Shedding of plasma membrane fragments. Neoplastic and developmental importance

The phenomenon of shedding of cell surface macromolecules and their importance in the cancer process has been reviewed with particular emphasis on tumor membrane fragments. With cell activation (during growth or stimulation of normal cells), there is an increase in synthesis, processing, insertion, and eventual, intact release of certain membrane proteins, some of which are proteases. In cancer, these events occur spontaneously and without the temporal, physiological, or hormonal control apparent in normal cells. In a previous review (Black, 1980), many of the consequences of shedding tumor products were described, but the nature of the shed material was not clear. It now seems likely that some proteolytic, procoagulant, and immunosuppressive activities of shed material are contained within membrane particulate material (vesicles). Under normal conditions, shed membrane material (particularly proteolytic activity) may be necessary for cell movement and tissue remodeling which occur during embryogenesis. In cancer, shedding of plasma membrane fragments may be responsible for the key features of the malignant phenotype by the presence and release of proteolytic activity producing the separation of tumor cells from the primary site, invasion of the surrounding tissues by tumor cells, and formation of distinct metastases. Shed plasma membrane fragments may play a central role in tumor progression by enhancing the steps of the metastatic cascade, in particular by increasing tumor embolus formation (by enhanced fibrin deposition and platelet aggregation) and vascular permeability, as well as increasing basement membrane degradation. Shed membrane fragments (containing tumor antigens) either alone or complexed with antibody, may be responsible for blocking the cell-mediated immune reaction by the formation of "blocking factors" or by suppressing the formation of cytotoxic immune pathways. The suppression of immune response formation may be due to blocking of antigen presentation by macrophages (due to inhibition of Ia) or by the induction of Ts1 cells.