Figure 4.

A distant home: tumor cell extravasation and engraftment at secondary sites are enhanced by ECM secretion and remodeling. Extravasation requires cancer cell adhesion to the vessel wall and an invasion into the foreign tissue. HA mediates an initial adherence as both endothelial and cancer cells bind to the GAG through CD44. A subsequent secretion of hyaluronidase breaks down HMW-HA. The local increase of LMW-HA disrupts the endothelial cell barrier supporting transendothelial migration of the cancer cells. After arrival at a distant site, cancer cells are exposed to a foreign environment. To allow survival under these different conditions, cancer cells secrete ECM components and ECM-remodeling enzymes to favor the engraftment at the foreign site. An example is tumor-derived LOX altering collagen cross-linking at pre-metastatic sites. Tumor cell-secreted tenascin C also enhances the establishment of micrometastases. However, tumor cells also induce stromal cells to produce cancer-promoting ECM proteins, creating a more permissive environment. Here, stromal periostin improves cancer cells adhesion by binding to αvβ5-integrin. In addition, periostin supports the self-renewal and proliferation of CSCs through the activation of the WNT signaling pathway, which may enhance outgrowth of metastases.