Invasiveness vs. Metastasis in Cancer

Invasiveness vs. Metastasis

• Invasiveness is cancer cells invading surrounding tissues, while metastasis is the spread of cancer cells to distant organs, creating secondary tumors.
• For invasion and metastasis, cells need the ability to move through physical barriers (extracellular matrix - ECM).
• Proteins like integrins and cadherins, which are involved in cell-cell and cell-matrix adhesion, are often abnormally altered in cancers.
• Cancer cells produce more extracellular proteases (like matrix metalloproteinases - MMPs and plasminogen activator) than normal cells. These break down ECM, creating pathways.
• Intravasation is the process of cancer cells entering the blood or lymphatic vessels, a step in metastasis.

Cellular Systems in Normal and Tumor Cell Movement

• Adhesion Molecules:
  • Integrins: Dimers that mediate cell-matrix interactions, anchoring to the ECM; altered profiles enhance cancer cell motility and survival.
  • Cadherins: Maintain cell-cell adhesions; loss of E-cadherin promotes epithelial-mesenchymal transition (EMT) and invasion.
• Extracellular Matrix (ECM): The substrate for cell movement; degraded by MMPs in cancer to create invasive paths.
• Actin Cytoskeleton: Drives cell protrusion and contractility; dysregulated dynamics increase invasive behavior.
  • Lamellipodia: Probe the environment, push the cell forward (Rac activation).
  • Filopodia: Sense directional cues, guides migration (Cdc42 activation).
  • Stress Fibers: Generate contractile force, support cell rear retraction(Rho activation).
  • Focal Contacts/Focal Adhesions: Connect integrins to ECM and actin cytoskeleton.
• Rho Family GTPases: Molecular switches regulating actin cytoskeleton dynamics; aberrant activity promotes uncontrolled migration.
  • Rac1: Promotes lamellipodia formation, actin polymerization at leading edge.
  • RhoA: Regulates stress fiber formation and focal adhesion maturation, essential to rear contraction and cell polarity.
  • Cdc42: Promotes filopodia formation, coordinates cell polarity.

Tumor Cell Types

• Parenchyma: The actual tumor cells.
• Stroma: The surrounding connective tissue support cells (fibroblasts), immune cells, and vasculature.

Integrin Signaling

• Integrin binding to ECM activates Focal Adhesion Kinase (FAK); FAK autophosphorylates, which activates signaling proteins.
• Src is used in integrin-mediated motility, activating several pathways.
• Grb2 leads to activation of the Ras/Raf/MEK/ERK (MAPK) pathway, affecting transcription.
• Ras can activate PI3K which promotes cell survival.
• Other small GTPases (Rac, Rho, Cdc42) are linked to cytoskeletal function, cell movement, and Raf activation.

MMPs and TIMPs

• Matrix Metalloproteinases (MMPs): A class of proteases that break down ECM proteins (require Zn++).
• MMP activity promotes invasion/metastasis; TIMPs (tissue inhibitors of MMPs) inhibit these processes.
• MMPs can free growth factors (e.g., VEGF) bound to ECM proteins, creating localized growth factor signaling.

"Seed & Soil" Theory

• Metastasis is a productive interaction between a cancer cell ("seed") and the tissues it spreads to ("soil").
• Successful metastasis depends on cells finding a new site with appropriate growth factors and ECM
• Those sites favor survival, proliferation, etc.

Epithelial-Mesenchymal Transition (EMT)

• EMT is the change from epithelial to mesenchymal cells.
• Features of EMT include: loss of epithelial markers (e.g., E-cadherin), gain of mesenchymal markers (e.g., N-cadherin, motility, invasiveness).
• Loss of E-cadherin and changes in B-catenin (a transcription factor) correlate with altered gene transcription for proliferation and differentiation.
• EMT promotes invasive and metastatic behavior.

Features Influencing Cancer Spread

• Cancer more often spreads along venous and drainage channels.
• Tumors near body cavities shed cancer cells into those cavities.

Studying Metastasis

• Difficulty in studying metastasis includes the need for appropriate experimental systems (e.g., successful in vivo metastasis is rare).
• Human tumor models in mice are limited because metastatic potential of human tumors in mice is often reduced and tumor growth and spread may differ from in humans.