The main steps involved in the<unk>  cascade of a<unk>  cell are: *Cell division and growth within the primary tumor *Invasion of the primary tumor border (basement membrane, or BM) and the tissue surrounding the tumor by the cell *Intravasation of the circulatory system: the cell enters the bloodstream or lymph channels. *The cell must survive the transit into the new environment, until it ultimately arrests in the microvasculature of the secondary site. *Extravasation to a distant site : The cell then invades into the BM of the target tissue. *Proliferation of the<unk>  cell at the<unk>  site *Formation of a micrometastasis inside the secondary site *Progressive colonization, forming a life-threatening metastasis The potential of a tumor cell to metastasize depends on its microenvironment, or “niche” interactions with local factors promoting tumor-cell growth, survival, angiogenesis, invasion and metastasis. This is explained by the seed and soil hypothesis. Extracellular matrix degradation in<unk>  Cell-cell and cell-ECM matrix adhesion, motility, and localised proteolysis are mediated mainly by matrix metalloproteases (MMPs). Degradation of the extracellular matrix begins the process of metastasis. The cell develops structures called invadopodia, which are highly concentrated in several proteases and have a highly dynamic actin cytoskeleton. Mechanisms of metalloprotease action in cell motility involve: * Proteolytic cleavage of growth factors, so they are readily available to cells not in direct physical contact * Degradation of the ECM is facilitated by MMPs, so cells can move across tissues into nearby stroma. * Regulated receptor cleavage to modulate migratory signaling Most of these processes require a delicate balance between the functions of matrix metalloproteases (MMPs) or metalloprotease-disintegrins (ADAMs) and natural tissue inhibitors of metalloproteases (TIMPs). Regulated proteolysis is an important mechanism to maintain homeostasis. There is increased expression of protease systems in<unk>  cells, to equip them with the tools necessary to degrade the extracellular matrix and release growth factors or transmembrane receptors. MMP-2 is upregulated in the bone, and increased levels of MMP-1 and MMP-19 are observed in the brain. This in turn, upregulates the signaling pathways necessary to provide increased cell adhesion, cell motility, cell migration, invasion,<unk> - cell proliferation and survival. Extracellular matrix components ECM-tumor cell interactions play a critical role in each of the events of the<unk>  cascade. Interactions of the breast<unk>  cells with integrins, fibronectin, laminins, collagens, hyaluronan and proteoglycans can contribute to the<unk>  process. Some of these proteins are discussed here in relation to breast-cancer metastasis. Fibrinogen-Integrin Fibronectin is an extracellular glycoprotein that can bind to integrins and other ECM components like collagen, fibrin and heparan sulphate proteoglycans(HSPGs). Several different integrins bind to fibronectin. Fibronectin-integrin interactions are important in tumor cell migration, invasion, metastasis and cell proliferation by signaling through integrins. Integrin-mediated tumor cell adhesion to ECM proteins can trigger signal transduction and cause upregulation of gene expression, increased tyrosine phosphorylytion of the focal adhesion kinase, and activation and nuclear translocation of mitogen-activated protein (MAP) kinases. Heparanase Heparanase cleaves heparin sulfate chains of HSPGs, which have an extensive network with several proteins on the cell surface and ECM. The basic HSPG structure consists of a protein core to which several linear heparin sulfate (HS) chains are covalently O-linked; this acts as an assembly of different ECM proteins, including fibronectin, laminins, interstitial collagens, heparin-binding growth factors, chemokines and lipoproteins. HSPGs are prominent components of blood vessels. to HS stabilizes fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs) and prevents them from inactivation. HS chains function as low-affinity co-receptors which promote dimerization of FGFs, aids in the sequestration of the growth factors (GFs) and causes activation of the signaling tyrosine kinase receptors even under low circulating concentrations of growth factors. Heparanase expressed by<unk>  cells participates in angiogenesis and neovascularization by degrading the polysaccharide scaffold of the endothelial BM, thereby releasing angiogenic growth factors from the ECM. Tenascin The ECM protein tenascin C (TNC) is up-regulated in<unk> . TNC is an adhesion-modulating extracellular matrix glycoprotein. It is highly expressed in tumor stroma and stimulates tumor-cell proliferation. It is hypothesised that TNC stimulates invasion via up-regulation of MMP-1 expression through activation of the MAPK pathway. MMP-1 (interstitial collagenase) cleaves collagen type I, II, III, VII and X. Therefore, tenascin C over-expression can significantly alter collagen in the ECM and influence tumor cell migration in cartilaginous tissues. Endoglin Endoglin is a cell-surface disulfide-linked homodimeric glycoprotein which binds to integrins and other RGD ligands and is a co-receptor for TGF-beta. Brain-metastatic breast-tumor cells express endoglin in large amounts. Endoglin-overexpressing cells develop large numbers of invadopodia; endoglin is localized in these structures. Endoglin expression in tumor cells contributes to metastasis by upregulating MMP-1 and MMP-19. MMP-19 cleaves components of the basal lamina such as collagen type IV, laminin 5, nidogen (entactin) and other ECM proteins such as tenascin, aggrecan and fibronectin. Therefore, endoglin over-expression alters the proteolytic balance of the cells to greater matrix degradation and increased invasive properties of breast<unk> . Mechanisms in bone metastases The primary extracellular matrix components and cell-surface receptors which aid in metastasis are: ;Integrin signalling: Integrin αvβ3 (a cell-surface adhesion molecule) is important for tumor attachment, cell-to-cell communication between the breast tumor cells and the environment in bone, osteoclast bone resorption and angiogenesis. Integrin-mediated adhesion between<unk>  cells and osteoclasts in bone metastases induces phosphorylation of extracellular signal-regulated kinases (ERK1/2) in osteoclasts, which in turn induces osteoclast differentiation and survival.<unk>  cell-blood platelet interaction:<unk>  cells excrete lysophosphatidic acid (LPA) which binds to receptors on tumor cells, inducing cell proliferation and release of cytokines(IL-6 and IL-8, potent bone resorptive agents) and stimulating bone resorption. After the breast-cancer cells have left the primary tumor, they interact with the bone microenvironment and secrete osteolytic factors capable of osteoclast formation and bone resorption. Apart from the breast tumor cells, the resident stromal cells also contribute to tumor survival. Growth factors such as epidermal growth factor (EGF), fibroblast growth factor (FGF) and transforming growth factor beta (TGF-β) are implicated in the development and progression of<unk> . ;Matrix metalloproteinases (MMPs): MMP-2 is the main metalloprotease secreted by breast-cancer cells or induced in the adjacent bone stroma; it plays an important role in the degradation of the extracellular matrix essential for metastasis. Tumor cells use MMP-2 secreted by bone marrow fibroblasts (BMFs). MMP-2 is stored in an inactive conformation in association with the cell surface (or extracellular matrix) of BMFs. Inactive MMP-2 present on the surface of BMFs is displaced by breast-cancer cells.<unk>  cells can then use the proteinase to facilitate tissue invasion, which requires the degradation of connective tissue associated with vascular basement membranes and interstitial connective tissue. MMP-2 is unlike other MMP's as its activity is modulated by metalloproteases called tissue inhibitor of metalloproteases (TIMP) and membrane type 1 MMP (Korhmann et at. 2009) Mechanism in brain metastasis The brain is a unique organ for metastasis, since the breast-tumor cells have to pass the blood–brain barrier (BBB) to form micrometastases. CD44 CD44 (a cell-surface transmembrane glycoprotein) is a receptor for hyaluronic acid, involved in cell adhesion by binding to specific extracellular matrix components. A proposed mechanism for the function of CD44 is to regulate the adhesion of circulating<unk>  cells in the brain to the endothelium at the secondary site with the help of a hyaluronate matrix ligand or by its cytoplasmic attachments to actin-associated proteins of the merlin/ezrin/radixin/moesin family. Sialyl transferase (glycosylation modifications of gangliosides) Cell-surface sialylation has been implicated in cell–to-cell interactions, and over-expression of a brain sialyltransferase in breast-cancer cells is a mechanism highlighting the role of cell-surface glycosylation in organ-specific<unk>  interactions. Breast-cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of BBB-crossing and brain colonization. Seed and soil hypothesis The "seed and soil" hypothesis states that specific organs harbor metastases from one type of<unk>  by stimulating their growth better than other types of<unk> . This interaction is dynamic and reciprocal, since<unk>  cells modify the environment they encounter. Tumor embolus = seed and Target organ = soil.
Metastatic breast cancer
Metastatic carcinoma
Cancer of unknown primary origin
Medullary carcinoma
Acinar cell carcinoma of the pancreas
Adrenocortical carcinoma
Hormone receptor positive breast tumor
Parathyroid carcinoma