              • FAK: activated by certain integrins, can stimulate downstream transduction events including division/survival
          • cancer cells receive signaling inputs from integrins on their surface which controls their cancer morphology

11. cancer cells

    • altered interactions
    • Cell-ECM recognition
      • cancer cells express different integrins than normal
        • alphavbeta3 has very broad ligand specificity
          • can allow cancer to interact w/ almost any matrix
            • w/ metalloproteases becomes able to digest its way through any matrix while interactin w/ it
      • integrin location is varied
        • alpha3beta1 is normally found on basal side but is all over in cancer cells
          • removes cell polarity
    • cell cell recognition
      • need to not have contact inhibition for metastasis
      • normally E-cadherin and N-CAM have homophilic interactions w/ neighbors and signal this has occured
        • loss of N-CAM associated w/ high metastatic likelihood
        • E-cadherin often lost in breast carcinogenesis
      • cancer cells often lose ability to express cell adhesion molecules, associated w/ metastasis