Tannehill-Gregg S H, Levine A L, Nadella M V P, Iguchi H, Rosol T J
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Evansville, IN, USA.
Clin Exp Metastasis. 2006;23(1):19-31. doi: 10.1007/s10585-006-9008-z. Epub 2006 May 20.
The pathogenesis of bone metastases may require the activation of osteoclasts by tumor-secreted factors, which promote important interactions with the bone microenvironment. We utilized an intratibial model of bone metastasis with bioluminescent imaging (BLI) to measure the effect of osteoclast inhibition on the interaction of human lung cancer cells with bone, and on tumor growth. Mice were injected with luciferase-transduced tumor cells (HARA, human pulmonary squamous carcinoma) and divided into three groups: (1) untreated, (2) twice weekly treatment with the bisphosphonate zoledronic acid (ZOL), or (3) osteoprotegerin (OPG). Histomorphometry and imaging were used to evaluate tumor burden, and parameters of osteoclast activity. Mice in the treated groups had increased bone density and decreased osteoclast numbers in nontumor-bearing tibiae. There was greater than 60% reduction in mean tumor volume in both treatment groups when evaluated by histomorphometry (P = 0.06 [OPG], P = 0.07 [ZOL]). However, bioluminescent imaging failed to show a reduction in tumor burden due to wide variability in the data. Osteoclast numbers along tumor-associated bone were significantly increased compared to tumor-free bone, and were not reduced by either treatment. Plasma calcium concentration was increased in all groups. Plasma tartrate-resistant acid phosphatase 5b was reduced in both treatment groups. Plasma PTHrP was significantly increased in the untreated tumor-bearing group, but was not significantly different in the two treatment groups compared to normal mice. OPG or ZOL did not change tumor cell proliferation, but ZOL increased HARA cell apoptosis. OPG and ZOL reduced tumor growth in the tibiae of treated mice, however, PTHrP production by HARA cells may have resulted in a high concentration in the bone microenvironment, partially overriding the antiosteoclast effects of both OPG and ZOL.
骨转移的发病机制可能需要肿瘤分泌的因子激活破骨细胞，这些因子促进与骨微环境的重要相互作用。我们利用带有生物发光成像（BLI）的胫骨内骨转移模型来测量破骨细胞抑制对人肺癌细胞与骨相互作用以及肿瘤生长的影响。给小鼠注射荧光素酶转导的肿瘤细胞（HARA，人肺鳞状细胞癌），并分为三组：（1）未治疗组，（2）每周两次用双膦酸盐唑来膦酸（ZOL）治疗组，或（3）骨保护素（OPG）治疗组。采用组织形态计量学和成像技术评估肿瘤负荷以及破骨细胞活性参数。治疗组小鼠非荷瘤胫骨的骨密度增加，破骨细胞数量减少。通过组织形态计量学评估，两个治疗组的平均肿瘤体积均减少了60%以上（OPG组P = 0.06，ZOL组P = 0.07）。然而，由于数据差异较大，生物发光成像未能显示肿瘤负荷的降低。与无肿瘤的骨相比，肿瘤相关骨的破骨细胞数量显著增加，且两种治疗均未使其减少。所有组的血浆钙浓度均升高。两个治疗组的血浆抗酒石酸酸性磷酸酶5b均降低。未治疗的荷瘤组血浆甲状旁腺激素相关蛋白（PTHrP）显著升高，但与正常小鼠相比，两个治疗组无显著差异。OPG或ZOL未改变肿瘤细胞增殖，但ZOL增加了HARA细胞凋亡。OPG和ZOL减少了治疗组小鼠胫骨中的肿瘤生长，然而，HARA细胞产生的PTHrP可能导致骨微环境中浓度升高，部分抵消了OPG和ZOL的抗破骨细胞作用。
