Fig. 6.27 Themetastaticcascade:Thesequentialstepsinvolvedinthehematogenousspreadofatumor.
Clonal expansion, growth, diversification, angiogenesis
Adhesion to and invasion of basement membrane
Interaction with host lymphoid cells
Adhesion to basement membrane epithelial cancers, either by mutational inactivation of E-cadherin genes, activation of β-catenin genes, or inappropriate expression of the SNAIL and TWIST transcription factors, which suppress E-cadherin expression.
• Local degradation of the basement membrane and interstitial connective tissue. Tumor cells may either secrete proteolytic enzymes themselves or induce stromal cells (e.g., fibroblasts and inflammatory cells) to elaborate proteases. Multiple different proteases, such as matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen activator, have been implicated in tumor cell invasion. MMPs regulate tumor invasion not only by remodeling insoluble components of the basement membrane and interstitial matrix but also by releasing ECM-sequestered growth factors, which have chemotactic, angiogenic, and growth-promoting effects. For example, MMP-9 is a gelatinase that cleaves type IV collagen of the epithelial and vascular basement membrane and also stimulates release of VEGF from ECM-sequestered pools. Benign tumors of the breast, colon, and stomach show little type IV collagenase activity, whereas their malignant counterparts overexpress this enzyme. Concurrently, the levels of metalloproteinase inhibitors are reduced so that the balance is tilted greatly toward tissue degradation. Indeed, overexpression of MMPs and other proteases has been reported for many malignant tumors.
Fig. 6.28 Sequenceofeventsintheinvasionofepithelialbasementmem-branesbytumorcells.Tumorcellsdetachfromeachotherbecauseofreducedadhesivenessandattractinflammatorycells.Proteasessecretedfromtumorcellsandinflammatorycellsdegradethebasementmembrane.Bindingoftumorcellstoproteolyticallygeneratedbindingsitesandtumorcellmigrationfollow.LamininType IV collagen Basement membrane Cadherins A LOOSENING OF INTERCELLULAR JUNCTIONS Type IV collagen cleavage Plasminogen activator Type IV collagenase Matrix metalloproteaseB DEGRADATION OF ECM C MIGRATION AND INVASION Laminin receptor Fibronectin receptor Autocrine motility factor Fibronectin http://ebooksmedicine.net
Changes in attachment of tumor cells to ECM proteins. Normal epithelial cells have receptors, such as integrins, for basement membrane laminin and collagens that are polarized at their basal surface; these receptors help to maintain the cells in a resting, differentiated state. Loss of adhesion in normal cells leads to induction of apoptosis, while, not surprisingly, tumor cells are resistant to this form of cell death. Additionally, the matrix itself is modified in ways that promote invasion and metastasis. For example, cleavage of the basement membrane proteins, collagen IV, and laminin by MMP-2 or MMP-9 generates novel sites that bind to receptors on tumor cells and stimulate migration.