Tungsten targets the tumor microenvironment to enhance breast cancer metastasis.

Tungsten is a naturally occurring transition metal that has many desirable characteristics including strength and flexibility. In the general population, individuals can be exposed to trace amounts of tungsten in food, drinking water, and air. Until recently, tungsten was thought to be an “inert” metal having low toxicity, which has led to its incorporation into a wide range of industrial goods and medical devices (Keith et al., 2007). Increased use of tungsten has resulted in increased contamination of air, soil, and water, especially near active tungsten mines or industrial sites. Due to this increase in contamination, the number of individuals exposed to high levels of tungsten is on the rise. A unique population at risk of tungsten exposure includes patients exposed to implanted medical devices containing tungsten. During a clinical trial in 2011, breast cancer patients were exposed to tungsten from a tungsten-based shield that was placed internally during intraoperative radiotherapy (clinicaltrials.gov: NCT01189851). The shield left residual tungsten particles in patient’s breast tissue, which increased the tungsten exposure levels in these women. These recent exposures to high levels of tungsten have raised public awareness and concern, regarding the lack of information of the potential toxic effects of tungsten exposure and long-term human health risks. In fact, the Environmental Protection Agency (EPA) classified tungsten as an emerging contaminant that warrants further toxicological investigation (EPA, 2008). Currently, very little is known regarding the potential carcinogenic effects of tungsten. Although epidemiological data are lacking, in vitro and in vivo studies provide evidence that tungsten may contribute to cancer progression. Tungsten-containing alloys are genotoxic in vitro (Anard et al., 1997) and have the ability to transform an osteoblast cell line (Miller et al., 2001). When tungsten alloy-based bullets were implanted in rats to test the effects of embedded ammunition shrapnel in wounded soldiers, 100% of the rats developed rhabdomyosarcoma (Kalinich et al., 2005). One limitation of these studies is that the alloys used contained not only tungsten, but also other metals, such as nickel and cobalt, which are also known carcinogens (Beyersmann and Hartwig, 2008). The individual contribution of tungsten in these experiments is not known. However, tungsten alone increased the incidence of cancer in rats using a mutagen-induced cancer model, providing evidence that tungsten may act as a tumor promoter (Wei et al., 1985). In addition, we have determined that tungsten can induce DNA damage and increase the clonogenic ability of B cells in the bone marrow (Kelly et al., 2012). We are currently monitoring this unique cohort of breast cancer patients accidently exposed to tungsten. However, given the limited data investigating the role of tungsten on cancer progression and metastasis, it is impossible to predict the potential effects of tungsten exposure, particularly in regards to their risk of recurrence or metastases. Thus, in this study, we investigated the role of tungsten on breast cancer progression and metastasis using a preclinical mouse model and provide the first experimental evidence that tungsten exposure can significantly enhance the lung metastatic potential of breast cancer cells in mice by stimulating a protumorigenic inflammatory microenvironment in the metastatic niche.