Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor
Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor
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DOI：
10.1002/ijc.20056
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发表时间：
2004-05-01
影响因子：
6.4
通讯作者：
Hill, PA
中科院分区：
文献类型：
--
作者：
Morgan, H;Tumber, A;Hill, PA
乳腺癌细胞经常转移到骨骼，在那里它们诱导OCL的形成和活动，导致广泛的骨破坏。然而，乳腺癌细胞介导骨溶解增加的机制仍不清楚。为了阐明这一点，我们利用小鼠成骨细胞-脾细胞共培养系统研究了3种人乳腺癌细胞系MDA-MB-231、MDA-MB-435和MCF-7如何诱导OCL的形成，并将它们与人结直肠癌细胞系HCT-15、人肺癌细胞系HT-1080和正常人乳腺细胞系HME进行了比较。只有在脾细胞共培养中存在成骨细胞时，乳腺癌细胞系才支持OCL的形成，而非乳腺癌细胞系和正常乳腺细胞系HME则没有影响。用超滤分离BCCM证实了破骨活性与具有M.W的因素有关。>；3 kDa。乳腺癌细胞株主要产生PTHrP，少量产生IL-6、IL-11和TNF-α。BCCM对成骨细胞-脾细胞共培养中OCL形成的影响可被抗人PTHrP的中和性抗体部分阻止，并可被小鼠IL-I或小鼠IL-I受体的中和性抗体完全阻止；中和性抗体对人IL-6、IL-11或肿瘤坏死因子-α无效。BCCM或人甲状旁腺素rP诱导小鼠成骨细胞IL-I m RNA和蛋白质产生增加，这种作用在人甲状旁腺素rP中和抗体的存在下被阻止。IL-I的破骨活性是通过促进成骨细胞产生前列腺素E(2)而实现的，而这种作用可被环氧合酶的抑制剂消除。由于重组小鼠GM-CSF抑制OCL的形成，而抗小鼠GM-CSF的中和性抗体可阻断这种抑制作用，因此PGE2通过下调脾细胞产生GM-CSF而明显促进OCL的形成。我们得出结论，乳腺癌细胞通过刺激成骨细胞产生IL-11来诱导OCL的形成。随后骨微环境中细胞释放PGE(2)并抑制GM-CSF的产生，在介导乳腺癌细胞对OCL的形成及其吸收活性的影响中起着重要作用。(C)2004年Wiley-Liss公司
Breast cancer cells frequently metastasize to the skeleton, where they induce OCL formation and activity, resulting in extensive bone destruction. However, the mechanisms by which breast cancer cells mediate increased osteolysis remain unclear. To elucidate this point, we investigated how 3 human breast cancer cell lines, MDA-MB-231, MDA-MB-435 and MCF-7, induce OCL formation using a murine osteoblast-spleen cell coculture system and compared their effects with a human colorectal cancer cell line, HCT-15; a human lung cancer cell line, HT-1080; and a normal human breast cell line, HME. The breast cancer cell lines supported OCL formation only when osteoblasts were present in spleen cell cocultures, whilst the non-breast cancer cell lines and the normal breast cell line, HME, had no effect. Fractionation of BCCM by ultrafiltration established that osteoclastogenic activity was associated with factors having m.w. >3 kDa. Breast cancer cell lines produced primarily PTHrP, with lesser amounts of IL-6, IL-11 and TNF-alpha. The effect of BCCM on OCL formation in osteoblast-spleen cell cocultures was partially prevented by a neutralising antibody to human PTHrP and completely prevented by a neutralising antibody to either murine IL- I I or the murine IL- I I receptor; neutralising antibodies to human IL-6, IL-11 or TNF-alpha were without effect. BCCM or human PTHrP induced an increase in murine osteoblast IL- I I m RNA and protein production, effects that were prevented in the presence of a neutralising antibody to human PTHrP. The osteoclastogenic activity of IL- I I was mediated by enhancing osteoblast production of PGE(2) effects, which were abrogated by an inhibitor of cyclooxygenase. PGE2 apparently enhanced OCL formation by downregulating GM-CSF production by spleen cells since recombinant murine GM-CSF inhibited OCL formation and a neutralising antibody to murine GM-CSF blocked these inhibitory effects. We conclude that breast cancer cells induce OCL formation by stimulating osteoblastic production of IL-11. The subsequent release of PGE(2) followed by inhibition of GM-CSF production by cells within the bone microenvironment plays an important part in mediating the effects of breast cancer cells on OCL formation and their resorptive activity. (C) 2004 Wiley-Liss, Inc.