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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-09-2907.
Submitted October 4, 2002
Accepted November 13, 2002
Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma
Guido Bisping, Regine Leo, Doris Wenning, Berno Dankbar, Teresa Padro, Martin Kropff, Christian Scheffold, Matthias Kroeger, Rolf M Mesters, Wolfgang E Berdel, and Joachim Kienast*
Dept of Medicine, Hematology and Oncology, University Hospital, Muenster, Germany
* Corresponding author; email: kienast{at}uni-muenster.de.
Myeloma cells express basic fibroblast growth factor (bFGF), an angiogenic cytokine triggering marrow neovascularization in multiple myeloma (MM). In solid tumors and some lymphohematopoietic malignancies, angiogenic cytokines have also been shown to stimulate tumor growth via paracrine pathways. Since interleukin-6 (IL-6) is a potent growth and survival factor for myeloma cells, we have studied the effects of bFGF on IL-6 secretion by bone marrow stromal cells (BMSC) and its potential reverse regulation in myeloma cells. Both myeloma-derived cell lines and myeloma cells isolated from the marrow of MM patients were shown to express and secrete bFGF. Cell sorting studies identified myeloma cells as the predominant source of bFGF in MM marrow. BMSC from MM patients and control subjects both expressed high affinity FGF receptors R1 through R4. Stimulation of BMSC with bFGF induced a time- and dose-dependent increase in IL-6 secretion (median 2-fold, P<.001), which was completely abrogated by anti-bFGF antibodies. Conversely, stimulation with IL-6 enhanced bFGF expression and secretion by myeloma cell lines (2-fold, P=.02) as well as MM patient cells (up to 3.6-fold, median 1.5-fold, P=.002). This effect was inhibited by anti-IL-6 antibody. When myeloma cells were co-cultured with BMSC in a non-contact transwell system, both IL-6 and bFGF concentrations in co-culture supernatants increased 2- to 3-fold over the sum of basal concentrations in the monoculture controls. The IL-6 increase was again partially, but significantly inhibited by anti-bFGF. The data demonstrate a paracrine interaction between myeloma and marrow stromal cells triggered by mutual stimulation of bFGF and IL-6.
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