Sandra E. Pike

Calreticulin and Tumor Suppression

Lymphoblastic cell lines derived by Epstein-Barr virus (EBV) immortalization of normal B lymphocytes can reproducibly inhibit tumor growth in nude mice. This anti-tumor activity is due, in part, to a mediator present in the culture supernatant of EBV-immortalized lymphoblastic cells identified as a fragment of calreticulin encompassing the NH2 terminal domain. Recombinant calreticulin NH2 domain (amino acids 1–180), but not calreticulin P domain (amino acids 181–189), can inhibit endothelial cell proliferation in vitro and angiogenesis in vivo. Calreticulin NH2 domain can bind specifically to the extracellular matrix protein laminin and through this binding can interfere with endothelial cell attachment and spread on laminin-coated surfaces. It can also bind directly to endothelial cell membranes. When inoculated subcutanously into nude mice, recombinant calreticulin NH2 domain prevents the development of subcutaneous tumors and reduces the growth of established tumors of various lineages. The capillary vascular network of tumor tissues from mice treated with calreticulin NH2 domain is reduced compared to controls and scattered tumor cell apoptosis is noted, but tumor histology is otherwise similar. Thus, the NH2 domain of calreticulin is detected in the culture supernatant of lymphoblastoid cells and can exert anti-tumor activities acting as an inhibitor of endothelial cell growth and neovascularization.

Growth Stimulation and Immunoglobulin (Ig) Secretion in Epstein-Barr Virus (Ebv)-Infected B Cells by Interleukin 6 (IL-6)

Human resting B lymphocytes infected by EBV proliferate, produce immunoglobulin and become immortalized (1). The mechanisms of B cell activation by EBV are largely unknown. Recently, attention has been focused on the observation that growth of EBV-immortalized B lymphocytes is dependent, at least in part, upon the availability of growth factors produced either by the same EBV-immortalized cells (autocrine growth factors) (2, 3) or by activated monocytes (paracrine growth factors) (4, 5). This has raised the possibility that maintenance of an immortalized state by EBV might require the establishment of an autocrine loop, and/or the expression of appropriate growth factor receptors (6).

Monocytes and a Monocyte Product Regulate Epstein-Barr Virus-Induced B Cell Activation

Epstein-Barr virus (EBV) infects human B cells and induces them to proliferate, to produce immunoglobulin (Ig) and to generate immortal cell lines in the absence of T cells and/or monocytes (1). In exploring cellular interactions involved in B cell activation by EBV we have found that normal human monocytes and a soluble product or products they secrete greatly enhance virus-induced B cell proliferation, Ig production and immortalization.