Morgan Hayley, Tumber Anthony, Hill Peter A
Department of Craniofacial Development, Guy's, King's, and St. Thomas' School of Medicine and Dentistry, Floor 22 Guy's Tower, London Bridge, London SE1 9RT, United Kingdom.
Int J Cancer. 2004 May 1;109(5):653-60. doi: 10.1002/ijc.20056.
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-11 or the murine IL-11 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-11 mRNA and protein production, effects that were prevented in the presence of a neutralising antibody to human PTHrP. The osteoclastogenic activity of IL-11 was mediated by enhancing osteoblast production of PGE(2) effects, which were abrogated by an inhibitor of cyclooxygenase. PGE(2) 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.
乳腺癌细胞常转移至骨骼，在那里它们诱导破骨细胞（OCL）的形成和活性，导致广泛的骨质破坏。然而，乳腺癌细胞介导骨溶解增加的机制仍不清楚。为阐明这一点，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形成，并将它们的作用与一种人结肠癌细胞系HCT - 15、一种人肺癌细胞系HT - 1080以及一种正常人乳腺细胞系HME进行比较。仅当脾细胞共培养物中存在成骨细胞时，乳腺癌细胞系才支持OCL形成，而非乳腺癌细胞系和正常人乳腺细胞系HME则无此作用。通过超滤对乳腺癌条件培养基（BCCM）进行分级分离表明，破骨细胞生成活性与分子量大于3 kDa的因子有关。乳腺癌细胞系主要产生甲状旁腺激素相关蛋白（PTHrP），白细胞介素 - 6（IL - 6）、白细胞介素 - 11（IL - 11）和肿瘤坏死因子 - α（TNF - α）的量较少。人PTHrP的中和抗体可部分阻止BCCM对成骨细胞 - 脾细胞共培养物中OCL形成的作用，而针对小鼠IL - 11或小鼠IL - 11受体的中和抗体则可完全阻止该作用；针对人IL - 6、IL - 11或TNF - α的中和抗体则无作用。BCCM或人PTHrP可诱导小鼠成骨细胞IL - 11 mRNA和蛋白产量增加，在存在人PTHrP中和抗体的情况下，这些作用可被阻止。IL - 11的破骨细胞生成活性是通过增强成骨细胞前列腺素E2（PGE2）的产生介导的，环氧合酶抑制剂可消除这些作用。PGE2显然通过下调脾细胞GM - 集落刺激因子（GM - CSF）的产生来增强OCL形成，因为重组小鼠GM - CSF可抑制OCL形成，而针对小鼠GM - CSF的中和抗体可阻断这些抑制作用。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形成。随后PGE2的释放以及骨微环境内细胞对GM - CSF产生的抑制在介导乳腺癌细胞对OCL形成及其吸收活性的作用中起重要作用。
