Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis.
Matrix metalloproteinase activity, bone matrix turnover, and tumor cell proliferation in prostate cancer bone metastasis.
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DOI：
10.1093/jnci/94.1.17
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发表时间：
2002-01
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影响因子：
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通讯作者：
J. Nemeth;Rafid Yousif;M. Herzog;M. Che;J. Upadhyay;B. Shekarriz;S. Bhagat;C. Mullins;R. Fridman;M. Cher
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文献类型：
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作者：
J. Nemeth;Rafid Yousif;M. Herzog;M. Che;J. Upadhyay;B. Shekarriz;S. Bhagat;C. Mullins;R. Fridman;M. Cher
背景：前列腺癌骨转移与骨基质转换的显著增加有关。基质金属蛋白酶（MMPs）在正常骨重建和前列腺癌的侵袭转移中发挥作用。本研究旨在确定MMP活性在前列腺癌骨转移中的作用。方法将单个人胎骨碎片植入免疫缺陷小鼠皮下。四周后，将PC 3人前列腺癌细胞直接注射到一些植入物中，并开始每天用巴马司他（一种广谱MMP抑制剂）治疗。有六只小鼠（即，六个植入物）：单独的骨，有和没有巴马司他，以及用PC 3细胞注射的骨，有和没有巴马司他。治疗14天后收集骨植入物，并分析MMP表达、骨组织形态计量学、破骨细胞计数、血管密度以及肿瘤细胞增殖和凋亡。从患者的骨活检样本和骨器官共培养系统中获得补充数据。所有统计检验均为双侧检验。结果MMPs在临床标本和实验性骨植入物的肿瘤细胞和基质细胞中均有表达。在体内，MMP抑制减少了PC 3注射植入物中每毫米破骨细胞的数量-从8.2（95%置信区间[CI] = 7.9至8.5）降至3.0（95% CI = 2.3至3.7）（P = 0.006）。此外，它还可防止骨植入物内的骨髓小梁降解（矿化小梁占据的植入物横截面积：未处理的植入物= 29.1% [95% CI = 27.1%-31.1%]，注射PC 3的植入物= 14.0% [95% CI = 10.9%-17.1%] [P = 0.005 vs未处理]，和巴马司他治疗的PC 3注射植入物= 27.2% [95% CI = 22.4%至32.0%] [P = 0.03 vs单独注射PC 3]）。MMP抑制使增殖的肿瘤细胞从20.8%（95%CI = 19.9%至21.7%）减少至7.4%（95%CI = 5.2%至9.6%）（P = 0.006），而不影响血管生成或凋亡。在体外，MMP抑制对PC 3细胞没有毒性作用，但阻止了与PC 3细胞共培养的骨碎片的钙释放。结论：当骨中存在前列腺癌细胞时，MMP活性似乎在骨基质转换中起重要作用。骨基质周转和转移性肿瘤生长似乎参与了一个相互支持的周期，该周期被MMP抑制破坏。
BACKGROUND The metastasis of prostate cancer to bone is associated with a substantial increase in bone matrix turnover. Matrix metalloproteinases (MMPs) play roles in both normal bone remodeling and invasion and metastasis of prostate cancer. This study was designed to determine the role of MMP activity in prostate cancer that has metastasized to bone. METHODS Single human fetal bone fragments were implanted subcutaneously in immunodeficient mice. Four weeks later, PC3 human prostate cancer cells were injected directly into some of the implants, and daily treatment was begun with batimastat (a broad-spectrum MMP inhibitor). There were six mice (i.e., six implants) in each of four experimental arms: bone alone with and without batimastat and bone injected with PC3 cells with and without batimastat. Bone implants were harvested after 14 days of treatment and analyzed for MMP expression, bone histomorphometry, osteoclast counts, blood vessel density, and tumor cell proliferation and apoptosis. Complementary data were obtained from bone biopsy samples from patients and a bone organ coculture system. All statistical tests were two-sided. RESULTS MMPs were detected in tumor and stromal cells of clinical specimens and experimental bone implants. In vivo, MMP inhibition reduced the number of osteoclasts per millimeter in PC3-injected implants-from 8.2 (95% confidence interval [CI] = 7.9 to 8.5) to 3.0 (95% CI = 2.3 to 3.7) (P =.006). In addition, it prevented degradation of marrow trabeculae within the bone implants (cross-sectional area of implant occupied by mineralized trabeculae: untreated implant = 29.1% [95% CI = 27.1% to 31.1%], PC3-injected implant = 14.0% [95% CI = 10.9% to 17.1%] [P =.005 versus untreated], and batimastat-treated PC3-injected implant = 27.2% [95% CI = 22.4% to 32.0%] [P =.03 versus PC3 injected alone]). MMP inhibition reduced proliferating tumor cells from 20.8% (95% CI = 19.9% to 21.7%) to 7.4% (95% CI = 5.2% to 9.6%) (P =.006), without affecting angiogenesis or apoptosis. In vitro, MMP inhibition had no toxic effect on PC3 cells but prevented calcium release from bone fragments cocultured with PC3 cells. CONCLUSIONS MMP activity appears to play an important role in bone matrix turnover when prostate cancer cells are present in bone. Bone matrix turnover and metastatic tumor growth appear to be involved in a mutually supportive cycle that is disrupted by MMP inhibition.