TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease

Vickman, Renee E.; Aaron‐Brooks, LaTayia M.; Zhang, Renyuan; Atallah, Nadia M.; Lapin, Brittany; Gil, Victoria; Greenberg, Mark; Sasaki, Takeshi; Cresswell, Gregory M.; Broman, Meaghan M.; Paez, Juan Sebastian; Petkewicz, Jacqueline; Talaty, Pooja; Helfand, Brian T.; Glaser, Alexander; Wang, Chi‐Hsiung; Franco, Omar E.; Ratliff, Timothy L.; Nastiuk, Kent L.; Crawford, Susan E.; Hayward, Simon W.

doi:10.1038/s41467-022-29719-1

Cited by 37 publications

(37 citation statements)

References 81 publications

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Section: Discussionmentioning

confidence: 99%

“…This suggests that TNF is a viable therapeutic target in men with BPH. Indeed, the incidence of BPH is reduced in men treated with anti-TNF drugs [46].…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of TNF-mediated promotion of prostatic hyperplasia is unknown, but inflammation-driven proliferation is likely [10]. We recently reported long-term (12 week) TNF signaling blockade reduced ventral prostate volume in Pb-PRL mice by diminishing epithelial cell proliferation [46]. Anti-TNF therapies reduced macrophages and NF-kB activity in both BPH patients and in non-obese diabetic (NOD) mice (which have autoimmune inflammation-associated prostatic hyperplasia).…”

Section: Discussionmentioning

confidence: 99%

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Stromal resistance to castration-induced prostate regression in a mouse model of benign prostatic hyperplasia

Zhang

Singh

Pan

et al. 2022

Preprint

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Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH. Here we examined the prostates of probasin promoter-driven prolactin (Pb-PRL) transgenic mice, a robust model of BPH that spontaneously develops prostate enlargement, to investigate prostate regression in response to surgical castration. Serial ultrasound imaging demonstrated very uniform self-limited growth of Pb-PRL prostate volume that is consistent with the benign, limited cellular proliferation characteristic of BPH and that contrasts with the highly variable, exponential growth of murine prostate cancer models. Castration elicited only a partial reduction in prostate volume, relative to castration-induced regression of the normal prostate gland. The anti-androgen finasteride induced a diminished reduction of Pb-PRL prostate volume versus castration alone. The limited extent of Pb-PRL mouse prostate volume regression correlated with the initial volume of the stromal compartment, suggesting a differential sensitivity to androgen withdrawal of the epithelial and stroma compartments. Indeed, two-dimensional morphometric analyses revealed a distinctly reduced rate of regression for the stromal compartment in Pb-PRL mice. The myofibroblast component of the Pb-PRL prostate stroma appeared normal, but contained more fibroblasts and extracellular collagen deposition. Like normal prostate, the rate of regression of the Pb-PRL prostate was partially dependent on TGF and TNF signaling, but unlike the normal prostate, the extent of castration-induced regression was not affected by TGF or TNF blockade. Our studies show that androgen deprivation can effectively reduce the overall volume of hyperplastic prostate, but the stromal compartment is relatively resistant, suggesting additional therapies might be required to offer an effective treatment for the clinical manifestations of BPH.

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Section: Discussionmentioning

confidence: 99%

“…This suggests that TNF is a viable therapeutic target in men with BPH. Indeed, the incidence of BPH is reduced in men treated with anti-TNF drugs [46].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Stromal resistance to castration-induced prostate regression in a mouse model of benign prostatic hyperplasia

Zhang

Singh

Pan

et al. 2022

Preprint

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“…In a recent study it was shown that patients with benign prostatic hyperplasia (BPH) and AI who received TNFα antagonists prior to BPH diagnosis were less likely to develop BPH [ 56 ]. Importantly, methotrexate did not have this effect, further implicating TNFα as a viable target in BPH [ 56 ]. Our RNA-seq patient data analysis implicates TNFα as a potential target in PCa.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of TNFα and IL-6 expression contributes to immune evasion in prostate cancer

et al. 2022

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Background The role of the inflammatory milieu in prostate cancer progression is not well understood. Differences in inflammatory signaling between localized and metastatic disease may point to opportunities for early intervention. Methods We modeled PCa disease progression by analyzing RNA-seq of localized vs. metastatic patient samples, followed by CIBERSORTx to assess their immune cell populations. The VHA CDW registry of PCa patients was analyzed for anti-TNF clinical outcomes. Results We observed statistically significant opposing patterns of IL-6 and TNFα expression between localized and metastatic disease. IL-6 was robustly expressed in localized disease and downregulated in metastatic disease. The reverse was observed with TNFα expression. Metastatic disease was also characterized by downregulation of adhesion molecule E-selectin, matrix metalloproteinase ADAMTS-4 and a shift to M2 macrophages whereas localized disease demonstrated a preponderance of M1 macrophages. Treatment with anti-TNF agents was associated with earlier stage disease at diagnosis. Conclusions Our data points to clearly different inflammatory contexts between localized and metastatic prostate cancer. Primary localized disease demonstrates local inflammation and adaptive immunity, whereas metastases are characterized by immune cold microenvironments and a shift towards resolution of inflammation and tissue repair. Therapies that interfere with these inflammatory networks may offer opportunities for early intervention in monotherapy or in combination with immunotherapies and anti-angiogenic approaches.

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“…Опубликованы научно-исследовательские работы, утверждающие, что пациенты с аутоиммунными заболеваниями имеют повышенную восприимчивость к ДГПЖ, и что лечение аутоиммунных заболеваний может приводить к подавлению ДГПЖ [14]. В качестве таких терапевтических возможностей предложены антагонисты фактора некроза опухоли (ФНО), дексаметазон, нестероидные противовоспалительные препараты, растительные противовоспалительные лекарственные средства [14,15].…”

Section: обсуждение результатовunclassified

Heterogeneity of benign prostatic hyperplasia

Ishchenko¹,

Badyukov²,

Badyoukova³

et al. 2022

Immunopathol Allergol Infectol

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Background. Benign prostatic hyperplasia (BPH) is a histologically determined condition of the male body and is characterized by glandular-stromal multi-focal proliferation originating from the paraurethral and (or) transition zone of the prostate gland. Proliferative processes in the body are under the control of the immune system. Identifying and understanding the immunological aspects of prostatic hyperplasia can help control prostate tissue growth, improving men's quality of life. The aim of our study was to conduct a pilot study, assessment of the immune status of patients with benign prostatic hyperplasia. Materials and methods. The study included patients having stage 2 BPH (according to Guyon’s updated classification system (n=8)) and patients who did not have clinical and morphological manifestations of BPH. The subjects underwent standard examinations in accordance with the clinical protocol of the Ministry of Health of the Republic of Belarus. The immunogram indicators included: the main subpopulations of lymphocytes (CD3 T lymphocytes, CD4 T helper cells, CD8 T cytotoxic lymphocytes), the ratio of Th/Tc, CD19 B lymphocytes, the level of serum immunoglobulins IgG, IgM, IgA and circulating immunocomplexes (CIC), as well as phagocytic index and phagocytic number. Results. Patients with BPH had statistically lower levels in the number of phagocytosed units compared to the patients without BPH. Furthermore, patients with BPH have highly variable results for immune system indices. Thus, the ratio of Th/Tc ranged from 1,3 to 2,3 units, and the level of CIC – from 10 to more than 300 units. The variability of the results obtained allowed us to divide patients with BPH into two groups: first group (n=3) with normal indices for levels of CIC and for the ratio of Th/Tc; the second group (n=5) with the indices for levels of CIC and for the ratio of Th/Tc that significantly exceeded the reference values. None of the patients in the second group had a concomitant autoimmune disease. Conclusions. Patients with BPH have a dysfunction of the immune system. Even having such a small number of enrolled subjects, it is possible to form subtypes of patients with BPH – they are future phenotypes. The study aiming at finding immunological disorders in patients with benign prostatic hyperplasia should be continued.

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TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease

Cited by 37 publications

References 81 publications

Stromal resistance to castration-induced prostate regression in a mouse model of benign prostatic hyperplasia

Stromal resistance to castration-induced prostate regression in a mouse model of benign prostatic hyperplasia

Differential regulation of TNFα and IL-6 expression contributes to immune evasion in prostate cancer

Heterogeneity of benign prostatic hyperplasia

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