Contribution of the intracellular domain of murine FC-gamma receptor type IIB1 to its tumor-enhancing potential

Abstract

We have previously shown that Fc gamma receptor type II B I (FcyRIIBI), when expressed on non-lymphoid tumor cells, significantly enhanced their tumorigenic phenotype. This study elucidates the role of the intracellular domain of FcyRllB I in the enhancement of the malignant phenotype of polyoma-transformed 3T3 cells. We investigated the tumorigenic potential conferred by different variants of the receptor: FcyRllBI, a full-length receptor (BI) whose intracellular region is encoded by exons 8, 9 and 10; FcyRIIBZ, a spliced variant (B2) whose cytoplasmic domain comprises exons 9 and I0 and lacks exon 8; and FcyRllBI-Cr53, a deleted mutant whose cytoplasmic domain contains the fragment encoded by exon 8 alone. We have investigated various properties of cells transfected with each of the above variants: tumorigenicity in syngeneic mice, formation of colonies in soft agar, growth rate, production of soluble receptor and capping of the ligand-bound receptor. Results show that while the presence of exon 8 did not enhance growth rate in vitro or production of soluble FcyR, it did enhance the tumorigenic phenotype of transfected cells (both in vivo and in vitro growth in soft agar). BI-expressing cells exhibited a significantly higher tumorigenic phenotype than 82 cells. The presence of exon 8 alone (Cr53 mutant) conferred the transfected cells a higher tumorigenic phenotype than FcyR-negative control cells but lower than intact B I or B2 cells, indicating that the presence of B I -specific exon 8 is not sufficient but that the presence of an intact B I intracellular domain is essential, for conferring the high tumorigenicity phenotype upon cells. We conclude that the capping, following ligand binding contributed by exon 8, and the function contributed by the specific localization of exons 9 and I0 in B I cells may determine their malignant o 19% Wiley-Liss, Inc. phenotype.Fc gamma receptor type I1 B (FcyRIIB) is a murine low-affinity receptor for the Fc portion of IgG. We havc established previously that the FcyRIIBl (Bl) variant of this receptor functions as a progression-enhancing factor when expressed on non-lymphoid tumor cells (BALB/c 3T3 cells transformed in vitro with polyoma virus [PyV]) (Zusman et al., 1996). PyV-transformed BALB/c 3T3 cells do not express B1 but sometimes acquire the ectopic expression of this receptor following an in vivo passage in syngeneic mice (Ran et aL, 1991). This leads in turn to an increased tumorigenicity (Ben Baruch-Langer et al., 1992). Moreover, PyV-transformed 3T3 cells that were transfected with FcyRIIBl cDNA exhibit a significantly higher tumorigenic phenotype than B1-negativc controls. Their ability to act as a tumorigenicity-enhancing factor was also demonstrated as B1-expressing cells dominated the tumor cell population over non-expressors originating from inoculation of a mixture of receptor-positive and -negative cells (Zusman et aL, 1996). The mechanism by which B1 exerts its progression-enhancing effect has, however, remained unanswered.Possible mechanisms by which B1 ...

Fc gamma receptors and cancer

“…Altogether, our results suggested that tumor FcγRIIB1 might be an anti-tumor factor and might render human non-hematopoietic tumor cells more sensitive to the action of therapeutic antibodies and/or it might be one component of the efficacy of such antibodies. Thus, our observations appeared to be in marked contrast with previous results from Witz and colleagues [52]. However, in our model, the anti-tumor IgG produced in nude mice and those injected in SCID mice are of the IgG3 isotype.…”

“…Subsequent studies using PyV-induced mouse tumors transfected with vector encoding mouse FcγRIIB1 confirmed these results. Indeed, it was shown that FcγRIIB1-expressing tumor cells exhibited a higher tumorigenic phenotype in comparison with FcγRIIB1-negative tumor, although the in vitro proliferation of both cell types was similar [52]. In the same study, the authors have also observed that the injection of a mixture of FcγRIIB1-positive and FcγRIIB1-negative tumor cells resulted in a tumor dominated by FcγRIIB1-expressing cells.…”

The IgG Fc receptor, FcγRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma

“…Over-expression of Fc␥RIIB in nonlymphoid tumor cells has been shown to significantly enhance their tumorigenic phenotype in vivo (48), and plasma concentrations of soluble FcR have been correlated with disease stage in chronic lymphocytic leukemia (49) and multiple myeloma (50). The mechanistic basis for these observations has not been investigated.…”

Deregulation of FCGR2B expression by 1q21 rearrangements in follicular lymphomas

“…Since overexpression of FcgR2Bb2 occurs in FL as an additional abnormality in the context of BCL2 deregulation, such hypotheses can be tested in transgenic mice overexpressing BCL2 and FCGR2B (b1 and b2 isoforms). Of interest in this context, FCGR2B has been shown to be a tumor-enhancing factor in non-lymphoid cells in a murine in vivo and in vivo model (Zusman et al, 1996;Witz and Rhan, 1992). In this study, two cases of FL with BCL2 aberrations and 1q21 rearrangements with a breakpoint within the FCGR2B/FCGR3B locus were identi®ed.…”