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Mitochondrial genetics and cellular metabolism regulate tumorigenicity and metastatic potential.

机译：线粒体遗传学和细胞代谢调节致瘤性和转移潜力。

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摘要

Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors combine to influence an individual's predilection for breast cancer and related metastatic tumor formation. The genetic component, in particular, has become the focus of many emergent studies. A renewed focus on cancer metabolism and the Warburg effect has similarly cast a spotlight on the role, if any, of the mitochondrion in directing disease progression. Analysis of the direct contribution of mitochondrial DNA on tumorigenicity is made possible through the use of mitochondrial-nuclear exchange (MNX) mice in which nuclei from normal FVB mice (the background strain of the tg: MMTV-PyMT) were transferred onto cytoplasms containing C57BL/6 or BALB/c mitochondria. Crossing male FVB:tg:MMTV:PyMT mice with FVB(nDNA)C57BL/6(mtDNA) or FVB(nDNA)BALB/c(mtDNA) females maintained nuclear FVB nDNA and takes advantage of maternal inheritance of mtDNA. These PyMT transgene positive female progeny were then scored for primary tumor onset and pulmonary metastatic density. Present data indicate primary tumor latency segregating by mitochondrial DNA as PyMT-FVB wild-type animals develop primary tumors in 57 days compared to PyMT-FVB n:C57mt which develop primary tumors in 65 days and PyMT-FVBn:BALBcmt animals having detectable tumors in 53 days. One group of animals were aged 40 days following primary tumor detection and a second group were sacrificed when aged to 70 days, allowing for evaluation of metastatic severity and confirmation of differential primary tumor growth, respectively. This work hypothesizes that the pre-existent "normal" mitochondrial haplotype harbored by an individual conveys risk in determining tumor latency and metastatic susceptibility. Furthermore, these changes in susceptibility will be accompanied by altered mitochondrial functional characteristics that can be attributed to differences in mitochondrial haplotype. To address those mitochondrial differences, primary mammary epithelial cells were isolated from resected tumors which were then assessed for Complex I and Complex IV activity. In addition, isolated mammary epithelial cells from tumor and healthy animals had bioenergetic profiles generated using the Seahorse XF24 analyzer. MNX crosses additionally suggest that cross-talk between mtDNA and nDNA has a greater influence on metastasis than previously appreciated and that mtDNA may be used clinically to improve patient prognosis.
机译：当前的致癌风险范例表明，遗传，激素和环境因素共同影响个人对乳腺癌的偏爱以及相关的转移性肿瘤形成。尤其是遗传成分已成为许多新兴研究的重点。对癌症新陈代谢和Warburg效应的重新关注也同样关注线粒体在指导疾病进展中的作用（如果有的话）。通过使用线粒体-核交换（MNX）小鼠来分析线粒体DNA对致瘤性的直接贡献，其中正常FVB小鼠（tg的背景菌株：MMTV-PyMT）的核被转移到含有C57BL的细胞质中/ 6或BALB / c线粒体。将具有FVB（nDNA）C57BL / 6（mtDNA）或FVB（nDNA）BALB / c（mtDNA）的雌性FVB：tg：MMTV：PyMT雄性小鼠杂交，保持了FVB nDNA核并利用了mtDNA的母体遗传优势。然后对这些PyMT转基因阳性女性子代进行原发肿瘤发作和肺转移密度评分。目前的数据表明，与PyMT-FVB n：C57mt在65天内发展为原发肿瘤的PyMT-FVB n：C57mt和PyMT-FVBn：BALBcmt动物在可检测到的肿瘤中相比，PyMT-FVB野生型动物在57天内发展为原发性肿瘤时，线粒体DNA隔离了原发肿瘤潜伏期53天。一组动物在发现原发肿瘤后40天成年，第二组在衰老至70天时被处死，从而分别评估转移的严重程度并确认原发性肿瘤的不同生长。这项工作假设个体所携带的先前存在的“正常”线粒体单倍型在确定肿瘤潜伏期和转移敏感性方面具有风险。此外，这些敏感性的改变将伴随着线粒体功能特征的改变，这可以归因于线粒体单倍型的差异。为了解决这些线粒体差异，从切除的肿瘤中分离出原代乳腺上皮细胞，然后评估其复合物I和复合物IV的活性。另外，从肿瘤和健康动物中分离出的乳腺上皮细胞具有使用Seahorse XF24分析仪生成的生物能谱。 MNX交叉还表明，mtDNA和nDNA之间的串扰对转移的影响要比以前认为的要大，并且mtDNA可以在临床上用于改善患者的预后。

著录项

  • 作者

    Feeley, Kyle P.;

  • 作者单位

    The University of Alabama at Birmingham.;

  • 授予单位 The University of Alabama at Birmingham.;
  • 学科 Oncology.;Cellular biology.;Biochemistry.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 134 p.
  • 总页数 134
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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