Tungsten and Breast Cancer: Impact of the Tumor Microenvironment

钨与乳腺癌：肿瘤微环境的影响

• 批准号: 10629352
• 负责人: Alicia M. Bolt
• 金额: $ 25.94万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629352
• 关键词: Accidents; Address; Affect; Animals; Automobile Driving; Biology; Birth; Bone Marrow; Brain; Breast Cancer Patient; Breast cancer metastasis; Cells; Classification; Complex; Cues; Data; Development; Epidemiology; Exposure to; Fibroblasts; Growth; Growth and Development function; Health; Heavy Metals; Human; Immune; In Vitro; Industrialization; Industry; Inhalation; Intraoperative Radiation Therapy; Invaded; Investigation; Knowledge; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Mediator; Medicine; Metals; Metastatic Neoplasm to the Lung; Mining; Molecular Mechanisms of Action; Mus; Navajo; Neoplasm Metastasis; New Mexico; Operative Surgical Procedures; Oral; Play; Population; Process; Proteins; Radiation therapy; Reporting; Research; Risk; Role; Route; Site; Soil; Source; Surveys; Testing; Time; Toxic Environmental Substances; Toxicology; Tumor Cell Invasion; Tumor Promotion; Tungsten; Universities; Woman; Work; bone; breast cancer progression; breast tumorigenesis; cancer therapy; carcinogenesis; carcinogenicity; cell growth; chemokine; cohort; cytokine; exposed human population; exposure route; implantation; in vivo; in vivo Model; lung metastatic; malignant breast neoplasm; mesenchymal stromal cell; mouse model; neoplastic cell; novel; novel therapeutic intervention; pharmacologic; recruit; toxicant; tumor; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic; tungsten carbide; urinary; wasting

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.

项目概要/摘要 钨是一种新兴的有毒物质，由于人类接触钨的增加，但人类对钨的了解有限 健康风险。一大研究空白是我们对钨的致癌/致瘤风险缺乏了解 接触。重要的是，一些体内研究确实表明钨可以增强肿瘤的促进作用。然而， 需要更多的研究来确定哪些形式和途径的钨暴露可以促进肿瘤发生 以及潜在的细胞/分子作用机制。乳腺癌患者的意外暴露 实验性放射治疗后使用钨，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 癌症小鼠模型。口服钨酸盐暴露可增强乳腺癌向肺部的转移并增加 转移部位的生长。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，已知与癌症相关的成纤维细胞（CAF） 驱动肿瘤进展。我们的研究首次确定了潜在的细胞作用机制 钨增强肿瘤促进作用。然而，CAF 在这个复杂的过程中扮演什么角色仍有待了解。 予以阐明。该提案将使用一种新颖的综合方法来研究钨何时以及如何 靶向肿瘤微环境以促进乳腺癌发生。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 影响乳腺癌从起始到转移进展的微环境。我将延长我最初的 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 到达多个部位，包括肺、肝、骨和脑。 AIM 2，我将测量钨丝后的 CAF 激活 体外暴露。我将解答以下问题。钨可以增强基质中的 CAF 激活吗？ 前兆？暴露于钨的 CAF 是否会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信号以增强 CAF 激活和/或募集？最后，在 AIM 3 中我将 在体内模型中测试钨改变的 CAF 对增强转移的影响。我会确定是否 钨改变的 CAF 通过回答以下问题来促进肺微环境中的转移和生长。 肺生态位中钨增强 CAF 的来源是什么？ CAF 是否来自钨的肺生态位？ 暴露的荷瘤小鼠细胞因子/趋化因子谱发生改变？并且，CAF 是关键调解者吗？ 钨增强肺转移？完成该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进展并定义其作用 肿瘤微环境，特别是钨增强乳腺肿瘤发生中的 CAF。这部作品也将 确定一种新的细胞作用机制，可以扩展我们对环境毒物如何作用的认识 可以驱动肿瘤发生并开发新的治疗干预措施。