Per- and polyfluoroalkyl substances target and alter human prostate stem-progenitor cells

Hu, Wen‐Yang; Lu, Ranli; Hu, Dan; Imir, Ozan Berk; Zuo, Qianying; Moline, Dan; Afradiasbagharani, Parivash; Liu, Lifeng; Lowe, Scott; Birch, Lynn; Griend, Donald J. Vander; Madak-Erdoğan, Zeynep; Prins, Gail S.

doi:10.1016/j.bcp.2021.114902

Cited by 15 publications

(8 citation statements)

References 58 publications

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“…Importantly, the concept that low doses of EDCs could have a biological effect start to be well-accepted by scientists [ 34 ]. In accordance with our data, the team of Gael Prins recently showed that per- and polyfluorinated alkyl substances (PFAS) at nanomolar (10 −9 M) concentrations increase the size and the number of prostaspheres and enhance tumor growth in a xenograft model [ 35 ]. This is a main concern for regulatory agencies since these very low concentrations correspond to those to which we are routinely exposed.…”

Section: Discussionsupporting

confidence: 87%

Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways

Charazac

Hinault

Dolfi

et al. 2022

IJMS

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Endocrine Disrupting Compounds (EDCs) are found in everyday products. Widely distributed throughout the environment, persistent organic pollutants (POPs) are a specific class of EDCs that can accumulate in adipose tissue. Many of them induce adverse effects on human health—such as obesity, fertility disorders and cancers—by perturbing hormone effects. We previously identified many compounds with EDC activity in the circulation of obese patients who underwent bariatric surgery. Herein, we analyzed the effects of four of them (aldrin, BDE28, PFOA and PCB153) on two cancer cell lines of hormone-sensitive organs (prostate and breast). Each cell line was exposed to serial dilutions of EDCs from 10−6 M to 10−12 M; cytotoxicity and proliferation were monitored using the IncuCyte® technology. We showed that none of these EDCs induce cytotoxicity and that PFOA and PCB153, only at very low doses (10−12 M), increase the proliferation of DU145 (prostate cancer) and MCF7 (breast cancer) cells, while the same effects are observed with high concentrations (10−6 M) for aldrin or BDE28. Regarding the mechanistic aspects, PFOA uses two different signaling pathways between the two lines (the Akt/mTORC1 and PlexinD1 in MCF7 and DU145, respectively). Thus, our study demonstrates that even at picomolar (10−12 M) concentrations PFOA and PCB153 increase the proliferation of prostate and breast cancer cell lines and can be considered possible carcinogens.

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Section: Discussionsupporting

confidence: 87%

Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways

Charazac

Hinault

Dolfi

et al. 2022

IJMS

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“…Of note, these actions are mediated, in part, through PPARα, providing the potential for enhanced tumor promotion. We recently showed that PFOS exposure and a high-fat diet synergize to increase prostate cancer xenograft growth in mice [ 122 , 162 ]. PFOS treatment increased glucose metabolism and pyruvate production in prostate cancer cells [ 122 ].…”

Section: The Case For Prostate Cancermentioning

confidence: 99%

“…PFOS treatment increased glucose metabolism and pyruvate production in prostate cancer cells [ 122 ]. In addition, we demonstrated that an enhancement of glycine and serine metabolism and enhanced glucose metabolism, through the Warburg effect in human prostate stem-progenitor cells, took place in response to PFOA and PFOS exposures [ 162 ]. Prostate stem-progenitor cells also express PPARα and retinoid X receptor-α which mediate PFAS effects in other tissues [ 162 ].…”

Section: The Case For Prostate Cancermentioning

confidence: 99%

“…In addition, we demonstrated that an enhancement of glycine and serine metabolism and enhanced glucose metabolism, through the Warburg effect in human prostate stem-progenitor cells, took place in response to PFOA and PFOS exposures [ 162 ]. Prostate stem-progenitor cells also express PPARα and retinoid X receptor-α which mediate PFAS effects in other tissues [ 162 ]. This suggests that PFAS exposure may synergize with a high-fat diet to activate PPARα, resulting in altered cell metabolism to potentially promote tumorigenesis in normal prostate and prostate cancer cells.…”

Section: The Case For Prostate Cancermentioning

confidence: 99%

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Toward a Mechanistic Understanding of Poly- and Perfluoroalkylated Substances and Cancer

Boyd

Ahmad

Singh

et al. 2022

Cancers

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Poly- and perfluoroalkylated substances (PFAS) are chemicals that persist and bioaccumulate in the environment and are found in nearly all human populations through several routes of exposure. Human occupational and community exposure to PFAS has been associated with several cancers, including cancers of the kidney, testis, prostate, and liver. While evidence suggests that PFAS are not directly mutagenic, many diverse mechanisms of carcinogenicity have been proposed. In this mini-review, we organize these mechanisms into three major proposed pathways of PFAS action—metabolism, endocrine disruption, and epigenetic perturbation—and discuss how these distinct but interdependent pathways may explain many of the proposed pro-carcinogenic effects of the PFAS class of environmental contaminants. Notably, each of the pathways is predicted to be highly sensitive to the dose and window of exposure which may, in part, explain the variable epidemiologic and experimental evidence linking PFAS and cancer. We highlight testicular and prostate cancer as models to validate this concept.

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“…Histone 3 displays altered acetylation at lysine 4, 9, and 27 in breast cancer cells that fail to respond to ER antagonists (65)(66)(67). Systemic metabolic changes impact hormone-dependent cancer cell metabolism (41,68) and composition of histone marks (39,69), and response to therapies (19,41). Our findings suggest an altered ERα activity in MBC cells residing in the liver microenvironment, and a role for metabolic and epigenetic enzymes to interact with ER in a Fulv-dependent manner to locally change epigenetic marks, which would lead to altered response to ERα antagonists.…”

Section: Discussionmentioning

confidence: 99%

Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

Zuo

Mogol

Liu

et al. 2022

Molecular Cancer Research

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Estrogen receptor-positive (ER+) metastatic tumors contribute to nearly 70% of breast cancer-related deaths. Most patients with ER+ metastatic breast cancer (MBC) undergo treatment with the estrogen receptor antagonist fulvestrant (Fulv) as standard-of-care. Yet, among such patients, metastasis in the liver is associated with reduced overall survival compared to other metastasis sites. The factors underlying the reduced responsiveness of liver metastases to ER-targeting agents remain unknown, impeding the development of more effective treatment approaches to improve outcomes for patients with ER+ liver metastases. We therefore evaluated site-specific changes in MBC cells and determined the mechanisms through which the liver metastatic niche specifically influences ER+ tumor metabolism and drug resistance. We characterized ER activity of MBC cells both in vitro, using a novel system of tissue-specific extracellular matrix hydrogels representing the stroma of ER+ tumor metastatic sites (liver, lung and bone), and in vivo, in liver and lung metastasis mouse models. ER+ metastatic liver tumors and MBC cells grown in liver hydrogels displayed upregulated expression of glucose metabolism enzymes in response to Fulv. Furthermore, differential ERα activity, but not expression, was detected in liver hydrogels. In vivo, increased glucose metabolism led to increased glycogen deposition in liver metastatic tumors, while a fasting-mimicking diet increased efficacy of Fulv treatment to reduce the metastatic burden. Our findings identify a novel mechanism of endocrine resistance driven by the liver tumor microenvironment. Implications: These results may guide the development of dietary strategies to circumvent drug resistance in liver metastasis, with potential applicability in other metastatic diseases.

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Per- and polyfluoroalkyl substances target and alter human prostate stem-progenitor cells

Cited by 15 publications

References 58 publications

Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways

Low Doses of PFOA Promote Prostate and Breast Cancer Cells Growth through Different Pathways

Toward a Mechanistic Understanding of Poly- and Perfluoroalkylated Substances and Cancer

Targeting Metabolic Adaptations in the Breast Cancer–Liver Metastatic Niche Using Dietary Approaches to Improve Endocrine Therapy Efficacy

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