title: Tungsten targets the tumor microenvironment to enhance breast cancer metastasis.
abstract: 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.
authors.affiliation: *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.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Bolt
authors.affiliation: *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.
authors.forename: Valérie
authors.initials: V
authors.lastname: Sabourin
authors.affiliation: *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.
authors.forename: Manuel Flores
authors.initials: MF
authors.lastname: Molina
authors.affiliation: *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.
authors.forename: Alice M
authors.initials: AM
authors.lastname: Police
authors.affiliation: *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.
authors.forename: Luis Fernando
authors.initials: LF
authors.lastname: Negro Silva
authors.affiliation: *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.
authors.forename: Dany
authors.initials: D
authors.lastname: Plourde
authors.affiliation: *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.
authors.forename: Maryse
authors.initials: M
authors.lastname: Lemaire
authors.affiliation: *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.
authors.forename: Josie
authors.initials: J
authors.lastname: Ursini-Siegel
authors.affiliation: *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 koren.mann@mcgill.ca.
authors.forename: Koren K
authors.initials: KK
authors.lastname: Mann
mesh_terms: D000818:Animals; D001706:Biopsy; D001822:Body Burden; D001943:Breast Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology* / Q000652:urine; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000627:therapeutic use; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000097:blood / Q000378:metabolism / Q000556:secondary* / Q000652:urine; D008327:Mammography; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D059016:Tumor Microenvironment; D017973:Tungsten Compounds / Q000097:blood / Q000633:toxicity* / Q000652:urine
chemical_list: D002614:Chelating Agents; D018836:Inflammation Mediators; D017973:Tungsten Compounds; C025399:sodium tungstate(VI)
keywords: breast cancer; metastasis; tumor microenvironment; tungsten