Cancer Cell Dissemination: Chapter 3

Special Topics Cancer cell dissemination PREPARED BY: Dr Samer ABDALLAH Dr Samer ABDALLAH  Definition: a process during which cancer cells start to detach and migrate from the primary tumor in order to metastasize....

Special Topics Cancer cell dissemination PREPARED BY: Dr Samer ABDALLAH Dr Samer ABDALLAH  Definition: a process during which cancer cells start to detach and migrate from the primary tumor in order to metastasize. Dr Samer ABDALLAH I-I : Composition of the ECM:  ExtraCellular Matrix (ECM) is present within all tissues and organs of the body  provides strength and elasticity to organs and protects them by a buffering action that maintains water retention and extracellular homeostasis. Dr Samer ABDALLAH Dr Samer ABDALLAH I-I : Characteristics of the ECM:  The physical, topological and biochemical composition of the ECM is tissue-specific.  The ECM provides architectural structure support, functions as a barrier and an anchorage site  provides tracks for the movement of cells  Dr Samer ABDALLAH Dr Samer ABDALLAH I-I : Characteristics of the ECM:  supports signalling by binding and presenting GFs to their respective receptors  possesses biomechanical properties that regulates cell behaviour ( viscosity of liquids, stiffness, topography). Dr Samer ABDALLAH I-I : Composition of the ECM:  A specialized ECM, basement membranes separate endothelia and epithelia layer from the underlying connective tissue.  Most basement membranes are composed of type IV collagen, laminin and other glycoproteins. Dr Samer ABDALLAH I-I : Composition of the ECM:  basement membranes Dr Samer ABDALLAH I-I : Composition of the ECM:  The composition and the structure of basement membranes can likely be modified in many ways to create specialized or context-specific assemblies  Its an active regulator of cell polarization and shape tissue morphology. Dr Samer ABDALLAH I-I : Composition of the ECM:  Changes to basement membranes deposition, structure and composition might organize tissue architecture Dr Samer ABDALLAH I-I : Composition of the ECM:  Matricellular proteins: Another group of ECM molecules  Examples: thrombospondin 1 and 2, a secreted protein acidic and rich in cysteine (SPARC) also known as osteonectin, tenascin-C Dr Samer ABDALLAH I-I : Composition of the ECM:  Matricellular proteins:  Plasminogen Activator Inhibitor Type-1 (PAI-1) and osteopontin do not function as structural elements but modulate cell-matrix interactions and cell functions  The original members of the matricellular family, thrombospondin 1, tenascin-C and SPARC were primarily de-adhesive and pro-migratory molecules Dr Samer ABDALLAH I-I : Composition of the ECM:  The ECM is constantly being remodelled to suit the needs of the tissues and matrix remodelling  It is especially important in developmental processes such as branching morphogenesis, angiogenesis. Dr Samer ABDALLAH I-I : Composition of the ECM:  Cells likewise respond to differences in biomechanical properties of the matrix and the interaction between cells and the ECM is therefore highly dynamic.  Defects in the processes regulating ECM dynamics can consequently be destructive for tissue homeostasis and contribute to cancer Dr Samer ABDALLAH I-II : Cell – matrix interactions:  Cell adhesion to the substrate surface elicits integrin mediated Focal Adhesion formation to connect the ECM with intracellular signalling and cytoskeletal complexes. Dr Samer ABDALLAH I-II : Cell – matrix interactions:  Cell-substrate adhesions occur at both the forward and rearward ends of the cell  thus facilitating forward migration through a substrate.  FAs formed at the cell front persist as cell-ECM anchors until the cell body has migrated over the FAs such that the FAs reach the cell rear. Dr Samer ABDALLAH I-II : Cell – matrix interactions: Dr Samer ABDALLAH I-III : Focal adhesions:  FAs : are dynamic structures located in lamellipodia regions with a capacity for rapid turnover.  FA generates traction forces and it organizes transmission of signals from the ECM to the cell to stimulate pathways involved in cell survival proliferation and migration. Dr Samer ABDALLAH I-III : Focal adhesions:  FAs are formed through the recruitment of a multitude of signalling and structural proteins to activated integrin tails at the interface of the plasma membrane and the ECM. Dr Samer ABDALLAH I-III : Focal adhesions:  The protein composition of adhesions fluctuates even within a single adhesion and is dependent on: ◦ adhesion age ◦ ECM composition ◦ substrate tension Dr Samer ABDALLAH I-III : Focal adhesions:  Cell motility requires an optimal balance of cell adhesion ◦ too little, the cell cannot generate enough traction to move ◦ too much, and the cell is unable to translocate Dr Samer ABDALLAH I-III : Focal adhesions:  During polarized cell migration: ◦ FAs act to stabilize cell adhesion to the ECM ◦ This allows the contraction of actomyosin, ◦ Thus enables the cell body to translocate Dr Samer ABDALLAH I-III : Focal adhesions: stress fibers Dr Samer ABDALLAH I-III : Focal adhesions during cell migration and the involved proteins: Dr Samer ABDALLAH I-III : Focal adhesions:  Early stages of FAs assembly is a Rac protein dependent  This process is characterised by the sequential recruitment of specific proteins to the integrins such as, talin, paxillin, vinculin, α-actinin, FAK and vasodilator-stimulated phosphoprotein (VASP) Dr Samer ABDALLAH I-III : Focal adhesions:  At this point, the FA may either disassemble or elongate and grow.  This is characterised by a RhoA activation switch from Rac signalling  local mechanical force generated by actomyosin contractility ( actin filaments contraction) Dr Samer ABDALLAH I-III : Focal adhesions:  Leading edge: front edge of the migrating cell  Trailing edge: back or rear edge of the migrating cell  FA maturation: Focal adhesion complex is fully formed and ready to be disassembled in order for a new FA forms in the leading egde Dr Samer ABDALLAH I-III : Focal adhesions: How the migration occurs  Lamellipodia adhere to the substrate by the formation of FAs and together with actomyosin contraction  the forces of the retrograde actin flow  the traction required for forward propulsion and thus translocation of the cell body is achieved Dr Samer ABDALLAH I-IIII : Integrins:  Integrins are alpha and Beta heterodimers formed by selective pairing between 18 alpha and 8 beta subunits. Dr Samer ABDALLAH I-IIII : Integrins:  Integrins contain a large extracellular domain that binds the ECM and links the actin cytoskeleton through a short cytoplasmic tail  There are 24 distinct integrin receptors  their binding specificity is determined by extracellular domain, that recognizes various matrix ligands Dr Samer ABDALLAH I-IIII : Integrins:  Integrins bind to specific motifs within the matrix proteins  changes in the integrin repertoire can correlate with changes in migration mode and invasive phenotypes. Dr Samer ABDALLAH I-IIII : Integrins:  As integrins lack intrinsic catalytic activity, they are activated upon engagement with the ECM.  Integrins provide a bi-directional conduit for mechanochemical information across the cell membrane, providing a link between the ECM and the interior of the cell. Dr Samer ABDALLAH I-IIII : Integrins:  Cell adhesion to the ECM transmits information via integrin receptors that regulates intracellular signalling via outside-in signalling, which is important, for example, in cell spreading and cell migration. Dr Samer ABDALLAH I-IIII : Integrins:  Conversely, intracellular signals can induce changes in integrin conformation activation that prolong its ligand-binding activity in a process termed inside-out signalling.  Integrin engagement with matrix can also affect integrin activation, providing bi-directional crosstalk between inside-out and outside-in signalling Dr Samer ABDALLAH I-IIII : Integrins:  Integrin-containing adhesion functions as signalling centers orchestrating a network of signalling pathways that mediate cell migration.  The Rho GTPases function to regulate actin polymerization and dynamics as well as adhesion itself Dr Samer ABDALLAH I-IIII : Integrins:  Signalling by adhesions can be highly localised and thereby drive the polarized phenomena that comprise migration.  In addition, the adhesions in protrusions particularly near the leading edge are thought to regulate actin polymerization and thereby localize protrusion Dr Samer ABDALLAH I-IIII : Integrins:  the transient (temporary) localized activation of intracellular signalling regulated by integrins contributes to temporal and spatial activation that mediates polarized cell migration. Dr Samer ABDALLAH