Welcome back. In this section, we will be talking about how the cancer cells invade locally. In order to understand how cancer cells invade a surrounding area, we first need to talk about the extracellular matrix. The extracellular matrix, or ECM, are molecules outside of cells that form a web-like matrix to form structural support for surrounding cells. We talked about the ECM in the previous section. You may remember that epithelial cells and mesenchymal cells bind to the ECM through focal adhesions. To invade the extratumoral space, cancer cells must break through the ECM. So, what is the ECM? You can see an electron scanning photograph of the ECM without any cells present on the far right. The ECM is made up of collagens, fibronecin, laminins, and many other non-collagenous proteins that are secreted by stromal cells. Maybe the easiest ECM to recognize is the calcified ECM of the bone. The ECM is present throughout all the body, however, and it's essential for structural integrity, cell signaling and migration. There are two major components of the ECM, the basement membrane, which is the part that cells bind to and that separates tissues and cell layers. The second is the interstitial matrix, and that is the ECM that is found between cells that provides tensile strength to tissues. The ECM both helps and hinders invasion. It's a case of Dr Jekyll and Mr Hyde. In order to invade, the cancer cell needs to use the ECM to anchor its movement while at the same time destroying the ECM to make room to invade the adjacent space. We'll start with the first part, using the ECM to migrate. During migration the mesenchymal cells attach the ECM via the endocrine rich focal adhesions. You can see these interactions here on the illustration to the right. Mesenchymal migration happens through a four part process. First, the cell protrudes a pseudopodia, and that means false foot. Next, the pseudopodia forms a focal adhesion with the ECM. The cell undergoes a dramatic morphology change, contracting the cell body towards the leading edge. Finally, the back focal adhesion is released, allowing the cell to move towards the right. This process is repeated again and again as the cell migrates. There is evidence of cancer cells moving both as individuals, or in clumps, and this is another active area of research. Individual movement may either be mesenchymal, as we described on the previous slide, or amoeboid gliding movement, which is mostly described as being like an amoeba. Collective cell movement requires cell-cell communication and cell-cell adhesion, in addition to cell matrix adhesion. We've talked about the necessity of the ECM for the cell to migrate. But, what about the destruction of the ECM to make space for the invading cell? ECM integrity is maintained by tightly regulated remodeling, and that's the destruction rebuilding of the ECM. In the tumor, that ECM remodeling is deregulated. There is increased expression and secretion of mini proteases that degrade the ECM, including matrix metalloproteinases and cathepsins. In addition to the whole tumor, the cancer cells deregulate ECM remodelling. The host cells that are recruited to the primary tumor also contribute. This leads to patchy and unstable ECM. And this weakened ECM is more permissible to cancer cell invasion, allowing the cancer cells to secrete proteases and break through the ECM surrounding the tumor. Once cells have disrupted the tumor ECM, they may both invade the local area within their organ of origin. For example, a prostate cancer invading healthy prostate tissue. In addition, the cells may also invade local tissues. A good example of this is that bladder cancer often invades local fat tissue. This phenomenon of local invasion is important in tumor staging, in regard to invasion and to adjacent muscle. This brings us to the end of the invasion section. Next, we'll discuss a specialized form of invasion, intravasation.