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首页> 外文学位 >The role of adrenomedullin in osteolytic breast cancer bone metastases.
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The role of adrenomedullin in osteolytic breast cancer bone metastases.

机译：肾上腺髓质素在溶骨性乳腺癌骨转移中的作用。

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摘要

The human adrenomedullin gene encodes preproadrenomedullin, which is processed into two secreted multifunctional peptides: the 52 amino acid adrenomedullin (AM) and the 20 amino acid proadrenomedullin N-terminal 20 peptide (PAMP). AM is increased by hypoxia and frequently produced by tumors, where it can stimulate angiogenesis and cell proliferation and suppress cancer cell apoptosis. Breast cancer cell lines that metastasize to bone consistently express AM mRNA. AM is also a potent stimulator of osteoblasts and bone formation, suggesting that it could play a specific role in skeletal metastases. A role of PAMP in breast cancer and bone has not been established.;We tested the role of AM in primary breast cancer and bone metastases by generating MDA-MB-231 osteolytic breast cancer clones with stable overexpression (+5-fold) or siRNA knockdown (-90%) of human AM mRNA, altering production of both AM and PAMP peptides. Clones were tested in vitro for changes in proliferation, cell cycle distribution, and expression of other tumor-secreted factors. Cells were tested for growth in the mammary fat pad (MFP) and bone metastasis mouse models.;Overexpression of AM mRNA did not significantly change cell proliferation in vitro, expression of other tumor-secreted factors, apoptosis, or cell cycle distribution. AM overexpression increased MFP tumor growth. It also increased bone metastases and decreased survival.;AM knockdown did not inhibit growth in vitro, but altered progression through the cell cycle. AM knockdown increased sensitivity to the chemotherapeutic agent taxol. It inhibited tumor establishment and growth in the MFP but not in bone; Knockdown increased tumor burden in bone and osteolytic bone destruction but did not affect survival.;The microenvironment affects the importance of AM in tumor growth. AM may function as a tumor survival factor for the initiation of tumor growth in the MFP but not in bone metastases. AM may induce bone metastases by increasing osteoblast numbers and recruitment of cells.;Small molecule AM inhibitors that inhibit AM-induced new bone formation could be developed for breast cancer treatment. Specific inhibition of AM, separate from PAMP, would reveal the potential of these inhibitors for bone metastasis treatment.
机译：人肾上腺髓质素基因编码preproadrenomedullin，其被加工成两个分泌的多功能肽：52个氨基酸的肾上腺髓质素（AM）和20个氨基酸的肾上腺髓质素N端20肽（PAMP）。缺氧会导致AM增加，并经常由肿瘤产生，在AM中它可以刺激血管生成和细胞增殖并抑制癌细胞凋亡。转移至骨骼的乳腺癌细胞系始终表达AM mRNA。 AM还是成骨细胞和骨形成的有效刺激剂，表明它可能在骨骼转移中起特定作用。尚未确定PAMP在乳腺癌和骨癌中的作用。；我们通过产生具有稳定过表达（+5倍）或siRNA的MDA-MB-231溶骨性乳腺癌克隆，测试了AM在原发性乳腺癌和骨转移中的作用。基因敲低（-90％）人类AM mRNA，改变AM和PAMP肽的产生。体外测试了克隆的增殖，细胞周期分布和其他肿瘤分泌因子表达的变化。在乳腺脂肪垫（MFP）和骨转移小鼠模型中测试了细胞的生长。AM mRNA的过表达并没有显着改变体外细胞增殖，其他肿瘤分泌因子的表达，细胞凋亡或细胞周期分布。 AM过表达增加了MFP肿瘤的生长。它也增加了骨转移并降低了存活率。AM敲低并没有抑制体外生长，但是改变了整个细胞周期的进程。 AM组合式增加了对化疗药物紫杉醇的敏感性。它抑制了MFP中的肿瘤的形成和生长，但不抑制骨骼中的肿瘤；击倒增加了骨中的肿瘤负担和溶骨性破坏，但没有影响生存。微环境影响了AM在肿瘤生长中的重要性。 AM可能在MFP中起肿瘤生长因子的作用，但在骨转移瘤中却不起作用。 AM可能通过增加成骨细胞数量和募集细胞来诱导骨转移。;可以开发出抑制AM诱导的新骨形成的小分子AM抑制剂来治疗乳腺癌。与PAMP分开对AM的特异性抑制将揭示这些抑制剂在骨转移治疗中的潜力。

著录项

  • 作者

    Siclari, Valerie Anne.;

  • 作者单位

    University of Virginia.;

  • 授予单位 University of Virginia.;
  • 学科 Biology Molecular.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 205 p.
  • 总页数 205
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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