Cell Adhesion and Migration - Complete Notes

Cell Adhesion and Migration

Cell Migration Importance

Cell migration is a crucial process involved in various biological events, including:

  • Cancer metastasis
  • Angiogenesis
  • Wound repair
  • Pregnancy
  • Embryo development
  • Immune response

Steps in Cell Migration

Cell migration involves a series of coordinated steps:

  1. Protrusion: The front of the cell extends forward.
  2. Adhesion: The cell adheres to the surface.
  3. Traction: The cell is pulled forward.
  4. Retraction: The rear of the cell retracts.

These steps enable cells to crawl over surfaces. Non-adherent cells utilize swimming modes of migration, employing flagella and cilia.

Lecture Outline

The lecture covers the following topics:

  • Protrusion of the leading edge
  • Adhesion to the surface
  • Generation of traction
  • Chemotaxis
  • Cell migration in cancer

Step 1: Protrusion of the Leading Edge

The Cytoskeleton: Actin Filaments

Actin filaments play a vital role in:

  • Determining cell shape
  • Providing mechanical stiffness
  • Enabling cell movement and muscle contraction

Individual actin filaments are 5-9 nm in diameter. They can bundle together to form thicker, stronger filaments.

Actin monomers, when bound to ATP, join a growing filament at the plus end.

Role of Actin in Cell Migration

Actin branching and polymerization at the leading edge cause the protrusion of the plasma membrane, forming a lamellipodium. The lamellipodium consists of the protruding area of the plasma membrane and the actin network behind it.

Detailed Actin Dynamics

The process involves a complex interplay of proteins:

  1. Extracellular stimuli produce active GTPases and PIP2.
  2. Activated GTPases and PIP2 activate WASP/Scar.
  3. WASP/Scar activates the Arp2/3 complex to initiate new filaments.
  4. The Arp2/3 complex initiates actin branching.
  5. Barbed ends of actin filaments elongate.
  6. Growing filaments push the membrane forward.
  7. Capping protein terminates elongation.
  8. Ageing of actin filaments occurs.
  9. ADF/cofilin severs and depolymerizes ADP-actin filaments.
  10. Profilin catalyses exchange of ADP for ATP.
  11. A pool of ATP-actin bound to profilin is maintained.

Step 2: Adhesion to the Surface

The Extracellular Matrix (ECM)

The ECM comprises molecules secreted by cells, including:

  • Long protein fibers like collagen
  • Large sugar-coated proteins called proteoglycans
  • Specialized molecules such as fibronectin, which aid cell attachment
Attaching to the ECM: Integrins

Integrins are cell surface molecules that act as matrix receptors. They:

  • Connect the cell to the ECM
  • Transmit signals into the cell, allowing it to sense and respond to its environment
  • Different integrin molecules bind to different components of the ECM.

Integrins exist in an inactive conformation until activated by binding to the appropriate ECM component. Activation causes a shape change, enabling binding of intracellular adaptor molecules that attach the intracellular domain of integrins to actin filaments.

Attaching to the ECM: Adhesion Complexes

Adaptor proteins connect integrins to actin filaments, providing strength to the attachment to the ECM. This protein complex is known as an adhesion complex or a focal adhesion. These complexes can be large, creating permanent attachment, or small and rapidly assembling/disassembling in moving cells.

Adhesion complexes can consist of over 100 different proteins. Talin can directly link integrins to actin, but stronger connections involve other proteins.

Adhesion Complexes and Cell Migration

Adhesion complexes are involved in various stages of cell migration:

  • Filopodial adhesion
  • Nascent adhesion
  • Focal complex
  • Focal adhesion
  • Disassembling adhesion

Step 3: Generating Traction and Moving

Motor Proteins

Three types of motor proteins transport vesicles around cells: Myosin (along actin microfilaments) and Kinesin and Dynein (along microtubules in opposite directions).

Myosin and Cell Migration

Myosin attaches to actin filaments linked to integrin via adhesion complexes. In the presence of ATP, myosin walks down the actin filament towards the adhesion complex, pulling the rest of the cell with it.

  • Non-muscle myosin II (NM II) is involved in slow retrograde flow.
  • NM II-independent mechanisms contribute to fast retrograde flow.

Step 4: Chemotaxis

Chemotaxis is the movement of cells towards a chemical signal. Single-celled organisms have receptors for nutrient molecules. Multicellular organisms use chemokines secreted during injury, stress, or infection. Cells move up the concentration gradient of these chemokines.

Cell migration can be random or directed, depending on the presence of chemotaxis cues.

Rho GTPases

The Rho GTPase family (Rac, Rho, Cdc42) controls the direction of cell migration. These proteins are activated at the plasma membrane by exchanging GTP for GDP.

  • GEF = guanine nucleotide exchange factor
  • GAP = GTPase-activating protein
  • GDI = GDP dissociation inhibitors

Rho GTPases play different but interacting roles in controlling the cytoskeleton during cell migration. They are activated at slightly different times following detection of a chemokine, allowing Cdc42 to direct the process of turning the cell.

Chemokines and Chemokine Receptors

Chemokines bind to chemokine receptors, initiating signaling cascades that influence cell behavior, including cell migration.

Cell Migration in Cancer

Overview of Metastasis

Metastasis is the spread of cancer from the primary tumor to distant sites. It involves:

  1. Local invasion
  2. Intravasation (entering the blood vessel)
  3. Circulation
  4. Extravasation (escaping into a new tissue)
  5. Colonization

Cancer cells break away from the tumor, move into circulation, escape into a new tissue, and adapt to the new environment. This process can take years and is responsible for most cancer deaths.

Metastasis in Detail
Breaking Away from the Primary Tumor

Most cancers are epithelial in origin. Carcinomas (epithelial tissue) represent 80-90% of cancer cases.

Cell-cell interactions in epithelium involve:

  • Tight junctions
  • Desmosomes
  • Gap junctions

Cell-cell interactions are mediated by:

  • Cadherins (homophilic interactions)
  • Ig-superfamily CAMS (NCAM) (heterophilic interactions)
  • Integrins (heterophilic interactions)
  • Selectins (heterophilic interactions)
Epithelial-Mesenchymal Transition (EMT)

EMT is a key event in cancer progression, enabling cancer cells to spread to distant sites.

The ECM acts as a barrier. Cancer cells break down the ECM using matrix metalloproteinases (MMPs).

Cancer and the ECM - MMPs

MMPs are enzymes involved in ECM breakdown. There are 25 mammalian MMPs. Some are secreted, while others are expressed on the cell surface. They are secreted as proenzymes and require extracellular activation. MMPs play numerous roles in cancer progression and spread.

Tumor cells can move individually or collectively, and may use other tumor-associated cells (such as fibroblasts) to help them navigate the ECM.

Cancer and the ECM - TIMPs

TIMPs (Tissue Inhibitors of Metalloproteinase) inhibit MMPs and are often downregulated in cancer.

Co-option of Tumor-Associated Fibroblasts

Tumor-associated fibroblasts can be co-opted for ECM remodeling, aiding cancer cell migration.

Entering & Leaving the Circulation

Cancer cells cross the endothelium to enter and exit the circulation. This process involves interactions with platelets, natural killer cells, monocytes/macrophages, and cytokines. Endothelial retraction can also facilitate cancer cell extravasation.

Entering the Circulation

Cancer cells can enter the circulation through blood capillaries or lymphatic capillaries. The lymphatic system collects lymph from tissues and brings it to lymph nodes, where it meets a high concentration of immune cells. Cancer cells commonly spread via the lymphatic system to lymph nodes and then on to the circulation.

Cancer Staging - TNM System

The TNM system is used to stage cancer based on:

  • Tumor size (T)
  • Lymph node involvement (N)
  • Metastases (M)

The TNM stage affects patient survival rates.

Summary

  • Cells adhere to surfaces using adhesion complexes linking integrin molecules, the ECM, and actin filaments.
  • Cell movement occurs when cells generate traction using myosin motor proteins attached to branched actin filaments at the leading edge.
  • Cancer cells break away from neighboring cells in the tumor by undergoing EMT.
  • MMPs are upregulated and TIMPs downregulated, thereby increasing degradation of the ECM.
  • Migrating tumor cells cross the endothelium into the bloodstream or enter the lymphatic system, spreading to distant tissues.