Cancer Biology Quiz: Tumor Invasion and Metastasis

Neoplasia II: Invasion, Metastasis, and Effects of Tumors

• Objectives include defining invasion and metastasis, describing mechanisms facilitating these processes, outlining metastasis routes and common sites, describing local effects of benign and malignant neoplasms, explaining systemic effects of neoplasms, and explaining why neoplasms cause death.

What is Invasion?

• Cells break through the basement membrane and spread through the stroma (extracellular matrix).
• Types of invasion:
  • Invasive carcinoma (into surrounding tissue)
  • Invasion into lymphatic/vascular channels (characteristic of malignant cells).

What is Metastasis?

• Spread of a malignant tumour to a distant (non-adjacent) site.
• A metastasis is often called a secondary tumour, originating from a primary tumour.

How do Cells Invade and Spread?

• Complex mechanisms involving multiple factors:
  • Adhesion: Malignant cells exhibit reduced adhesion compared to normal cells.
  • Enzyme Synthesis: Enzymes are altered to break down basement membrane and stroma.
  • Motility factors: Factors that aid cellular motility are produced.
  • Interaction with stroma: Malignant cells modify their interaction with surrounding stroma.

Altered Cell Adhesion

• Cadherins: Calcium-dependent glycoproteins at cell membranes, mediating homotypic cell-cell interactions.

• Linked to actin cytoskeleton via catenins.

• Reduced expression and altered interactions in cancer cells, allowing cells to separate.

• Integrins: Surface glycoproteins composed of alpha and beta subunits. They bind extracellular matrix components and cytoskeleton.

• Reduced expression of integrins modifies contact between cells and stroma, enabling cell movement.

Altered Enzyme Synthesis and Interaction

• Matrix metalloproteinases (MMPs): Zinc-dependent enzymes degrading basement membrane and interstitial connective tissue.
• Example MMPs: MMP2 and MMP9 (collagen IV), MMP1 (collagen I).
• Impact on ECM proteins: Changes in attachment of tumor cells to extracellular matrix (ECM) proteins.

Motility

• Cells are propelled through degraded basement membrane and lysed stroma.
• Potentiated and directed by factors:
  • Cell-derived motility factors (autocrine motility factors).
  • Cleavage products of matrix proteins (e.g., laminin).
  • Ligands like Wnt5a (e.g., 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 common route for carcinomas, potentially impacting lung lymphatics.
• Blood vessels: Spread through capillaries and veins to various organs (e.g., lung, liver, bone, brain).
  • Specific examples of tumors that metastasize to lung: Sarcomas (e.g., osteosarcoma), carcinomas (e.g., breast, stomach, large intestine).
  • Specific examples of tumors that metastasize to liver: Carcinomas of large intestine (through portal vein), bronchial carcinoma, breast carcinoma.
  • Specific examples of tumors that metastasize to bone: Bronchial carcinoma, breast carcinoma, thyroid carcinoma, renal carcinoma, and prostate.
  • Specific examples of tumors that metastasize to brain: Bronchial carcinoma, breast carcinoma, testicular carcinoma, and malignant melanoma.
• Coelemic spaces

Why Don't All Malignant Cells Metastasize?

• Insufficient cell invasion and circulation.
• Inappropriate environment at distant sites for cell growth.
• Incorrect receptors.
• Metabolic factors.
• Failure of angiogenesis.

Angiogenesis

• Tumour growth halted after reaching 1-2mm³ due to nutrient/oxygen deficiency.
• Hypoxic conditions lead to upregulation of pro-angiogenesis factors (e.g., angiopoietin, VEGF).
• This stimulates the formation of new blood vessels, enabling continued tumour growth and access to the bloodstream.
• Thalidomide is a therapeutic target for angiogenesis in renal cancer

Tumour Effects - Site and Spread

• Primary tumor:
  • Site where malignant neoplasm originates (e.g., breast, stomach).
• Secondary tumor/metastasis:
  • Tumor that has spread to another organ (e.g., breast carcinoma spreading to another organ).
  • Site of extravasation (exit from blood/lymphatic vessel) and organotropism (preferential organ localisation) are often predicted by primary tumor features (lymph node drainage/vascular supply)

Effects of Tumors

• Local effects depend on tumour site, extent of local spread, site of metastasis, and extent of metastatic spread, as well as functional effects.
• Small tumours can cause severe consequences in specific locations.
• Effects of benign neoplasms include compression, pressure atrophy, altered function (e.g., pituitary), obstruction (hollow viscus), ulceration, and bleeding

Local Effects of Benign Neoplasms

• Compression and pressure atrophy.
• Altered function (e.g., pituitary).
• Obstruction in hollow organs.
• Ulceration and bleeding of surface mucosa.
• Space-occupying lesion (e.g., in the brain).

Local Effects of Malignant Neoplasms

• Tissue destruction.
• Obstruction and constriction in hollow organs.
• Ulceration.
• Infiltration of nerves, blood vessels, and lymphatics.
• Space-occupying lesion (e.g., in the brain).

Systemic Effects of Neoplasms

• Haematological (e.g., anaemia, low white blood cells, low platelets, thrombosis).
• Endocrine (e.g., excessive hormone secretion, ectopic hormone secretion).
• Skin pigmentation, herpes zoster, pruritus, jaundic, dermatomyositis
• Neuromuscular (e.g., balance problems, neuropathies, myopathy).
• Cachexia (weight loss, muscle atrophy, loss of appetite).
• Malaise (general discomfort).
• Pyrexia (fever).

Why Do Neoplasms Kill People?

• Local effects (e.g., raised intracranial pressure, perforation, hemorrhage).
• Replacement of key organs (e.g., bone marrow, lung tissue, liver parenchyma).