Effects of Anti-repulsive Guidance Molecule C (RGMc/Hemojuvelin) Antibody on Hepcidin and Iron in Mouse Liver and Tumor Xenografts.
Effects of Anti-repulsive Guidance Molecule C (RGMc/Hemojuvelin) Antibody on Hepcidin and Iron in Mouse Liver and Tumor Xenografts.
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DOI：
10.4172/2161-1459.1000223
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发表时间：
2016-11
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影响因子：
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通讯作者：
S. Torti;E. Lemler;B. Mueller;A. Popp;F. Torti
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文献类型：
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作者：
S. Torti;E. Lemler;B. Mueller;A. Popp;F. Torti
目的：Hepcidin是一种由肝脏产生的调节全身铁稳态的肽激素。Hepcidin也可由肿瘤合成，通过增加肿瘤铁潴留来促进肿瘤生长。因此，靶向减少hepcidin可能有助于减少肿瘤生长。H5F9-AM8是一种临床前开发的抗体，用于慢性疾病贫血，通过与RGMc结合减少hepcidin的合成，RGMc是一种参与BMP6转录诱导hepcidin的共受体。我们探索了H5F9-AM8作为抗肿瘤药物的能力。方法采用qRTPCR方法，在H5F9-AM8或生理盐水处理小鼠的组织培养、肿瘤移植和肝脏中检测抗血青素抗体对hepcidin合成的影响。用卡尺测量评估肿瘤生长情况。血清铁采用比色法测定，组织铁采用western blotting和电感耦合质谱法测定。结果在组织培养中，抗haemjuvelin抗体H5F9-AM8显著降低bmp6刺激的HepG2和其他癌细胞的hepcidin合成。在小鼠中，H5F9-AM8降低了肝脏中的hepcidin，增加了血清铁、肝总铁和肝铁蛋白。虽然肿瘤中的hepcidin也显著降低，但H5F9-AM8并没有降低肿瘤中的铁含量、铁蛋白或肿瘤生长。结论抗血juvelin抗体均能降低肿瘤和肝脏中的hepcidin，但在这两个靶器官中的作用不同：降低肝脏中的铁含量和铁蛋白，但不降低肿瘤中的铁含量和铁蛋白，也不抑制肿瘤生长。这些结果表明，尽管它们能够在肿瘤中诱导hepcidin，但全身性非靶向hepcidin拮抗剂的抗肿瘤功效可能受到其同时升高血浆铁的能力的限制。可能需要肿瘤特异性hepcidin抑制剂来克服针对全身和肿瘤hepcidin合成的药物的局限性。
OBJECTIVE Hepcidin is a peptide hormone produced by the liver that regulates systemic iron homeostasis. Hepcidin is also synthesized by tumors, where it contributes to tumor growth by increasing the tumoral retention of iron. Targeted reduction of hepcidin may therefore be useful in reducing tumor growth. H5F9-AM8 is an antibody in preclinical development for the anemia of chronic disease that reduces hepcidin synthesis by binding to RGMc, a co-receptor involved in the transcriptional induction of hepcidin by BMP6. We explored the ability of H5F9-AM8 to act as an anti-tumor agent. METHODS Effects of anti-hemojuvelin antibody on hepcidin synthesis were assessed by qRTPCR in tissue culture and in tumor xenografts and livers of mice treated with H5F9-AM8 or saline. Tumor growth was assessed using caliper measurements. Serum iron was measured colorimetrically and tissue iron was measured using western blotting and inductively coupled mass spectrometry. RESULTS In tissue culture, the anti-hemojuvelin antibody H5F9-AM8 significantly reduced BMP6-stimulated hepcidin synthesis in HepG2 and other cancer cells. In mice, H5F9-AM8 reduced hepcidin in the liver and increased serum iron, total liver iron, and liver ferritin. Although hepcidin in tumors was also significantly decreased, H5F9-AM8 did not reduce tumor iron content, ferritin, or tumor growth. CONCLUSION Anti-hemojuvelin antibody successfully reduces hepcidin in both tumors and livers but has different effects in these target organs: it reduces iron content and ferritin in the liver, but does not reduce iron content or ferritin in tumors, and does not inhibit tumor growth. These results suggest that despite their ability to induce hepcidin in tumors, the anti-tumor efficacy of systemic, non-targeted hepcidin antagonists may be limited by their ability to simultaneously elevate plasma iron. Tumor-specific hepcidin inhibitors may be required to overcome the limitations of drugs that target the synthesis of both systemic and tumor hepcidin.