BIOCHEMISTRY: A TEXTBOOK FOR UNIVERSITIES - E. S. Severin - 2004

SECTION 16. ONCOGENESIS

VI. Invasion and Metastasis

Benign tumors may sometimes grow rapidly and reach large sizes, but they do not metastasize. The ability to infiltrate other Tissues—both neighboring and distant—where they form secondary tumors is characteristic exclusively of malignant tumors.

Initially, tumor Cells form a clone of genetically identical (monoclonal) cells that divide more frequently than neighboring normal cells. They are not programmed for locomotion. However, the composition and behavior of such cells are not static, and the progeny of a single Cell begin to "diverge" both genetically and phenotypically. Each successive generation of cells exhibits an increasing deviation from the norm.

When The Cell mass of a tumor reaches a diameter of about 2 mm, the cells secrete protein factors that stimulate the growth of Connective Tissue to surround the tumor, as well as vascular factors that induce Blood vessel growth, or angiogenesis. Vascular growth has been established to be a key link in tumor progression. Acidic and basic fibroblast growth factors secreted by tumor cells stimulate endothelial cell proliferation and The formation of new capillaries. Angiogenesis provides tumor cells with additional advantages for growth and invasion.

A. Alteration in Membrane Protein Composition

Metastasizing cells undergo a significant change in the composition of their Membrane Proteins. In epithelial cells, the primary protein responsible for adhesive properties is E-cadherin (see Section 5), whose extracellular domain is responsible for forming intercellular bonds with E-cadherin molecules of neighboring cells. Another Class of proteins, catenins, is responsible for linking E-cadherin to the Cytoskeleton.

In tumor cells, E-cadherin content is reduced, and catenin molecules are either functionally inactive or absent. Mutations in the E-cadherin Gene are rare, but when they do occur, patients exhibit poorly differentiated forms of Cancer. Contact inhibition and intercellular adhesion are disrupted, and the intracellular architecture bears little resemblance to The Structure of normal cells.

It has been proven that β-catenin is also involved in the intracellular signal Transduction system and stimulates cell proliferation. However, when complexed with the APC protein (adenomatous polyposis coli), it inhibits division and participates in the destruction of defective cells via apoptosis. If one of these proteins is altered As a result of mutations, the complex fails to form, and β-catenin, unrestrained by the APC protein, interacts with DNA and stimulates cells to enter the Cell Cycle. The appearance of mutations in APC correlates with the growth of polyps (small benign tumors) in the rectum, and individuals with a hereditary form of mutant APC have an increased risk of polyps degenerating into tumors.

Integrin proteins are involved in binding cells to Collagen, whereas Fibronectin and laminins are involved in binding to Other components of the Extracellular matrix and basement membranes (see Section 15). Upon cell transformation, the quantitative and qualitative composition of these proteins changes. In most tumors, The amount of fibronectin is reduced, and modified Integrins are synthesized that help invasive cells migrate through connective tissue and capillary walls.

B. Enzymes Adapting Tumor Cells for Locomotion

Invasion is an active process that includes stages in which a tumor cell:

✵ passes through the extracellular matrix to reach a blood or lymphatic vessel;

✵ overcomes the vessel wall and enters the bloodstream or Lymph;

✵ circulates in the bloodstream as supramolecular complexes with proteins and Blood Cells;

✵ attaches to the vessel wall and repeats the process in reverse, advancing 2 to 3 cell diameters into the invaded tissue;

✵ anchors itself and begins to form a new tumor.

Performing these Functions requires the Synthesis of specific enzymes, receptors, and energy. Metastasizing cells and fibroblasts surrounding the tumor tissue secrete a whole set of enzymes that ensure the destruction of the extracellular matrix and basement membranes: collagenases, which cleave the collagen of the extracellular matrix; heparanase, which catalyzes the Hydrolysis of heparan sulfate, the predominant proteoglycan of the basement membrane; cathepsin B, a potent protease that is localized in Lysosomes in normal cells, but embedded in The Plasma Membrane in metastasizing cells, helping them leave the parent tissue. This enzyme activates procollagenase, which specifically cleaves type IV collagen (see Section 15); plasmin, which cleaves certain extracellular matrix proteins of non-collagenous origin; and the metalloproteinase family, which is involved in the degradation of various Components of the extracellular matrix. They are secreted as proenzymes and activated either by cathepsin B or urokinase-type plasminogen activator.

C. Circulation of Metastasizing Cells

Following successful passage through the connective tissue of an organ, tumor cells advance toward the nearest blood vessel, squeeze between the endothelial cells lining the vascular wall, and enter the bloodstream (Fig. 16-15).

Fig. 16-15. Migration of tumor cells into a blood or lymphatic vessel. 1 — dividing tumor cell; 2 — non-dividing tumor cell; 3 — endothelial cell; 4 — basement membrane; 5 — stroma; 6 — lumen of a blood vessel.

Blood Vessels serve as channels through which tumor cells are delivered to new localization sites. They are transported via the blood as complexes with platelets, migration factors, and extracellular matrix fragments, which mask them from immune surveillance and ensure attachment to the basement membrane in target Organs.

D. Formation of secondary Tumors

CARBOHYDRATES exposed On the surface of tumor cells bind to selectins, which are carbohydrate components of endothelial cell receptors. The plasma membrane of each tumor cell type features a characteristic carbohydrate moiety capable of interacting only with specific oligo- and Polysaccharides of endothelial cells. However, these carbohydrate-carbohydrate interactions are weak, and the cell ultimately anchors to the vessel wall via integrins (Fig. 16-16).

Fig. 16-16. Initiation of secondary tumor formation. 1 — tumor cell; 2 — endothelial cell; 3 — blood vessel lumen; 4 — basement membrane; 5 — stroma.

These Specific features of tumor cell attachment in another organ underlie the organ tropism of the process: metastases do not develop randomly, but rather in preferred sites characteristic of a given tumor type. For instance, prostate cancer typically metastasizes to bones, breast and lung cancers to the Brain, and Colorectal Cancer to the Liver.