Matricellular Proteins: A Sticky Affair with Cancers

Figure 2

Schematic illustration of cancer progression from primary tumor to metastasizing cancer and the involvement of various matricellular proteins in each process. Aberrant expression of matricellular proteins in tumors or in the surrounding stromal cells induces or inhibits the following tumorigenic and cancer progression events. (a) Epithelial-to-mesenchymal transition allows a normal epithelial cell, which normally adheres to basement membrane, to undergo a series of cellular and biochemical changes (i.e., a switch from E-cadherin to N-cadherin and increased vimentin expression) to adopt a mesenchymal phenotype. (b) Promotion of cell proliferation and survival in tumor cells lead to uncontrolled tumor growth. (c) Secretion of matrix metalloproteinases by tumor cells and acquisition of tumor cell motility result in basement membrane degradation and the increased invasiveness of the tumor cells. (d) Intravasation of invasive cancer cells through the basal membrane and endothelial monolayer allows the cancer cells to invade into the circulation. (e) Diminished immune surveillance and leukocyte recruitment against the circulating cancer cells permit the cells to survive in the circulation. (f) Matricellular proteins also promote resistance against anoikis and chemotherapy in order for the cancer cells to survive in the circulation. (g) Interactions of the matricellular proteins secreted by cancer cells with the surface receptors on endothelial cells result in an intermediate cell adhesion that allows the cancer cells to dock on the endothelial monolayer. (h) Adhered cancer cells subsequently undergo trans-endothelial migration through a process called extravasation to invade a distant site. (i) Establishment of new tumors at the metastatic site is dependent on the proliferation of invaded cancer cells; (j) Neovascularization within the tumor mass via angiogenesis is crucial for tumors to grow beyond a certain size. (+) and (−) denote positive and negative effects, respectively, imposed by the indicated matricellular proteins on the selected events. The disparate functions of any given matricellular proteins are dependent on the cell-type context and the specific structural domains that are expressed.