Cell Migration and Invasion by Dr. Anke Brüning-Richardson

Cell Migration and Invasion

Introduction

Study by Dr. Anke Brüning-Richardson

Overview of cell migration in health and cancer, mechanisms, and modes of migration in 2D and 3D environments.

Cell Migration

Importance and Evolution

• Fundamental process: Cell migration has evolved as a vital function for the survival of various organisms, facilitating essential biological processes.

• Prokaryotes: Some prokaryotes swim using flagellae or glide along surfaces to escape colonies or find nutrients. This movement is crucial for their adaptation to environmental changes.

• Eukaryotes: Unicellular eukaryotes, like amoebae, migrate via chemotaxis, allowing them to respond to chemical gradients for food sources or to avoid harmful substances.

• Higher organisms: In multicellular organisms such as mammals, various cell types exhibit distinct migration patterns that respond to diverse extracellular stimuli, which are critical for processes like tissue morphogenesis, regeneration, immune responses in infections, and inflammatory responses.

Role in Disease

• Alterations in migration patterns: Changes in the migration capabilities of specific cell types, such as leukocytes, contribute to various conditions, including autoimmune diseases, where improper cell movement can lead to tissue damage.

• Cancer: Migration plays a crucial role in cancer metastasis and invasion; the ability of cancer cells to move from their original site to distant organs is a key factor in cancer lethality. Insufficient migration can also hinder successful regenerative therapies, as it may prevent necessary cellular interactions and tissue integration during healing processes.

Cell Migration in Health

Development and Repair

• Migrations in Development:

  • Mesoderm Formation: Individual and collective cell migrations are essential for forming different germ layers during embryonic development. The coordination of these movements ensures proper layer organization and differentiation.

  • Neurulation: The formation of the neural tube involves pivotal migration of neural crest cells, with disruptions in this process leading to neural tube defects.

• Wound Healing:

  • Process: The wound healing process involves multiple coordinated phases, including hemostasis (blood clotting), inflammation, proliferation (cell growth), angiogenesis (formation of new blood vessels), and remodeling of tissue. Each phase relies heavily on efficient cell migration.

  • Cell types involved: Key players include platelets for clot formation, neutrophils and lymphocytes for immune response, fibroblasts for structural integrity, and keratinocytes for epithelial regeneration.

Cell Migration in Cancer

• Metastasis: The movement of cancer cells from their original site to establish new tumors elsewhere is a complex process that significantly impacts cancer prognosis.

  • Events: Metastasis relies on interactions and signaling pathways both within tumor cells and the surrounding stroma, including activation of epithelial-mesenchymal transition (EMT), a crucial step that allows epithelial cells to acquire migratory and invasive properties.

  • Complexity: This process is highly coordinated and regulated, allowing stationary tumor cells to become motile, navigate through the extracellular matrix, and ultimately invade distant tissues.

Mechanisms of Cell Migration

Key Players

• Actin Filaments: The most abundant protein in eukaryotic cells, critical for cell motility. Actin filaments facilitate various functions, including contraction and the generation of dynamic protrusions like lamellipodia and filopodia. It exists in two forms:

  • G-actin (monomeric)

  • F-actin (polymeric)

• Microtubules: Composed of dimers of α- and β-tubulin, microtubules dynamically polymerize and depolymerize, playing crucial roles in maintaining cell shape, intracellular transport, and facilitating the positioning of organelles during migration.

Process of Migration

1. Protrusion of the leading edge (through structures such as lamellipodia and filopodia).

2. Adhesion at the leading edge to the substrate via focal adhesions, where integrins interact with the extracellular matrix.

3. Deadhesion at the trailing end, which involves detaching from the substrate and managing the cytoskeletal rear.

4. Contraction of the cell body pulling it forward, resulting in cell movement.

Types of Cell Migration

Classifications

• Amoeboid Migration: Typically involves single-cell movement through physical deformation, which is common in immune cells that need to traverse through narrow spaces between tissues.

• Mesenchymal Migration: This more organized form of migration occurs in tissues where cells move within extracellular matrices, often requiring enhanced signaling and structural support from the surrounding environment.

• Collective Migration: A group movement seen during development or in certain cancers, allowing cells to maintain communication and mechanical connections while migrating, which can be critical for maintaining tissue architecture and function.

Migration in 2D vs 3D

• 2D Migration: Cells migrate along flat surfaces where interactions with the substrate are prolonged, influencing cell behavior and signaling. This model is often used in laboratory studies to simplify migration mechanisms.

• 3D Migration: In contrast, migration occurs in a confined three-dimensional environment that mimics in vivo conditions. This requires specialized adaptations to the extracellular matrix, influencing migration speed, morphology, and directionality, making it more representative of actual biological processes.

Focal Adhesions

• Structure: Focal adhesions are large, dynamic protein complexes that link the actin cytoskeleton to the extracellular matrix (ECM). They are crucial for providing the adhesive forces necessary for cell migration, allowing the cell to sense and respond to its surrounding environment.

• Components: Major components include paxillin, focal adhesion kinase (FAK), vinculin, and talin, which play significant roles in adhesion strength, spatial signaling, and the mechanotransduction processes that govern cell behavior during migration.

Summary of Concepts

• Cell migration is essential in both health and disease contexts, influencing fundamental processes such as development, immune responses, and cancer metastasis.

• Understanding the mechanistic roles of the cytoskeleton and focal adhesions provides critical insights into the cellular changes related to migration and their implications in various physiological and pathological states.

• Different modes of migration reflect distinct functional adaptations in varying microenvironments, which are vital for targeted therapeutic strategies in regenerative medicine