Lecture 9.1 - Neoplasia 2

Cancer Development and Metastasis

• Cancer is a population of cells that have lost normal controls of growth and differentiation, proliferating without check.
• Metastasis is the process by which a tumor cell leaves the primary tumor, travels to a distant site via the circulatory system, and establishes a secondary tumor.

Steps of Metastasis

• Invasion and infiltration of surrounding normal host tissue with penetration of small lymphatic or vascular channels.
• Release of neoplastic cells into the circulation.
• Survival in the circulation.
• Arrest in the capillary beds of distant organs.
• Penetration of the lymphatic or blood vessel walls followed by growth of the disseminated tumor cells.

Stages of Metastasis

• Invasion: primary tumor cells enter circulation.
• Circulation: to the secondary site of tumor growth.
• Colonization: formation of secondary tumor.

Tumor Invasion

• Translocation of cells across extracellular matrix barriers.
• Lysis of matrix protein by specific proteinases.
• Cell migration.

Components of Invasion

• Matrix degrading enzymes.
• Cell adhesion.
• Cell motility.

Matrix Degrading Enzymes

• Required for controlled degradation of extracellular matrix components.
• Proteases involved in this process are classified into serine-, cysteine-, aspartyl-, and metalloproteinases.
• Examples: matrix metalloproteinases (MMPs), collagenase, gelatinase, and stromelysins.

Matrix Metalloproteinases (MMPs)

• 16 members, subdivided into 4 groups, based on structural characteristics and substrate specificities.
• Soluble and secreted groups; collagenase, gelatinase, and stromelysins.
• Membrane type (MT-MMP) group is anchored in the plasma membrane.
• Zinc ion in the active center of the protease is required for catalytic activities.

Regulation of MMP

• Controlled by increased expression on a transcriptional level.
• MMPs are calcium-dependent proteases, synthesized as inactive proenzymes and activated by cleavage of a propeptide.
• MMP activity is regulated by specific inhibitors, tissue inhibitors of MMP (TIMPs).

Cell Attachment

• Integrin: cell-matrix adhesion.
• E-cadherin/catenin adhesion complex: cell-cell adhesion.

Cell Migration

• Small Rho GTPase family.
• Motility promoting factors: hepatocyte growth factor/scattering factor, insulin-like growth factor II, and autotaxin.

Routes of Metastasis

• Lymphatics.
• Blood vessels.
• Coelomic spaces.

Lymphatics

• Spread to local and distant lymph nodes.
• Frequent route of spread of carcinomas.
• Can involve lymphatics of lung.

Vascular Spread

• Spread through capillaries and veins to various organs.
• Common sites are lung, liver, bone, and brain.

Metastatic Inefficiency

• A sequence of inefficient steps.
• Not all malignant cells metastasize.

Local Effects of Neoplasms

• Benign: compression, altered function, obstruction, ulceration, and space-occupying lesions.
• Malignant: destruction of surrounding tissue, obstruction, constriction, ulceration, and infiltration.

Systemic Effects of Neoplasms

• Haematological: anaemia, low white cell and platelet counts, and thrombosis.
• Endocrine: excessive secretion of hormones, ectopic hormone secretion.
• Neuromuscular: problems with balance, sensory/sensorimotor neuropathies, myopathy, and myasthenia.

Why Do Neoplasms Kill People?

• Local effect: e.g., brain, perforation, haemorrhage.
• Replacement of essential body organs: malignant.

Learn about the gradual changes in cell morphology and properties that lead to cancer development, including the 5 major steps of metastasis.