Invasion & Metastasis - steps in metastasis:

1) 2) 3) 4) 5) 6) 7) 8) 9) Tumor (primary) Breakthrough (of basement membrane) Invasion Angiogenesis Intravasation (into blood vessels) Transport Lodgement Extravasation Metastasis!

Invasion: - 3 events: altered cell attachment (to ECM and basement membrane) local proteolysis migration - at many of these stages, membrane changes occur - e.g. changes to Cell Adhesion Molecules (CAMs) is critical for many steps

- Cell Adhesion Molecules: - two main types: i. cell-cell interactions: cadherins: part of junctions and desmosomes e.g. E-cadherin on one cell binds to E-cadherin on neighboring cell maintains tissue architecture/differentiation ~20 types immunoglobulin CAMs: homotypic: mediate interactions b/w similar cells heterotypic: interactions b/w different types of cells large families

 selectins: only in blood vessel cells prefix: L=lymphocytes, P=platelets, E=endothelium bind to glycoproteins of tumor cell membrane arrest tumor cell movement (stop where selectins are located) ii. cell-matrix interactions: laminin receptors: receptors on cell surface bind to laminin in basement membrane and ECM cancer can increase # of receptors or alter distribution of receptors (releases tumor cell?) integrin receptors: cancer introduces new types and distribution of the receptor alters binding to basement membrane and connective tissue also associated with cell shape changes, mobilitiy

- Local Proteolysis: - cancer cells have alteration in balance of protease enzyme activators and inhibitors - protease activation: plasminogen activator is produced by most cancer cells plasminogen is converted to the active plasmin form plasmin also converts inactive precursors of MMP into active forms both plasmin and MMP are enzymes that degrade the basal lamina and extracellular matrix

- Migration - motility factors are produced which stimulate movement of the tumor cells - e.g. autocrine motility factors, migration stimulatory factor (stimulate protusion of pseudopodia)

Angiogenesis: - it is the formation of new blood vessels - crucial for growth of tumor - due to an altered balance of inhibitors and activators - steps: cancer cell secretes VEGF, vascular endothelial growth factor VEGF binds to receptor on endothelial cell and stimulates signal transduction leads to endothelial cell proliferation and migration and secretion of MMPs to degrade the ECM (similarities with invasion!) there is release of angiogenic factors endothelial cells migrate into stroma towards source of angiogenic factors there is proteolysis of stroma to form a lumen proliferation of endothelial cells

Note: these abnormal structures are very leaky; tumor cells can get in very easily!

Intravasation & Transport - intravasation = penetration of a cell into a blood or lymphatic vessel - steps: tumor cell attaches to stromal face of vessel basement membrane degraded tumor cell passes between the endothelial cells enters the bloodstream

- transport: travels as embolus P-selectin and L-selectin bind to glycoproteins on tumor cells, holding them together T-lymphocytes involved with the clot release cytokines which stimulate endothelial cells to synthesize V-CAM and E-selectin V-CAM and E-selectin acts as brakes, landing pads for embolus V-CAM, on the endothelium, binds with integrin, on the cancer cell E-selectin, on the endothelium, binds to glycoproteins, on the cancer cell

Extravasation - extravasation = escape from blood vessel - attaches via integrins and glycoproteins - proteolysis of the epithelium basement membrane leads to invasion

Metastasis: - establishment of new growth - it is inefficient: 10-100 million cells released in blood per day => few secondary cancers - there are many protective mechanisms! - metastasis is specific - the distribution of metastases of different cancers is not random nor is it the same for every type of cancer - concept: pre-metastatic niche: there is an alteration of a site of future metastasis in preparation for arrival of tumor cells - two models of metastasis: i. hemodynamic model: tumor embolus lodges and invades into first capillary bed it encounters explains ~2/3 of all cancer metastases e.g. stomach and colon => metastasize to liver organ preference model: seed and soil seed: there are receptors on tumor cells soil: growth factors produced by target organ e.g. bone cells produce GFs that can stimulate proliferation of prostate cancer cells (seed and soil match)

ii.