Invadopodia

In the early 1980s, researchers noticed protrusions coming from the ventral membrane of cultured chicken embryo fibroblasts that had been transformed by the Rous Sarcoma Virus and that they were at the sites of cell-to-extracellular matrix (ECM) adhesion.) and invadopodia are the structures in invading cancer cells. However, there remains controversy around this nomenclature, with some scientists arguing that the two are different enough to be considered distinct structures while others argue that invadopodia are simply disregulated podosomes and cancer cells don't simply "invent" new mechanisms. Due to this confusion and the high similarity between the two structures, many have begun to group the two under the collective term invadosomes. ==Structure and formation==

Invadopodia have an actin core, which is surrounded by a ring structure enriched in actin-binding proteins, adhesion molecules, integrins, and scaffold proteins. Initiation of invadopodia involves the formation of buds in the plasma membrane and is initiated by growth factors like epidermal growth factor (EGF), transforming growth factor beta (TGFB) or platelet-derived growth factor (PDGF), which act through phosphoinositide 3-kinase (PI3K) to activate Src family kinases. A key step during invadopodia formation is the stabilization of invadopodia, which involves the interaction of PX domain of Tks5 (a scaffold protein) with phospholipid, PI(3,4)P2 to anchor the invadopodia core to the plasma membrane. Maturation of invadopodia requires sustained actin polymerization and there are several regulators of actin polymerization involved in this step, including cofilin, fascin, Arg kinase, and mDia2. Invadopodia are considered mature when matrix metalloproteases (MMPs), specifically MMP2, 9, and 14, are recruited to the invadopodium to be released into the extracellular matrix. ==Role in cancer metastasis==

Metastasis is the leading cause of mortality in cancer patients; it relies on the ability of cancer cells to degrade the surrounding extracellular matrix and invade other tissues. The mechanisms of this process are still not completely understood, and because of the invasive properties of invadopodia, they have been investigated in this context. Indeed, invadopodia have been implicated in many cancers and cancer cells. Increased invasiveness of cancer cells correlates with invadopodia presence, and cancer cells have been observed to project them into the endothelium of blood vessels during extravasation, an important step in metastasis. Invadopodia have also been shown to correlate with a poorer prognosis in breast cancer patients. Tks5, a protein specific for invadopodia, has been implicated in cancer invasiveness. Increased levels of tks5 have been detected in prostate cancer and overexpression of Tks5 was sufficient to induce invadopodia formation and degradation of the extracellular matrix in an Src-dependent manner. Increased Tks5 expression has been shown to correlate with poor patient prognosis in gliomas. In a mouse model of lung adenocarcinoma, invasive tumors were shown to have an increased expression of a long isoform of tks5 while non-metastatic tumors had a short isoform. It was also shown that overexpression of the long isoform of tks5 was sufficient to cause non-metastatic tumors to become invasive. ==Therapeutic relevance==

Due to the invasive nature of invadopodia in cancer cells, research has focused on targeting invadopodia as a potential therapeutic target to inhibit metastasis. Inhibiting invadopodia formation by targeting Src kinase with Saracatinib in a chicken model system showed a decreased incidence of invadopodia and decreased cancer extravasation. In mice, inhibiting invadopodia formation directly, through RNAi against tks4 or tks5, significantly reduced cancer extravasation. These results show potential for invadopodia as a therapeutic target, and research in this field continues. == See also ==