Malignant B-Lymphoid Cells with Bone Lesions Express Receptor Activator of Nuclear Factor-κB Ligand and Vascular Endothelial Growth Factor to Enhance Osteoclastogenesis

Abstract

Purpose: Receptor activator of nuclear factor-nB ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction also develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms. Experimental Design and Results: Immunohistochemistry of bone specimens resected from patients with primary B-cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL as well as vascular endothelial cell growth factor (VEGF). The tumor cells isolated from the bone specimens enhanced osteoclastogenesis in vitro. In contrast, B-cell lymphoma infiltrating to the bone marrow without bone destruction did not express RANKL. Both RANKL and VEGF were expressed by a portion of B-lymphoid cell lines, including Daudi and IM-9. These RANKL-expressing tumor cells enhanced osteoclastogenesis from RAW264.7 cells and human monocyte-derived preosteoclasts in the absence of stromal cells/osteoblasts in a RANKL-dependent manner. Furthermore, conditioned media from Daudi cells enhanced transmigration of preosteoclasts that was inhibited by anti-VEGF antibody, suggesting that tumor cell^derived VEGF mediates recruitment of osteoclast precursors. Moreover, cocultures of B-lymphoid cell lines with osteoclasts enhanced the growth of B-lymphoid cells. Conclusions: Some malignant B cells aberrantly express functional RANKL as well as VEGF to enhance osteoclastogenesis. The coexpression of RANKL and VEGF may also contribute to the close cellular interactions with osteoclastic cells, thereby forming a vicious cycle between osteoclastic bone destruction and tumor expansion in bone.Certain types of B-lymphoid neoplasms, such as lymphoma of bone origin and multiple myeloma, exclusively develop and expand in the skeleton. These tumors cause lytic bone lesions, which lead to the debilitating clinical symptoms including intractable bone pain and disabling fractures. In those destructive bone lesions, osteoclasts seem to surround tumor cells and actively resorb bone. Several bone-resorbing factors, including parathyroid hormone -related protein (1), interleukin (IL)-1h (2 -4), and IL-6 (3 -5), have been implicated as causative factors for bone destruction in multiple myeloma, and recent reports including those from ourselves indicate that a C-C chemokine, macrophage inflammatory protein-1a and macrophage inflammatory protein-1h, plays an important role in the development of lytic bone lesions by multiple myeloma (6 -10). However, the pathogenesis as well as the mechanism of bone destruction by B-cell lymphoma of bone origin is largely unknown.Binding of receptor activator of nuclear factor-nB ligand (RANKL; refs. 11 -13) to its receptor (RANK; ref. 14) is essential for the enhancement of osteoclast differentiation, activation, and survival, whereas its decoy receptor, osteoprotegerin (15), inhibits RANKL-RANK signaling. Along with RANKL, macrophage colony-stimulating f...

Interaction of VEGF to gastric low grade MALT lymphoma by Helicobacter heilmannii infection in C57/BL/6 mice

“…As to the relation of VEGF on the tumor expansion, many studies have suggested its interaction (Grunstein, 1999;Shibata, 2005). The present results strongly support that the observed MALT lymphoma has characteristics as a neoplasm.…”

Multiple bone lesions and hypercalcemia presented in diffuse large B cell lymphoma: mimicking multiple myeloma?

“…In our case, we also detected a decreased OPG level in MSCs which increased significantly after treatment. Contrary to previous report by Matsuhashi [9] and Shibata [15], we found no mRNA and protein expression of RANKL in the lymphoma cells which account for more than 50% of the bone marrow mono-nucleated cells before treatment. There has been a controversy whether myeloma cells express RANKL [17].…”

“…It has been demonstrated that stromal/osteoblastic cells and activated T lymphocytes express RANKL in response to cytokines that stimulate bone resorption, such as PTH, dexamethasone, vitamin D3, IL-1, TNF and IL-11 [13,14]. Shibata et al [15] performed immunohistochemistry of bone specimens resected from patients with primary B cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL. In our case report, real-time PCR and western blot revealed that expression of RANKL in MSCs decreased sharply after several cycles of chemotherapy accompanied by The protein expressions of DKK-1, RANKL, OPG and PTHrP.…”

Myeloma Cell-Osteoclast Interaction Enhances Angiogenesis Together with Bone Resorption: A Role for Vascular Endothelial Cell Growth Factor and Osteopontin

“…VEGF is one of the most potent angiogenic factors produced by tumor cells, including multiple myeloma cells (11,31). In contrast to osteopontin, all multiple myeloma cell lines examined thus far constitutively secrete VEGF (12,32). However, osteoclasts do not produce detectable levels of VEGF.…”