Prostatic chronic inflammation and prostate cancer risk at baseline random biopsy: Analysis of predictors

Tafuri, Alessandro; Sebben, Marco; Novella, Giovanni; Pirozzi, Marco; Processali, Tania; Shakir, Aliasger; Rizzetto, Riccardo; Amigoni, Nelia; Bernasconi, Riccardo; Brunelli, Matteo; Cerruto, Maria Angela; Siracusano, Salvatore; Antonelli, Alessandro; Artibani, Walter; Porcaro, Antonio Benito

doi:10.1080/2090598x.2020.1757335

Cited by 4 publications

(3 citation statements)

References 34 publications

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“…Acute inflammation is associated with a low risk of PCa development [ 57 ], which is in line the acute IL-1 cytotoxicity observed for LNCaP cells. But the clinical significance of chronic inflammation is unresolved, with studies showing association with increased [ 58 – 60 ] or, conversely, reduced PCa incidence [ 57 , 61 ]. Irrespective, we show that, mechanistically, IL-1 can promote aggressive PCa phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence

Dahl¹,

Kanchwala²,

Thomas‐Jardin³

et al. 2020

PLoS ONE

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Chronic inflammation promotes prostate cancer (PCa) initiation and progression. We previously reported that acute intereluekin-1 (IL-1) exposure represses androgen receptor (AR) accumulation and activity, providing a possible mechanism for IL-1-mediated development of androgen- and AR-independent PCa. Given that acute inflammation is quickly resolved, and chronic inflammation is, instead, co-opted by cancer cells to promote tumorigenicity, we set out to determine if chronic IL-1 exposure leads to similar repression of AR and AR activity observed for acute IL-1 exposure and to determine if chronic IL-1 exposure selects for androgen- and AR-independent PCa cells. We generated isogenic sublines from LNCaP cells chronically exposed to IL-1α or IL-1β. Cells were treated with IL-1α, IL-1β, TNFα or HS-5 bone marrow stromal cells conditioned medium to assess cell viability in the presence of cytotoxic inflammatory cytokines. Cell viability was also assessed following serum starvation, AR siRNA silencing and enzalutamide treatment. Finally, RNA sequencing was performed for the IL-1 sublines. MTT, RT-qPCR and western blot analysis show that the sublines evolved resistance to inflammation-induced cytotoxicity and intracellular signaling and evolved reduced sensitivity to siRNA-mediated loss of AR, serum deprivation and enzalutamide. Differential gene expression reveals that canonical AR signaling is aberrant in the IL-1 sublines, where the cells show constitutive PSA repression and basally high KLK2 and NKX3.1 mRNA levels and bioinformatics analysis predicts that pro-survival and pro-tumorigenic pathways are activated in the sublines. Our data provide evidence that chronic IL-1 exposure promotes PCa cell androgen and AR independence and, thus, supports CRPCa development.

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Section: Discussionmentioning

confidence: 99%

Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence

Dahl¹,

Kanchwala²,

Thomas‐Jardin³

et al. 2020

PLoS ONE

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show abstract

“…Acute inflammation is associated with a low risk of PCa development[57], which is in line the acute IL-1 cytotoxicity observed for LNCaP cells. But the clinical significance of chronic inflammation is unresolved, with studies showing association with increased[58–60] or, conversely, reduced PCa incidence[57, 61]. Irrespective, we show that, mechanistically, IL-1 can promote aggressive PCa phenotypes.…”

Section: Resultsmentioning

confidence: 59%

Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence

Dahl¹,

Kanchwala

Thomas‐Jardin³

et al. 2020

Preprint

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TX 75390RUNNING TITLE: Chronic IL-1 promotes androgen and AR independence CORRESPONDING AUTHOR: Nikki A. ABSTRACT:Background: Chronic inflammation is a known cause of prostate cancer (PCa) initiation and progression. Interleukin-1 (IL-1) is an inflammatory cytokine secreted by tumor cells and bonederived immune cells that contributes to chronic inflammation in the tumor microenvironment. IL-1 is elevated in PCa patients and contributes to PCa progression and treatment resistance. IL-1 has been shown to promote PCa metastasis and bone colonization, shown to recruit mesenchymal stems cells to the tumor to support castration-resistant PCa (CRPCa) development and chronic IL-1 exposure was shown to promote PCa anti-androgen resistance. We previously reported that acute IL-1 exposure represses androgen receptor (AR) accumulation and activity, providing a possible mechanism for IL-1-mediated development of androgen-and ARindependent PCa. Given that acute inflammation is quickly resolved, and chronic inflammation is, instead, co-opted by cancer cells to promote tumorigenicity, we set out to determine if chronic IL-1 exposure leads to similar repression of AR and AR activity observed for acute IL-1 exposure and to determine if chronic IL-1 exposure selects for androgen-and AR-independent PCa cells. Methods:We isolated isogenic LNCaP sublines from LNCaP cells chronically exposed for 3-4 months to IL-1α or IL-1β. LNCaP and the IL-1 sublines were treated with IL-1α, IL-1β, TNFα or conditioned medium from the HS-5 bone marrow stromal cell line to assess cell viability in the presence of cytotoxic inflammatory cytokines. Cell viability was also assessed following serum starvation, AR siRNA silencing and treatment with the anti-androgen, enzalutamide. RNA sequencing and bioinformatics analysis were also performed for the IL-1 sublines.Results: MTT, RT-qPCR and western blot analysis show that the sublines evolved resistance to inflammation-induced cytotoxicity and intracellular signaling and evolved reduced sensitivity to siRNA-mediated loss of AR, serum deprivation and enzalutamide. Furthermore, differential gene expression reveals that canonical AR signaling is aberrant in the IL-1 sublines, where the cells show constitutive PSA repression and basally high KLK2 and NKX3.1 mRNA levels and bioinformatics analysis predicts that pro-survival and pro-tumorigenic pathways are activated in the sublines. Conclusions:Our data provide evidence that chronic IL-1 exposure promotes PCa cell androgen and AR independence and, thus, supports CRPCa development.

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“…For many years, chronic inflammation has been suspected of playing a major role in the pathogenesis of cancer [21]. However, this relationship remains unclear and controversial with respect to PCa.…”

Section: Discussionmentioning

confidence: 99%

Inflammation and Prostate Cancer: Pathological Analysis from Pros-IT CNR 2

Sessa

Nicoletti²,

Nunzio³

et al. 2023

Cancers

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Background: Extensive research effort has been devoted to investigating the link between inflammation and PCa. However, this relationship remains unclear and controversial. The aim of our multi-center study was to investigate this association by histologically evaluating the distribution of PI and PCA in prostate biopsy cores from patients of eight referral centers in Italy. Results: We evaluated 2220 cores from 197 patients; all the frustules were re-evaluated by dedicated pathologists retrospectively. Pathologists assigned IRANI scores and determined the positions of PIs; pathologists also re-evaluated the presence of PCa and relative ISUP grade. PCa was recorded in 749/2220 (33.7%). We divided this sample into a PCa PI group (634/749 cores [84.7%]) and a non-PCa + PI group (1157/1471 cores [78.7%]). We observed a statistically significant difference in the presence of inflammation among cores with cancer (p < 0.01). Moreover, periglandular inflammation was higher in the cores with neoplasia, while stromal inflammation was higher in cores without neoplasia (38.5% vs. 31.1% and 55.4% vs. 63.5% p < 0.01). Conclusions: In our experience, there is evidence of an association between PI and PCa at a tissue level. Further studies are needed to confirm our findings and to identify patients who might benefit from target therapies to prevent PCa occurrence and/or progression.

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Prostatic chronic inflammation and prostate cancer risk at baseline random biopsy: Analysis of predictors

Cited by 4 publications

References 34 publications

Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence

Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence

Chronic IL-1 exposure drives LNCaP cells to evolve androgen and AR independence

Inflammation and Prostate Cancer: Pathological Analysis from Pros-IT CNR 2

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