A role for IL-34 in osteolytic disease of multiple myeloma

Abstract

Multiple myeloma (MM) is a hematological malignancy that grows in multiple sites of the axial skeleton and causes debilitating osteolytic disease. Interleukin-34 (IL-34) is a newly discovered cytokine that acts as a ligand of colony-stimulating factor-1 (CSF-1) receptor and can replace CSF-1 for osteoclast differentiation. In this study, we identify IL-34 as an osteoclastogenic cytokine that accelerates osteolytic disease in MM. IL-34 was found to be expressed in the murine MM cell line MOPC315.BM, and the expression of IL-34 was enhanced by stimulation with proinflammatory cytokines or by bone marrow (BM) stromal cells. MM-cell–derived IL-34 promoted osteoclast formation from mouse BM cells in vitro. Targeting Il34 by specific small interfering RNA impaired osteoclast formation in vitro and attenuated osteolytic disease in vivo. In BM aspirates from MM patients, the expression levels of IL-34 in CD138+ populations vary among patients from high to weak to absent. MM cell–derived IL-34 promoted osteoclast formation from human CD14+ monocytes, which was reduced by a neutralizing antibody against IL-34. Taken together, this study describes for the first time the expression of IL-34 in MM cells, indicating that it may enhance osteolysis and suggesting IL-34 as a potential therapeutic target to control pathological osteoclastogenesis in MM patients.

Prognostic value of IL-34 in colorectal cancer patients

“…The association of IL-34 staining in colorectal cancer tissues with patients' characteristics is summarized in Table 1. Together, these data indicate that colorectal cancers have the potential to express IL-34, consistent with previous reports [8][9][10][11][12][13][14][15][16][17][18][19].…”

“…In disease, IL-34 expression can be induced by various cells, where it plays pathological roles such as in autoimmune disease, inflammation, infection and metabolic disorders [7]. Accumulating evidence also suggests important roles for IL-34 in cancer, including tumor growth, angiogenesis, metastasis, immunosuppression, therapeutic resistance and pathological osteoclastogenesis [8][9][10][11][12][13][14][15][16][17][18][19]. In particular, IL-34 contributes to the induction of immunosuppressive tumor microenvironment.…”

Expression of IL‐34 correlates with macrophage infiltration and prognosis of diffuse large B‐cell lymphoma

“…13,14 In contrast, the role of IL-34 in tumor development and progression is not fully understood, although recent studies demonstrated the IL-34 expression in solid tumors, such as osteosarcoma, 15 hepatocellular carcinoma 16 and lung cancer cells. 19 Here, we show that IL-34 is also expressed in approximately 36% of lymphoma tissues of patients with diffuse large B-cell lymphoma (DLBCL). 19 Here, we show that IL-34 is also expressed in approximately 36% of lymphoma tissues of patients with diffuse large B-cell lymphoma (DLBCL).…”

“…17 Interestingly, we and others recently reported the IL-34 expression in haematological malignancies such as adult T-cell leukaemia/ lymphoma 18 and multiple myeloma. 19 Here, we show that IL-34 is also expressed in approximately 36% of lymphoma tissues of patients with diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common subtype of non-Hodgkin lymphoma and curable even in advanced stages, but up to onethird of patients will not achieve cure with initial therapy.…”

Role of Interleukin-34 in Cancer

“…IL-34 produced by giant cells of bone tumors supports RANKL-driven osteoclastogenesis, even in the absence M-CSF-1, by inducing M-CSF1-R-dependent activation of ERK 1/2 and Akt [18]. Moreover, in multiple myeloma (MM), IL-34 accelerates MM-induced osteoclast formation from monocytes and increases the severity of bone lesions [50], whereas, in sporadic vestibular schwannoma, IL-34 expression is not related to clinicopathologic characteristics and tumor growth [51]. Finally, in adult T-cell leukemia/lymphoma (ATLL), IL-34 and M-CSF-1 co-expression was found to correlate with tumor aggressiveness [52].…”