Tungsten and Breast Cancer: Impact of the Tumor Microenvironment

项目摘要/摘要 钨是一种新兴的毒物，由于人类接触的增加，但对人类的了解有限 健康风险。一个很大的研究缺口是我们对钨的致癌/致癌风险缺乏了解 曝光。重要的是，一些体内研究确实表明，钨可以增强肿瘤促进作用。然而， 需要更多的研究来确定哪些形式和途径的钨暴露会导致肿瘤发生 以及潜在的细胞/分子作用机制。一例乳腺癌患者的意外暴露 对于实验性放射治疗后的钨，促使我们研究钨对乳房的作用 癌症进展和转移，通过使用侵袭性原位乳腺进行动物研究 肿瘤小鼠模型。口服钨酸盐可增加乳腺癌向肺的转移并增加 转移部位的生长。有趣的是，钨强化的转移与强化有关。 肿瘤微环境中的间质，重要的是癌症相关成纤维细胞(CAF)，已知 推动肿瘤的发展。我们的研究首次发现了一种潜在的细胞作用机制 钨增强的促癌作用。然而，CAF在这一复杂过程中扮演的角色仍有待于 将被澄清。这项提案将使用一种新颖的综合方法来研究钨的时间和方式 针对肿瘤微环境，促进乳腺癌的发生。目标1我将评估不同形式的 钨(口服钨酸盐、吸入碳化钨和植入钨金属碎片)靶向肿瘤。 微环境影响乳腺癌从起始到转移的进展。我将延长我的首字母 确定不同形式的钨如何改变乳腺癌的发展、生长和转移的研究结果 包括肺、肝、骨和脑在内的多个部位。目标2，我将测量钨后CaF的激活 在体外暴露。我将回答以下问题。钨能增强基质中钙激活因子的活性吗 前兆？暴露于钨的CAF是否增强肿瘤细胞的侵袭、生长和免疫细胞募集？ 而且，钨是否会改变肿瘤细胞的信号以增强CAF的激活和/或募集？最后，在AIM 3中，我将 在活体模型中测试钨改变的CAF对促进转移的影响。我会决定是否 钨改变的CAF通过回答以下问题促进肺转移和生长。 肺内钨强化CAF的来源是什么？从钨的肺脏做CAF- 暴露的荷瘤小鼠的细胞因子/趋化因子特征发生了变化？而且，CAF是关键的调解人吗 钨强化肺转移？这项提议的完成将扩大我们对 确定不同形式的钨如何影响乳腺癌的进展并确定其作用 钨增强乳腺肿瘤发生中的肿瘤微环境，尤其是CAF。这项工作还将 识别一种新的细胞作用机制，可以扩大我们对环境毒物如何 可以推动肿瘤的形成，并开发新的治疗干预措施。

Project Summary/Abstract Tungsten is an emerging toxicant, due to increased human exposure, yet limited knowledge of the human health risks. One large research gap is our lack of knowledge of the carcinogenic/tumorigenic risks of tungsten exposure. Importantly, a few in vivo studies do suggest that tungsten can enhance tumor promotion. However, more research is needed to determine which forms and routes of exposure of tungsten can drive tumorigenesis and the underlying cellular/molecular mechanisms of action. An accidental exposure of breast cancer patients to tungsten following experimental radiotherapy, prompted us to investigate the role of tungsten on breast cancer progression and metastasis, by conducting an animal study using an aggressive orthotopic mammary cancer mouse model. Oral tungstate exposure enhanced breast cancer metastasis to the lung and increased growth at the metastatic site. Interestingly, tungsten-enhanced metastasis was associated with enhanced stroma in the tumor microenvironment, importantly, cancer-associated fibroblasts (CAFs) that are known to drive tumor progression. Our research identified, for the first time, a potential cellular mechanism of action for tungsten-enhanced tumor promotion. However, what role the CAFs plays in this complex process remains to be elucidated. This proposal will use a novel, integrative approach to investigate when and how tungsten targets the tumor microenvironment to promote breast cancer. AIM 1 I will evaluate how different forms of tungsten (oral tungstate, inhaled tungsten carbide and implantation tungsten metal fragments) target the tumor microenvironment to affect breast cancer progression from initiation to metastasis. I will extend my initial findings to determine how different forms of tungsten alter breast cancer development, growth and metastasis to multiple sites including lung, liver, bone, and brain. AIM 2, I will measure CAF activation following tungsten exposure in vitro. I will address the following questions. Can tungsten enhance CAF activation from stromal precursors? Do tungsten-exposed CAFs enhance tumor cell invasion, growth, and immune cell recruitment? And, does tungsten alter tumor cell cues to enhance CAF activation and/or recruitment? Finally, in AIM 3 I will test the impact of tungsten-altered CAFs to enhance metastasis in an in vivo model. I will determine if tungsten-altered CAFs promote metastasis and growth in the lung niche by answering the following questions. What is the source of tungsten-enhanced CAFs in the lung niche? Do CAFs from the lung niche of tungsten- exposed tumor-bearing mice have an altered cytokine/chemokine profile? And, are CAFs critical mediators of tungsten-enhanced lung metastasis? Completion of this proposal will extend our toxicological knowledge of tungsten to determine how different forms of tungsten impact breast cancer progression and define the role of the tumor microenvironment, particularly CAFs in tungsten-enhanced breast tumorigenesis. This work will also identify a novel cellular mechanism of action that can expand our knowledge of how environmental toxicant can drive tumorigenesis and develop new therapeutic interventions.