Week 7 A - Cell Adhesion and Migration

Cell Adhesion and Migration

• Importance of Cell Migration:

  • Critical in various biological processes such as:

    • Cancer metastasis

    • Angiogenesis

    • Wound repair

    • Pregnancy

    • Embryo development

    • Immune response

• Steps in Cell Migration:

  1. Protrusion of the Leading Edge:

     • The front of the cell extends outwards.

  2. Adhesion to Surface:

     • The cell attaches to the substratum (extracellular matrix).

  3. Traction:

     • The cell is pulled forward by its own generated forces.

  4. Retraction of Rear Cell:

     • The back end of the cell contracts, allowing forward movement.

• Movement Mechanisms:

  • Adherent cells crawl over surfaces, while non-adherent cells employ swimming movements using structures like flagella and cilia.

The Cytoskeleton’s Role

• Actin Filaments:

  • Crucial for determining cell shape, providing stiffness, and facilitating movement.

  • Diameter of individual filaments: 5-9 nm.

  • Actin monomers polymerize into filaments at the plus end in the presence of ATP.

• Lamellipodium:

  • The network of actin that protrudes at the leading edge during migration.

Mechanisms of Cell Migration

Step 1: Protrusion and Actin Dynamics

• Role of Actin in Migration:

  • Actin Polymerization: At the leading edge, actin monomers add to the filament, causing the membrane to push forward and create the lamellipodium.

  • Key proteins involved: GTPases, WASP/Scar, and the Arp2/3 complex, which activates new filaments to propel movement.

Step 2: Adhesion to the ECM

• Extracellular Matrix (ECM):

  • Composed of various proteins (collagen, proteoglycans, fibronectin) that support cell adhesion.

• Integrins:

  • Surface receptors connecting cells to ECM; they transmit intracellular signals.

  • Different integrins interact with specific ECM components, promoting adhesion and signaling.

• Adhesion Complexes:

  • Formed by integrins and adaptor proteins linking to actin filaments.

Step 3: Generating Traction

• Myosin and Movement:

  • Myosin motor proteins link actin filaments and generate force, pulling the cell forward.

  • Utilizes ATP for energy to walk along actin filaments.

Step 4: Chemotaxis

• Mechanism of Chemotaxis:

  • Directed movement towards chemical signals (chemokines) in response to injury or infection.

  • Utilizes Rho GTPases (Rac, Rho, Cdc42) to control directional migration and cell shape during movement.

Cancer and the ECM

• Metastasis Mechanism:

  • Cancer cells must break away from the primary tumor, invade ECM, and move into circulation or lymphatics via various enzymes (MMPs) that degrade ECM.

  • Multi-step process including: breaking away, traveling through blood, and colonizing distant tissues.

• Cancer Staging (TNM System):

  • Key for assessing the extent of cancer:

    • T (tumor size), N (lymph node involvement), M (metastasis).

• Prognosis Related to Staging:

  • Survival rates significantly decrease with advanced staging due to complications from metastasis.

Summary

• Key Points in Cell Migration:

  • Adhesion through integrins connected to actin is essential for movement.

  • Myosin-driven traction facilitates forward motion.

  • Cancer metastasis involves ECM remodeling through MMP action and resulting cellular dynamics.

  • Successful migration leads to cancer spreading, influencing treatment and patient outcomes.