Bolt Alicia M, Sabourin Valérie, Molina Manuel Flores, Police Alice M, Negro Silva Luis Fernando, Plourde Dany, Lemaire Maryse, Ursini-Siegel Josie, Mann Koren K
*Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada, H3T 1E2, Department of Oncology, McGill University, Montréal, Québec, Canada, H2W 1S6, Pacific Breast Care Center, Costa Mesa, California, 92627, Division of Surgical Oncology, University of California, Irvine School of Medicine, Irvine, California, 92627; and Division of Experimental Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3 *Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada, H3T 1E2, Department of Oncology, McGill University, Montréal, Québec, Canada, H2W 1S6, Pacific Breast Care Center, Costa Mesa, California, 92627, Division of Surgical Oncology, University of California, Irvine School of Medicine, Irvine, California, 92627; and Division of Experimental Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3.
*Lady Davis Institute for Medical Research, McGill University, Montréal, Québec, Canada, H3T 1E2, Department of Oncology, McGill University, Montréal, Québec, Canada, H2W 1S6, Pacific Breast Care Center, Costa Mesa, California, 92627, Division of Surgical Oncology, University of California, Irvine School of Medicine, Irvine, California, 92627; and Division of Experimental Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3.
Toxicol Sci. 2015 Jan;143(1):165-77. doi: 10.1093/toxsci/kfu219. Epub 2014 Oct 15.
The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients' years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans.
接触高剂量钨的个体数量正在增加，但人们对其潜在的人类健康风险知之甚少。最近，一组乳腺癌患者在术中放疗期间对一种钨基防护罩进行测试后，乳房中残留了钨。在监测这些患者血液和尿液中的钨水平时，我们利用66Cl4细胞模型，在体外和小鼠体内研究钨暴露对乳腺肿瘤生长和转移的影响。我们仍然在患者术后数年的尿液中检测到钨（术后至少20个月的平均尿钨浓度=1.76纳克/毫升），即使是那些选择了乳房切除术的患者，这表明钨不会残留在乳房中。此外，标准的螯合疗法在动员钨方面无效。在小鼠模型中，钨略微延迟了原发性肿瘤的生长，但显著增强了肺转移。在体外，钨没有增强66Cl4的增殖或侵袭，这表明钨不是直接作用于66Cl4原发性肿瘤细胞以增强侵袭。相反，钨改变了肿瘤微环境，增强了已知对细胞侵袭和转移很重要的参数，包括活化的成纤维细胞、基质金属蛋白酶和髓源性抑制细胞。我们首次表明，钨通过靶向微环境增强了乳腺癌动物模型中的转移。重要的是，所有这些肿瘤微环境变化都与人类的不良预后相关。
