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首页> 外文学位 >Acquisition of neuronal traits in breast cancer cells demonstrates tumor cell plasticity during metastatic colonization.
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Acquisition of neuronal traits in breast cancer cells demonstrates tumor cell plasticity during metastatic colonization.

机译：乳腺癌细胞中神经元性状的获得证明肿瘤细胞在转移定植过程中具有可塑性。

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摘要

Metastatic spread to the bone is the most common cause of mortality amongst breast cancer patients. Metastasis is a complex multi-step process whereby tumor cells invade the basement membrane of primary tissue (mammary gland), enter the circulation by traversing the vascular endothelium, and finally extravasate the circulatory system to colonize a site with permissive microenvironment, such as the bone marrow (BM). Tumor cell dissemination and invasion can occur as early as the premalignant phase of mammary tumorigenesis, thus highlighting metastasis as an early event and further emphasizing the necessity to identify the molecular events leading to tumor metastasis.;The purpose of this study was to identify the molecular events responsible for tumor metastasis and determine the factors that provide metastatic efficiency to tumor cells. We developed a novel three-dimensional in vitro reconstructed metastasis (rMet) model that incorporates extracellular matrix (ECM) elements characteristic of the primary (breast, prostate or lung) and metastatic (bone marrow, BM) sites. A cytokine-rich liquid interphase separates the primary and distant sites recapitulating circulation. Similar to main events underlying the metastatic cascade, the rMet model fractionated human tumor cell lines into sub-populations with distinct invasive and migratory abilities: 1) a primary tumor-like fraction mainly consisting of non-migratory spheroids; 2) an invasive fraction that invaded through the primary tumor ECM, but failed to acquire anchorage-independence and reach the BM; and 3) a highly migratory BM-colonizing population that invaded the primary ECM, survived in the `circulation-like' media, and successfully invaded and proliferated within BM ECM. BM-colonizing fractions successfully established metastatic lesions in vivo, whereas the tumor-like spheroids were latent in forming metastatic lesions, showing the ability of rMet model to faithfully select for highly aggressive sub-populations with a propensity to colonize a metastatic site. We validated the specificity of the rMet model to study metastasis by using various human breast cancer (MCF7, MDA-MB-231, MDA-MB-231-BO, MCF10CA1a), prostate cancer (LNCaP, PC3) and lung cancer (A549) cell lines in the rMet model. Metastatic MDA-MB-231, MDA-MB-231-BO, PC3, and A549 cells colonized the BM successfully whereas non-metastatic MCF7 and LNCaP cells failed to colonize the BM. Using MCF10CA1a and MCF10AneoT cells, we established a distinct pro-metastatic gene signature for invasive and BM-colonizing cells. The gene signature comprises cell adhesion molecules, ECM remodeling enzymes, stem cell signaling proteins, growth factors, and chemokines.;We studied morphologic and phenotypic changes in breast cancer cells during distinct stages of metastasis, a phenomenon also known as tumor cell plasticity. MCF10CA1a breast cancer cells underwent partial epithelial-mesenchymal transitions, as evident from reduced expression of E-cadherin (epithelial) and vimentin (mesenchymal) in the BM-colonizing fraction, and an increased expression of N-cadherin (mesenchymal) in the BM-colonizing fraction. We also found a sub-population within BM-colonizing cells with a morphology, resembling neurons, rather than epithelial or mesenchymal cells, suggesting morphologic plasticity of cells during metastatic colonization. A subset of BM-colonizing cells was also positive for GAP-43 (growth associated protein), NCAM (neural cell adhesion molecule), microtubule associated proteins MAPT (Tau), and MAP1b, all of which are known to play a role in neuronal migration. Using PCR arrays, we showed that genes with a role in neuronal migration, neuron-specific functions such as axonogenesis, and neuron projection development were upregulated in the BM-colonizing fraction. Some examples of upregulated genes included brain derived neurotrophic factor, netrin1, tenascin R, neuronal-glial related cell adhesion molecule, and pleiotrophin, further reflective of the ability of metastatic cells to hijack mechanisms to gain a survival advantage during metastatic colonization. Our study shows that the rMet model recapitulates the complexity of metastatic disease and hence, is a robust system to study metastatic colonization. Identification of novel features of phenotypic and morphologic plasticity during metastasis provides insights into mechanisms and cellular features governing metastatic efficiency to cancer cells and also suggests molecular targets for development of anti-metastatic strategies in the future.
机译：转移至骨骼的转移是乳腺癌患者中最常见的死亡原因。转移是一个复杂的多步骤过程，肿瘤细胞会侵入原始组织（乳腺）的基底膜，并穿过血管内皮进入循环系统，最后渗入循环系统，从而在具有允许的微环境的部位（例如骨骼）上定植。骨髓（BM）。肿瘤细胞的扩散和侵袭可早在乳腺肿瘤发生的癌变前期发生，因此强调转移是早期事件，并进一步强调了鉴定导致肿瘤转移的分子事件的必要性。导致肿瘤转移的事件，并确定为肿瘤细胞提供转移效率的因素。我们开发了一种新型的三维体外重建转移（rMet）模型，该模型结合了主要（乳腺，前列腺或肺）和转移性（骨髓，BM）部位的细胞外基质（ECM）元素。富含细胞因子的液体中间相将主要部位和远端部位分开，从而概括了循环。与转移级联反应的主要事件相似，rMet模型将人类肿瘤细胞系分为具有不同侵袭和迁移能力的亚群：1）主要由非迁移性球体组成的原发性肿瘤样组分； 2）通过原发性肿瘤ECM侵入但未获得锚固独立性并达到BM的侵入性部分； 3）高度迁徙的BM殖民化人口入侵了主要的ECM，在“循环样”媒介中幸存下来，并成功地在BM ECM内入侵和扩散。 BM定殖部分成功地在体内建立了转移灶，而肿瘤样球体则潜在地形成了转移灶，这表明rMet模型能够忠实地选择高度侵袭性亚群并倾向于定居转移位点。我们通过使用各种人类乳腺癌（MCF7，MDA-MB-231，MDA-MB-231-BO，MCF10CA1a），前列腺癌（LNCaP，PC3）和肺癌（A549）验证了rMet模型用于研究转移的特异性rMet模型中的细胞系。转移性MDA-MB-231，MDA-MB-231-BO，PC3和A549细胞成功地定居于BM，而非转移MCF7和LNCaP细胞未能定居于BM。使用MCF10CA1a和MCF10AneoT细胞，我们为侵袭性和BM殖民化细胞建立了独特的促转移基因标记。基因标记包括细胞粘附分子，ECM重塑酶，干细胞信号蛋白，生长因子和趋化因子。我们研究了在转移的不同阶段乳腺癌细胞的形态和表型变化，这种现象也称为肿瘤细胞可塑性。 MCF10CA1a乳腺癌细胞经历了部分上皮-间充质转化，这从BM殖民化部分中E-钙黏着蛋白（上皮）和波形蛋白（间质）的表达降低，以及BM-定殖部分。我们还发现BM殖民化细胞内的亚群具有类似于神经元的形态，而不是上皮或间充质细胞，这表明在转移定居过程中细胞的形态可塑性。 BM殖民化细胞的子集也对GAP-43（生长相关蛋白），NCAM（神经细胞粘附分子），微管相关蛋白MAPT（Tau）和MAP1b呈阳性，所有这些均在神经元中起作用移民。使用PCR阵列，我们表明在BM殖民化部分中，与神经元迁移，神经元特定功能（如轴突生成）和神经元投射发育有关的基因被上调。上调基因的一些例子包括脑源性神经营养因子，netrin1，tenascin R，神经胶质相关的细胞粘附分子和多卵磷脂，进一步反映了转移细胞劫持转移性定植过程中获得生存优势的机制的能力。我们的研究表明，rMet模型概括了转移性疾病的复杂性，因此是研究转移性定殖的强大系统。鉴定转移过程中的表型和形态可塑性的新特征，可提供有关控制癌细胞转移效率的机制和细胞特征的见解，并为将来开发抗转移策略提供分子靶标。

著录项

  • 作者

    Parikh, Mukti R.;

  • 作者单位

    Purdue University.;

  • 授予单位 Purdue University.;
  • 学科 Biology Cell.;Biology Systematic.;Health Sciences Oncology.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 224 p.
  • 总页数 224
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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