Cancer Invasiveness and Metastasis Overview

Invasiveness vs. Metastasis

• Invasiveness is the ability of cancer cells to penetrate surrounding tissues.
• Metastasis is the spread of cancer cells from the primary tumor to distant organs/tissues, forming secondary tumors.

Cellular Mechanisms in Cancer Cell Movement

• Adhesion Molecules:
  • Integrins: Cell-matrix adhesion, crucial for normal migration; altered in cancer for enhanced motility and survival.
  • Cadherins: Maintain cell-cell junctions; loss of E-cadherin promotes epithelial-mesenchymal transition (EMT) and invasion.
• Extracellular Matrix (ECM):
  • Substrate for cell movement; degraded by Matrix Metalloproteinases (MMPs) to enable invasion.
• Actin Cytoskeleton:
  • Drives cell protrusion and contraction; dysregulation promotes invasive behavior.
  • Lamellipodia: Probe the environment, pushing the cell forward.
  • Filopodia: Sense directional cues, guiding migration.
  • Stress fibers: Generate contractile force, for cell rear retraction.
  • Focal Contacts: Connect ECM to actin cytoskeleton.
• Rho Family GTPases:
  • Molecular switches regulating actin. Aberrant activity promotes uncontrolled migration.
    • Rac1: Promotes lamellipodia formation.
    • RhoA: Regulates stress fiber formation and focal adhesion maturation.
    • Cdc42: Promotes filopodia formation.

Tumor Cell Types

• Parenchyma: The tumor cells themselves.
• Stroma: Surrounding connective tissue, immune cells, and vasculature.

Integrin Signaling

• Integrin binding to ECM activates FAK (Focal Adhesion Kinase), which can activate downstream signaling pathways (Src, Grb2, Ras, PI3K), impacting transcription, proliferation, and survival.

MMPs and TIMPs

• Matrix Metalloproteinases (MMPs): Proteases that degrade the ECM, crucial for invasion and metastasis. Require Zn++ for activity.
• Tissue Inhibitors of Metalloproteinases (TIMPs): Inhibit MMP activity.

"Seed and Soil" Theory

• Metastasis depends on an interaction between cancer cells ("seed") and the environment ("soil") in a distant location. The "soil" provides specific growth factors/ECM allowing cells to survive and proliferate,

Epithelial-Mesenchymal Transition (EMT)

• EMT is a process where epithelial cells lose their characteristics and gain mesenchymal features, such as motility and invasiveness.
• Key features include loss of E-cadherin (critical for cell-cell contact), changes in cell shape, and production of invasive enzymes (MMPs).
• EMT is correlated with increased invasiveness and metastasis.

Factors Influencing Metastasis to Specific Sites

• Cancer cells often spread to specific organs based on blood/lymph drainage patterns and interactions with that organ's environment (growth factors, ECM). For example, tumors near body cavities can spread to those cavities.

Challenges in Studying Metastasis

• Difficulty in replicating human metastasis in animal models (such as mice).