Neoplasia II: Tumor Invasion and Metastasis

Neoplasia II: Invasion, Metastasis, and Effects of Tumors

• Invasion: Ability of cells to penetrate the basement membrane and spread through the stroma (extracellular matrix). Two key mechanisms:
  • Spreading into surrounding tissue (Invasive Carcinoma).
  • Entering lymphatic/vascular channels, characteristic of malignant cells.

Metastasis

• The spread of a malignant tumor to a distant (non-adjacent) site.
• A metastasis is also known as a secondary tumor, originating from the primary tumor.

Mechanisms of Cell Invasion and Spread

• Malignant cells have altered adhesion compared to normal cells, sticking less.
• Changes in enzyme production break down basement membranes and stroma.
• Motility factors help cells move.
• Malignant cells change their interaction with surrounding stroma.

Altered Cell Adhesion

• Cadherins: Calcium-dependent glycoproteins at cell membranes. Interact homotypically to bind cells together. Linked to the actin cytoskeleton via catenins. Reduced expression in cancer cells allows cells to separate. (Examples: esophagus, colon, breast, prostate cancers)
• Integrins: Cell surface glycoproteins with α and β subunits. Many biological functions (e.g., leukocyte and platelet adhesion). Receptors for different components of the basement membrane (e.g., fibronectin, collagen) . Reduced expression alters cell-stroma contact, facilitating cell movement.

Altered Enzyme Synthesis and Interaction

• Different enzymes modify the stroma, allowing cells to breach basement membranes and spread.
• Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that degrade the extracellular matrix (ECM).
  • MMP2 and MMP9 break down collagen IV.
  • MMP1 breaks down collagen I.
• These changes in attachment alter tumor cell interactions with ECM proteins.

Cell Motility

• Disrupted basement membrane and stroma allow cells to move.
• Potentiated and directed by factors:
  • Cell-derived motility factors (autocrine motility factors).
  • Cleavage products of matrix proteins (e.g., laminin).
  • Other ligands, such as Wnt5a (in melanoma).
  • Increased expression of receptors for motility factors (e.g., Met oncogene, HGF receptor).

Metastasis Routes

• Lymphatics: Spread to local and distant lymph nodes; a frequent route for carcinomas; lungs can be involved.
• Blood vessels: Spread via capillaries and veins to other organs. Common sites include lungs, liver, bone, and brain.
• Coelemic spaces: Another pathway.

Importance of ECM

• The extracellular matrix (ECM, or stroma) isn't passive; it can promote or inhibit invasion.
• Malignant cells manipulate the ECM for facilitated passage (e.g., using growth, angiogenic, and chemotactic factors)

Why Don't All Malignant Cells Metastasize?

• Cells may invade and circulate but the environment might not be suitable.
• Incorrect receptor expression or metabolic factors may hinder their growth.
• Failure of angiogenesis can be another reason.

Angiogenesis

• Tumor growth halts beyond 1-2mm³ due to nutrient/oxygen depletion, altering the microenvironment.
• Upregulation of pro-angiogenesis factors (e.g., angiopoietin, VEGF) occurs, leading to new blood vessel growth.
• This growth enables continued tumor growth, providing access to the bloodstream.
• Thalidomide is a therapeutic target in renal cancers.

Definitions: Primary and Secondary Tumors

• Primary: The site where the malignant neoplasm first arises (e.g., breast, stomach).
• Secondary: A metastasis; a cancerous tumor that has spread to another organ (e.g., Breast carcinoma that spread to another organ).

Effects of Tumors

• Tumor effects depend on factors:
  • Tumor site.
  • Extent of local spread.
  • Metastatic site.
  • Extent of metastatic spread.
  • Functional effects (e.g., pituitary).

Local Effects of Benign Neoplasms

• Compression (pressure atrophy).
• Altered function.
• Obstruction (hollow viscus).
• Erosion/ulceration.
• Space-occupying lesion.

Local Effects of Malignant Neoplasms

• Tissue destruction.
• Obstruction or constriction.
• Ulceration.
• Invasion and infiltration around nerves, blood vessels, and lymphatics.
• Space-occupying lesion.

Systemic Effects: Haematological

• Anemia (due to ulceration, bone marrow infiltration, or haemolysis).
• Low white blood cell and platelet counts (bone marrow infiltration).
• Thrombosis (e.g., pancreatic carcinoma).

Systemic Effects: Endocrine

• Excessive hormone secretion (benign and malignant endocrine glands).
• Ectopic hormone secretion (e.g., ACTH by small cell lung cancer).

Systemic Effects: Skin and Others

• Pigmentation changes.
• Herpes zoster.
• Jaundice.
• Dermatomyositis.
• Hodgkin's disease.
• Neuromuscular issues (e.g., balance problems, neuropathies, myopathy).
• Cachexia (weight loss).
• Malaise (general discomfort).
• Fever (pyrexia).

Why Neoplasms Kill People

• Local effects (raised intracranial pressure, perforation, hemorrhage).
• Replacement of essential body organs (bone marrow, lung, liver).