IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells

BMC Cancer

Xu Feng²  Hawley C Pruitt²  Huixian Hong¹  Erin M McCoy² 

[1]Department of Hematology, First Municipal People’s Hospital, Guangzhou Medical College, Guangdong, 510000, China

[2]Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

关键词: RANKL;    Bone resorption;    Osteolysis;    Osteoclast;    Bone metastasis;    Breast cancer;    Interleukin-11;   

Others  :  1079974
DOI  :  10.1186/1471-2407-13-16

 received in 2012-08-30, accepted in 2012-12-22,  发布年份 2013

【 摘 要 】

Background

Interleukin (IL)-11, a cytokine produced by breast cancer, has been implicated in breast cancer-induced osteolysis (bone destruction) but the mechanism(s) of action remain controversial. Some studies show that IL-11 is able to promote osteoclast formation independent of the receptor activator of NF-κB ligand (RANKL), while others demonstrate IL-11 can induce osteoclast formation by inducing osteoblasts to secrete RANKL. This work aims to further investigate the role of IL-11 in metastasis-induced osteolysis by addressing a new hypothesis that IL-11 exerts effects on osteoclast progenitor cells.

Methods

To address the precise role of breast cancer-derived IL-11 in osteoclastogenesis, we determined the effect of breast cancer conditioned media on osteoclast progenitor cells with or without an IL-11 neutralizing antibody. We next investigated whether recombinant IL-11 exerts effects on osteoclast progenitor cells and survival of mature osteoclasts. Finally, we examined the ability of IL-11 to mediate osteoclast formation in tissue culture dishes and on bone slices in the absence of RANKL, with suboptimal levels of RANKL, or from RANKL-pretreated murine bone marrow macrophages (BMMs).

Results

We found that freshly isolated murine bone marrow cells cultured in the presence of breast cancer conditioned media for 6 days gave rise to a population of cells which were able to form osteoclasts upon treatment with RANKL and M-CSF. Moreover, a neutralizing anti-IL-11 antibody significantly inhibited the ability of breast cancer conditioned media to promote the development and/or survival of osteoclast progenitor cells. Similarly, recombinant IL-11 was able to sustain a population of osteoclast progenitor cells. However, IL-11 was unable to exert any effect on osteoclast survival, induce osteoclastogenesis independent of RANKL, or promote osteoclastogenesis in suboptimal RANKL conditions.

Conclusions

Our data indicate that a) IL-11 plays an important role in osteoclastogenesis by stimulating the development and/or survival of osteoclast progenitor cells and b) breast cancer may promote osteolysis in part by increasing the pool of osteoclast progenitor cells via tumor cell-derived IL-11. However, given the heterogeneous nature of the bone marrow cells, the precise mechanism by which IL-11 treatment gives rise to a population of osteoclast progenitor cells warrants further investigation.

【 授权许可】

   
2013 McCoy et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Mundy GR: Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002, 2(8):584-593.
• [2]Weilbaecher KN, Guise TA, McCauley LK: Cancer to bone: a fatal attraction. Nat Rev Cancer 2011, 11(6):411-425.
• [3]Solakoglu O, Maierhofer C, Lahr G, Breit E, Scheunemann P, Heumos I, Pichlmeier U, Schlimok G, Oberneder R, Kollermann MW, et al.: Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proc Natl Acad Sci U S A 2002, 99(4):2246-2251.
• [4]Roodman GD: Mechanisms of bone metastasis. N Engl J Med 2004, 350(16):1655-1664.
• [5]Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J: A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003, 3(6):537-549.
• [6]Mancino AT, Klimberg VS, Yamamoto M, Manolagas SC, Abe E: Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. J Surg Res 2001, 100(1):18-24.
• [7]Pederson L, Winding B, Foged NT, Spelsberg TC, Oursler MJ: Identification of breast cancer cell line-derived paracrine factors that stimulate osteoclast activity. Cancer Res 1999, 59(22):5849-5855.
• [8]Yamasaki K, Taga T, Hirata Y, Yawata H, Kawanishi Y, Seed B, Taniguchi T, Hirano T, Kishimoto T: Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science 1988, 241(4867):825-828.
• [9]Hilton DJ, Hilton AA, Raicevic A, Rakar S, Harrison-Smith M, Gough NM, Begley CG, Metcalf D, Nicola NA, Willson TA: Cloning of a murine IL-11 receptor alpha-chain; requirement for gp130 for high affinity binding and signal transduction. EMBO J 1994, 13(20):4765-4775.
• [10]Leng SX, Elias JA: Interleukin-11. Int J Biochem Cell Biol 1997, 29(8–9):1059-1062.
• [11]Morinaga Y, Fujita N, Ohishi K, Tsuruo T: Stimulation of interleukin-11 production from osteoblast-like cells by transforming growth factor-beta and tumor cell factors. Int J of cancer J Int du cancer 1997, 71(3):422-428.
• [12]Hughes FJ, Howells GL: Interleukin-11 inhibits bone formation in vitro. Calcif Tissue Int 1993, 53(5):362-364.
• [13]Lacroix M, Siwek B, Marie PJ, Body JJ: Production and regulation of interleukin-11 by breast cancer cells. Cancer Lett 1998, 127(1–2):29-35.
• [14]Sims NA, Jenkins BJ, Nakamura A, Quinn JM, Li R, Gillespie MT, Ernst M, Robb L, Martin TJ: Interleukin-11 receptor signaling is required for normal bone remodeling. J Bone Miner Res 2005, 20(7):1093-1102.
• [15]Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA: Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 2003, 32(1):1-7.
• [16]Girasole G, Passeri G, Jilka RL, Manolagas SC: Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest 1994, 93(4):1516-1524.
• [17]Morgan H, Tumber A, Hill PA: Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor. Int J of cancer J Int du cancer 2004, 109(5):653-660.
• [18]Hill PA, Tumber A, Papaioannou S, Meikle MC: The cellular actions of interleukin-11 on bone resorption in vitro. Endocrinology 1998, 139(4):1564-1572.
• [19]McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO, Teitelbaum SL: Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 2000, 105(4):433-440.
• [20]Morinaga Y, Fujita N, Ohishi K, Zhang Y, Tsuruo T: Suppression of interleukin-11-mediated bone resorption by cyclooxygenases inhibitors. J Cell Physiol 1998, 175(3):247-254.
• [21]Ma T, Miyanishi K, Suen A, Epstein NJ, Tomita T, Smith RL, Goodman SB: Human interleukin-1-induced murine osteoclastogenesis is dependent on RANKL, but independent of TNF-alpha. Cytokine 2004, 26(3):138-144.
• [22]Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL: IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 2005, 115(2):282-290.
• [23]Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL: TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 2000, 106(12):1481-1488.
• [24]Li P, Schwarz EM, O’Keefe RJ, Ma L, Boyce BF, Xing L: RANK signaling is not required for TNFalpha-mediated increase in CD11(hi) osteoclast precursors but is essential for mature osteoclast formation in TNFalpha-mediated inflammatory arthritis. J Bone Miner Res 2004, 19(2):207-213.
• [25]Jules J, Shi Z, Liu J, Xu D, Wang S, Feng X: Receptor activator of NF-{kappa}B (RANK) cytoplasmic IVVY535-538 motif plays an essential role in tumor necrosis factor-{alpha} (TNF)-mediated osteoclastogenesis. J Biol Chem 2010, 285(48):37427-37435.
• [26]Jules J, Zhang P, Ashley JW, Wei S, Shi Z, Liu J, Michalek SM, Feng X: Molecular basis of requirement of receptor activator of nuclear factor kappaB signaling for interleukin 1-mediated osteoclastogenesis. J Biol Chem 2012, 287(19):15728-15738.
• [27]Crichton MB, Nichols JE, Zhao Y, Bulun SE, Simpson ER: Expression of transcripts of interleukin-6 and related cytokines by human breast tumors, breast cancer cells, and adipose stromal cells. Mol Cell Endocrinol 1996, 118(1–2):215-220.
• [28]Sotiriou C, Lacroix M, Lagneaux L, Berchem G, Body JJ: The aspirin metabolite salicylate inhibits breast cancer cells growth and their synthesis of the osteolytic cytokines interleukins-6 and −11. Anticancer Res 1999, 19(4B):2997-3006.
• [29]Sotiriou C, Lacroix M, Lespagnard L, Larsimont D, Paesmans M, Body JJ: Interleukins-6 and −11 expression in primary breast cancer and subsequent development of bone metastases. Cancer Lett 2001, 169(1):87-95.
• [30]Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen CR, Manova-Todorova K, Blasberg R, Gerald WL, Massague J: Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci U S A 2005, 102(39):13909-13914.
• [31]Singh B, Berry JA, Shoher A, Lucci A: COX-2 induces IL-11 production in human breast cancer cells. J Surg Res 2006, 131(2):267-275.
• [32]Hanavadi S, Martin TA, Watkins G, Mansel RE, Jiang WG: Expression of interleukin 11 and its receptor and their prognostic value in human breast cancer. Ann Surg Oncol 2006, 13(6):802-808.
• [33]Gupta J, Robbins J, Jilling T, Seth P: TGFbeta-dependent induction of interleukin-11 and interleukin-8 involves SMAD and p38 MAPK pathways in breast tumor models with varied bone metastases potential. Cancer Biol Ther 2011, 11(3):311-316.
• [34]Pollari S, Kakonen RS, Mohammad KS, Rissanen JP, Halleen JM, Warri A, Nissinen L, Pihlavisto M, Marjamaki A, Perala M, et al.: Heparin-like polysaccharides reduce osteolytic bone destruction and tumor growth in a mouse model of breast cancer bone metastasis. Mol Cancer Res 2012, 10(5):597-604.
• [35]Romas E, Udagawa N, Zhou H, Tamura T, Saito M, Taga T, Hilton DJ, Suda T, Ng KW, Martin TJ: The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures. J Exp Med 1996, 183(6):2581-2591.
• [36]Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999, 20(3):345-357.
• [37]Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Goto M, Mochizuki SI, Tsuda E, Morinaga T, Udagawa N, et al.: A novel molecular mechanism modulating osteoclast differentiation and function. Bone 1999, 25(1):109-113.