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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-01-0102.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3311-3318
NEOPLASIA
In the presence of bone marrow stromal cells human multiple
myeloma cells become independent of the IL-6/gp130/STAT3
pathway
Manik Chatterjee,
Dirk Hönemann,
Suzanne Lentzsch,
Kurt Bommert,
Christine Sers,
Pia Herrmann,
Stephan Mathas,
Bernd Dörken, and
Ralf C. Bargou
From the Department of Hematology, Oncology, and
Tumorimmunology, Robert-Rössle Cancer Center at the
Max-Delbrück-Center for Molecular Medicine, Charité, Campus
Berlin-Buch, and Institute of Pathology, University Hospital
Charité, Humboldt University of Berlin, Berlin, Germany.
The interleukin 6/glycoprotein 130/signal transducer and activator
of transcription 3 (IL-6/gp130/STAT3) pathway has been reported
to play an important role in the pathogenesis of multiple myeloma (MM)
and for survival of MM cells. However, most data concerning the role of
IL-6 and IL-6-triggered signaling pathways were obtained from
experiments performed with MM cell lines and without considering the
bone marrow microenvironment. Thus, the precise role of IL-6 and its
intracellular signaling pathways for survival of human MM cells is
still unclear. Here we show that treatment of human MM cells
(IL-6-dependent MM cell line INA-6 and primary MM cells) with the IL-6
receptor antagonist Sant7 or with an anti-gp130 monoclonal antibody
(mAb) induced apoptosis if the cells were cultured in the absence of
bone marrow stromal cells (BMSCs). In contrast, apoptosis could not be
observed if the MM cells were cocultured with BMSCs. The analysis of
intracellular pathways revealed that Sant7 and anti-gp130 mAb were
effectively inhibiting the phosphorylation of gp130 and STAT3 in the
absence and presence of BMSCs, whereas ERK1 and ERK2 (ERK1,2)
phosphorylation was only slightly affected. In contrast, treatment with
the farnesyl transferase inhibitor, FPT III, induced apoptosis in MM
cells in the absence or presence of BMSCs and led to a complete
inhibition of the Ras/mitogen-activated protein kinase pathway.
These observations indicate that the IL-6/gp130/STAT3 pathway is not
essential for survival of human myeloma cells if they are grown in the
presence of cells from the bone marrow microenvironment. Furthermore,
we provide evidence that farnesyl transferase inhibitors might be useful for the development of novel therapeutic strategies for the
treatment of MM.
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