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Adhesion of human myeloma-derived cell lines to bone marrow stromal cells
stimulates interleukin-6 secretion
H Uchiyama, BA Barut, AF Mohrbacher, D Chauhan and KC Anderson
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA
02115.
Previous studies show that human myeloma-derived cell lines specifically
adhere to fibronectin (FN) through very late antigen-4 (VLA-4; alpha 4 beta
1 integrin complex) and RGD-peptide mechanisms, which may contribute to the
localization of tumor cells in bone marrow (BM). In these studies, we
characterized the adhesion of myeloma- derived cell lines to both normal
and myeloma BM stromal cells (BMSCs) and the effect of adhesion on DNA
synthesis. Because interleukin-6 (IL- 6) plays an important role in the
pathogenesis of multiple myeloma, we also examined the effects of tumor
cell adhesion on IL-6 secretion by BMSCs. In 51chromium binding assays, the
U266, ARH-77, and IM-9 cell lines showed 52% +/- 12%, 55% +/- 6%, and 47%
+/- 7% specific adherence, respectively, to normal BMSCs and 74% +/- 4%,
60% +/- 3%, and 61% +/- 6% specific adherence, respectively, to myeloma
BMSCs. In contrast, only 12% to 13% specific binding of HS-Sultan cells to
BMSCs was noted. The binding of myeloma cells to BMSCs was partially
blocked with anti-beta 1 monoclonal antibody (MoAb), anti-beta 2 integrin
MoAb, and excess RGD peptide, suggesting multiple mechanisms for the
adhesion of myeloma cell lines to BMSCs. Binding of cell lines to FN or
myeloma BMSCs did not affect cell line proliferation; however, adhesion of
myeloma cell lines to normal BMSCs decreased DNA synthesis, ie, stimulation
indices are 0.1 +/- 0.04, 0.2 +/- 0.1, 0.2 +/- 0.07, and 0.1 +/- 0.06 for
the adherent non-IL-6-dependent U266, ARH-77, HS- Sultan, and IM-9 cells,
respectively (n = 5, P < .01). In contrast, adherence of IL-6-dependent
B9 cells increased their proliferation (stimulation index, 3.2 +/- 0.7).
Significant (twofold to eightfold) increases in IL-6 secretion were evident
in cell line-adherent (> or = 12 hours) normal and myeloma BMSC
cultures. Paraformaldehyde fixation of BMSCs before adhesion completely
abrogated IL-6 secretion, suggesting that IL-6 secretion was triggered in
BMSCs rather than in cell lines. Partial blocking of cell line adhesion to
BMSCs, using anti- beta 1 integrin and anti-beta 2 integrin MoAbs and RGD
peptide, also partially blocked the triggering of IL-6 secretion by BMSCs.
When cell lines were placed in Transwell inserts and then cultured with
either normal or myeloma BMSCs, permitting juxtaposition without cell to
cell contact between myeloma cell lines and BMSCs, no increase in IL-6
secretion was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 82,
Issue 12,
pp. 3712-3720,
12/15/1993
Copyright © 1993 by The American Society of Hematology
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