Tungsten and Breast Cancer: Impact of the Tumor Microenvironment

项目总结/摘要 钨是一种新兴的有毒物质，由于人类接触的增加，但对人类的认识有限。 健康风险。一个很大的研究差距是我们缺乏对钨的致癌/致瘤风险的了解 exposure.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，在这方面， 需要更多的研究来确定钨的暴露形式和途径可以驱动肿瘤发生 以及潜在的细胞/分子作用机制。乳腺癌患者的意外暴露 对钨进行实验性放疗后，促使我们探讨钨对乳腺的作用 癌症进展和转移，通过使用侵袭性原位乳房植入体进行动物研究， 癌症小鼠模型。口服钨酸盐暴露增强了乳腺癌向肺的转移， 在转移部位生长。有趣的是，钨增强的转移与增强的 肿瘤微环境中的基质，重要的是，已知癌症相关成纤维细胞（CAF） 推动肿瘤进展。我们的研究首次确定了一种潜在的细胞作用机制， 钨增强的肿瘤促进。然而，CAFs在这一复杂过程中发挥的作用仍有待于进一步研究。 被阐明。该提案将使用一种新颖的综合方法来调查钨何时以及如何 靶向肿瘤微环境以促进乳腺癌。目的1我将评估如何不同形式的 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开始到转移的进展。我会把我最初的 研究结果确定不同形式的钨如何改变乳腺癌的发展，生长和转移 多个部位包括肺肝骨和脑目标2，我将测量CAF激活后钨 体外暴露。我将回答以下问题。钨能增强间质细胞CAF的激活吗 前兆？钨暴露的CAFs是否会增强肿瘤细胞的侵袭、生长和免疫细胞的募集？ 并且，钨改变肿瘤细胞的线索，以增强CAF激活和/或招聘？最后，在AIM 3中， 测试钨改变的CAF在体内模型中增强转移的影响。我会决定 钨改变的CAF通过回答以下问题促进肺小生境中的转移和生长。 肺龛中钨增强CAF的来源是什么？从钨的肺龛里做咖啡因- 暴露的荷瘤小鼠具有改变的细胞因子/趋化因子谱？而且，CAFs是 钨增强的肺转移完成本提案将扩展我们的毒理学知识， 钨，以确定不同形式的钨如何影响乳腺癌的进展，并定义的作用， 肿瘤微环境，特别是钨增强乳腺肿瘤发生中的CAFs。这项工作还将 确定一种新细胞作用机制，可以扩展我们对环境毒物如何 可以驱动肿瘤发生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.