Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma

Abstract

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 (BMSCs) 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. BMSCs from MM patients and control subjects expressed high-affinity FGF receptors R1 through R4. Stimulation of BMSCs 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 cocultured with BMSCs in a noncontact transwell system, both IL-6 and bFGF concentrations in coculture 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.

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

“…This explains why FGF-2 concentrations in marrow aspirates and peripheral blood correlate with MM activity (Di Raimondo et al, 2000;Sezer et al, 2001;Sato et al, 2002). Bisping et al (2003) have illustrated the expression of highaffinity FGFR-1 through R-4 in RPMI-8226 and U266 MM cell lines and patients' plasma cells, as well as in BMSC, and hence the likelihood of both autocrine and paracrine loops of growth and angiogenesis. Moreover, they demonstrated that FGF-2 induces a time-and dose-dependent increase in IL-6 secretion by BMSC, in the absence of vessels, indicating that its paracrine effects of FGF-2 do not depend on the presence of microvascular EC in the vicinity of plasma cells.…”

“…Fibroblast growth factor-2 Plasma cells are the prevailing source of FGF-2 in the bone marrow of patients with active MM Bisping et al, 2003). This explains why FGF-2 concentrations in marrow aspirates and peripheral blood correlate with MM activity (Di Raimondo et al, 2000;Sezer et al, 2001;Sato et al, 2002).…”

Angiogenesis and Multiple Myeloma

“…bFGF's role in MM-induced angiogenesis has been demonstrated through the capacity of an anti-bFGF blocking antibody to inhibit the in vitro vessel formation induced by BM plasma cell samples [8]. Myeloma cells may produce bFGF, however not all MM patients' plasma cells produce bFGF [41,47,48]. Bisping et al [47] have reported that human myeloma cell lines and sorted CD138 + cells obtained from 12 of 15 MM patients produced bFGF, concluding that myeloma cells are the predominant source of bFGF.…”

“…Myeloma cells may produce bFGF, however not all MM patients' plasma cells produce bFGF [41,47,48]. Bisping et al [47] have reported that human myeloma cell lines and sorted CD138 + cells obtained from 12 of 15 MM patients produced bFGF, concluding that myeloma cells are the predominant source of bFGF. Others have shown that neither human myeloma cells nor EBV-positive B cell lines secret bFGF [41].…”

Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction

“…[2][3][4][5][6][7][8] The angiogenic switch in MM is mainly sustained by the overproduction of vascular endothelial growth factors (VEGFs) by MM cells and the BM microenvironment. 2,9,10 Other proangiogenic molecules, such as basic fibroblast growth factor, 11,12 interleukin-8 (IL-8), 13 angiopoietin-1 14 and osteopontin 15 are involved in the pro-angiogenic process. Hypoxia is a common feature of solid tumors and is associated with angiogenesis and malignant phenotype.…”