Inorganic Arsenic-Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell-Conditioned Media Model

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Inorganic Arsenic-Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell-Conditioned Media Model. / Shearer, Joseph J; Wold, Eric A; Umbaugh, Charles S; Lichti, Cheryl F; Nilsson, Carol; Figueiredo, Marxa L.

In: Environmental Health Perspectives, Vol. 124, No. 7, 07.2016, p. 1009-15.

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Shearer, Joseph J ; Wold, Eric A ; Umbaugh, Charles S ; Lichti, Cheryl F ; Nilsson, Carol ; Figueiredo, Marxa L. / Inorganic Arsenic-Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell-Conditioned Media Model. In: Environmental Health Perspectives. 2016 ; Vol. 124, No. 7. pp. 1009-15.

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TY - JOUR

T1 - Inorganic Arsenic-Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell-Conditioned Media Model

AU - Shearer, Joseph J

AU - Wold, Eric A

AU - Umbaugh, Charles S

AU - Lichti, Cheryl F

AU - Nilsson, Carol

AU - Figueiredo, Marxa L

PY - 2016/7

Y1 - 2016/7

N2 - BACKGROUND: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal-epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer.OBJECTIVE: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs).RESULTS: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure.CONCLUSIONS: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications.CITATION: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL, Figueiredo ML. 2016. Inorganic arsenic-related changes in the stromal tumor microenvironment in a prostate cancer cell-conditioned media model. Environ Health Perspect 124:1009-1015; http://dx.doi.org/10.1289/ehp.1510090.

AB - BACKGROUND: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal-epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer.OBJECTIVE: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs).RESULTS: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure.CONCLUSIONS: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications.CITATION: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL, Figueiredo ML. 2016. Inorganic arsenic-related changes in the stromal tumor microenvironment in a prostate cancer cell-conditioned media model. Environ Health Perspect 124:1009-1015; http://dx.doi.org/10.1289/ehp.1510090.

KW - Journal Article

U2 - 10.1289/ehp.1510090

DO - 10.1289/ehp.1510090

M3 - Article

VL - 124

SP - 1009

EP - 1015

JO - EHP Toxicogenomics

T2 - EHP Toxicogenomics

JF - EHP Toxicogenomics

SN - 1552-9924

IS - 7

ER -