Tumor-expressed adrenomedullin accelerates breast cancer bone metastasis.
Tumor-expressed adrenomedullin accelerates breast cancer bone metastasis.
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DOI：
10.1186/s13058-014-0458-y
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发表时间：
2014-12-02
期刊：
影响因子：
--
通讯作者：
Chirgwin JM
中科院分区：
文献类型：
--
作者：
Siclari VA;Mohammad KS;Tompkins DR;Davis H;McKenna CR;Peng X;Wessner LL;Niewolna M;Guise TA;Suvannasankha A;Chirgwin JM
肾上腺髓质素（AM）由乳腺癌细胞分泌，并在缺氧时增加。它是刺激血管生成和增殖的多功能肽。该肽也是成骨细胞和骨形成的有效旁分泌刺激物，表明在骨骼肌中的作用，骨骼肌是晚期疾病患者治疗难治性肿瘤生长的主要部位。肾上腺髓质素在骨转移中的作用通过在MDA-MB-231乳腺癌细胞中的稳定过表达来测试，所述MDA-MB-231乳腺癌细胞在标准动物模型中引起溶骨性骨转移。AM表达增加五倍的细胞在体外进行了表征，接种到免疫缺陷小鼠中，并与对照亚克隆比较其形成骨转移的能力。通过X线监测骨破坏，并通过定量组织形态计量学测定肿瘤负荷和破骨细胞数量。测定AM过表达对乳腺脂肪垫中肿瘤生长和血管生成的影响。体外实验观察AM肽对破骨细胞样多核细胞形成的影响。测试了小分子AM拮抗剂对AM刺激的离体骨细胞培养物和与肿瘤细胞共培养物的影响，其中通过物种特异性实时PCR区分肿瘤和骨的反应。AM mRNA的过表达并不改变体外细胞增殖、肿瘤分泌因子的表达或细胞周期进程。AM过表达细胞导致溶骨性骨转移发展更快，这是伴随着生存率下降。在乳腺脂肪垫中，肿瘤生长更快，血管形成不变。骨中的肿瘤生长也更快，破骨细胞增加。AM肽有效地刺激离体骨培养;在没有细胞毒性的情况下，小分子肾上腺髓质素拮抗剂阻断了这种反应。拮抗剂治疗显著抑制骨中的肿瘤生长并降低破骨细胞活性的标志物。结果确定AM作为针对骨转移的治疗干预的靶点。肾上腺髓质素增强骨对转移性乳腺癌细胞的溶骨性反应。小分子拮抗剂可以有效地阻断骨介导的反应，肿瘤分泌的肾上腺髓质素，这样的代理人值得开发体内测试。本文的在线版本（doi：10.1186/s13058-014-0458-y）包含补充材料，可供授权用户使用。
Adrenomedullin (AM) is secreted by breast cancer cells and increased by hypoxia. It is a multifunctional peptide that stimulates angiogenesis and proliferation. The peptide is also a potent paracrine stimulator of osteoblasts and bone formation, suggesting a role in skeletal metastases—a major site of treatment-refractory tumor growth in patients with advanced disease. The role of adrenomedullin in bone metastases was tested by stable overexpression in MDA-MB-231 breast cancer cells, which cause osteolytic bone metastases in a standard animal model. Cells with fivefold increased expression of AM were characterized in vitro, inoculated into immunodeficient mice and compared for their ability to form bone metastases versus control subclones. Bone destruction was monitored by X-ray, and tumor burden and osteoclast numbers were determined by quantitative histomorphometry. The effects of AM overexpression on tumor growth and angiogenesis in the mammary fat pad were determined. The effects of AM peptide on osteoclast-like multinucleated cell formation were tested in vitro. A small-molecule AM antagonist was tested for its effects on AM-stimulated ex vivo bone cell cultures and co-cultures with tumor cells, where responses of tumor and bone were distinguished by species-specific real-time PCR. Overexpression of AM mRNA did not alter cell proliferation in vitro, expression of tumor-secreted factors or cell cycle progression. AM-overexpressing cells caused osteolytic bone metastases to develop more rapidly, which was accompanied by decreased survival. In the mammary fat pad, tumors grew more rapidly with unchanged blood vessel formation. Tumor growth in the bone was also more rapid, and osteoclasts were increased. AM peptide potently stimulated bone cultures ex vivo; responses that were blocked by small-molecule adrenomedullin antagonists in the absence of cellular toxicity. Antagonist treatment dramatically suppressed tumor growth in bone and decreased markers of osteoclast activity. The results identify AM as a target for therapeutic intervention against bone metastases. Adrenomedullin potentiates osteolytic responses in bone to metastatic breast cancer cells. Small-molecule antagonists can effectively block bone-mediated responses to tumor-secreted adrenomedullin, and such agents warrant development for testing in vivo. The online version of this article (doi:10.1186/s13058-014-0458-y) contains supplementary material, which is available to authorized users.
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