The Effects of Inorganic Arsenic Exposure on the Tumor Microenvironment

Joseph Justin Shearer, Purdue University

Abstract

Prostate cancer (PCa) remains the second most common form of cancer in men in the United States with over 160,000 new cases a year. Unfortunately, PCa also remains one of the deadliest forms of cancer, with nearly 27,000 yearly deaths in the United States alone. Much of this is due to the lack of effective treatment options due to the complex disease progression associated with PCa. This is why elucidating the mechanisms associated with PCa risk factors may have a greater therapeutic effect by unraveling the etiology of the disease. Inorganic arsenic (iAs) represents one of those risk factors that has been shown to be associated with PCa through both epidemiological and experimental models. This is concerning, considering that over 200 million people worldwide are exposed to high levels of iAs daily in their drinking water. Many of the proposed mechanisms behind the association of PCa and iAs have remained tumor-cell centric, while the effects on tumor microenvironment (TME) have largely remained unexplored. This is why we hypothesized that exposure to iAs might affect the enriched stromal cell population adipose-derived mesenchymal stem/stromal cells (ASCs), creating a TME that is conducive for the progression of PCa. Our results have shown that in vitro exposure to 75 ppb iAs for one week is enough to shift the secretome of human ASC from antiproliferative to proliferative when applied to PCa cells. We identified a range of cytokines altered in a concentration-dependent manner and through proteomic analysis we identified a potential novel mechanism for iAs-induced downregulation of transforming growth factor beta (TGFβ) activation through a heme oxygenase/thrombospondin axis. In vivo our results have shown exposure to iAs can alter the ability of ASCs to induce differentiation-specific gene expression when isolated and differentiated ex vivo. These changes in gene expression may be through a TGFβ-mediated mechanism as TGFβ mRNA levels emulated those observed in differentiation-specific genes. Using an in vivo PCa model, we observed that commixing ASCs with PCa cells increased tumor size after 26 days but this effect was not observed in mice exposed to iAs. Finally, we identified the effects that iAs exposure can have on ASC-mediated recruitment of myeloid-derived suppressor cells, macrophages, and CD4+ cells into the prostate TME, whose recruitment may be initiated by changes in interferon gamma expression seen in PCa tumors commixed with ASCs. What our results suggest is that stromal cell populations, such as ASCs, are susceptible to environmental exposures and cause a range of effects on the ASCs themselves and also alter the cell-cell communication within the TME. These results are important moving forward for recognizing that tumor progression is not only mediated through the malignant epithelial cells but also through a complex cell-cell crosstalk network that is also affected by environmental exposures. Future work can utilize this information in order to begin developing stromal-based cancer interventions that can reverse the effects of environmental exposures and restore the TME to a homeostatic state.

Degree

Ph.D.

Advisors

Figueiredo, Purdue University.

Subject Area

Toxicology

COinS