Prostate tumor–derived GDF11 accelerates androgen deprivation therapy–induced sarcopenia

Pan, Chengjun; Jaiswal, Neha; Zulia, Yanni; Singh, Shalini; Sha, Kai; Mohler, James L.; Eng, Kevin H.; Chakkalakal, Joe V.; Krolewski, John J.; Nastiuk, Kent L.

doi:10.1172/jci.insight.127018

Cited by 9 publications

(6 citation statements)

References 48 publications

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“…VP volume then increased rapidly from 20 weeks to 30 weeks of age to ~120 mm 3 and then growth slowed and plateaued at ~180 mm 3 . In comparison, we previously reported a murine model of prostate cancer (PbCre4 ×Pten flox/flox ; PTEN-deficient) tumor grew from ~200 mm 3 at 15 weeks to ~1000 mm 3 at 30 weeks [20]. In a larger cohort of this prostate cancer model, serial imaging revealed an exponential increase in tumor volume as well as significant animal to animal variability (Fig.…”

Section: Resultsmentioning

confidence: 77%

“…Paracrine TNF and TGFβ1 signaling mediate castration-induced regression in both normal and neoplastic prostate [11, 17, 19, 20]. Therefore, we investigated the role of these multi-functional cytokines in hyperplastic prostates following castration, using the Pb-PRL model.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, the PTEN-loss mouse model of prostate cancer exhibited a variable, exponential prostate (tumor) growth pattern (refs. [20, 37] and Figure 1).…”

Section: Discussionmentioning

confidence: 99%

“…In normal prostate, TNF and TGFβ1 signaling are required for castration-induced regression [11, 17]. TNF and TGFβ1 also mediate regression after ADT in prostate cancer mouse models [19, 20]. The potential role of ADT in the treatment of BPH has been complicated by the observations that increased prostate volume does not always correlate with the clinical syndromes of LUTS [2].…”

Section: Introductionmentioning

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: Resultsmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 99%

“…In contrast, the PTEN-loss mouse model of prostate cancer exhibited a variable, exponential prostate (tumor) growth pattern (refs. [20, 37] and Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Protein concentration was determined using bicinchoninic acid reagent (Pierce, ThermoFisher Scientific). Immunoblotting was performed essentially as described previously (13), with the following modifications. Twentyfive to 40 µg of protein extract were separated on 7.5% SDS-PAGE.…”

Section: Immunoblot Analysismentioning

confidence: 99%

Glucocorticoid signaling delays castration-induced regression in murine models of prostate cancer

Maolake

Zhang

Sha

et al. 2021

Preprint

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Androgen deprivation therapy (ADT) is the mainstay therapy for recurrent and advanced prostate cancer. While human prostate cancers initially regress following ADT, many tumors fail this therapy and recur. To understand the response of prostate cancers to ADT, we have employed high frequency ultrasound imaging to track the kinetics of tumor volume in murine models of prostate cancer. Previously, we showed that normal (non-tumor) prostate regression begins within two days of castration. Following castration, murine prostate cancers also regress but only after a delay of 3-14 days, dependent on initial tumor size. Delayed regression is observed in two distinct mouse models (MYC over-expression, PTEN-deficient) implying that the genetic lesion which initiates carcinogenesis does not play a role. Intra-tumoral androgen levels are undetectable 16 hours post-castration, arguing that residual androgen signaling is not the cause of delayed regression. Castration induces tumor cell proliferation during this period. There is an increase in the active glucocorticoids, as well as glucocorticoid receptor (GR) mRNA and protein and a set of GR-regulated genes. A selective GR inhibitor eliminates the delayed regression phenotype in both models. Thus, GR signaling is activated following castration and transiently enhances tumor proliferation. This response to ADT resembles the GR-dependent mechanism of escape for prostate cancers that are resistant to anti-androgen therapies and may provide mechanistic insight into the development of castration resistant prostate cancer. If ADT-induced GR signaling is similar in human prostate cancers, simultaneous blockade of GR and androgen receptor signaling could improve prostate cancer therapy.

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Low Alanine Aminotransferase, as a Marker of Sarcopenia and Frailty, Is Associated with Shorter Survival Among Prostate Cancer Patients and Survivors. A Retrospective Cohort Analysis of 4064 Patients

Laufer,

Perelman,

Sarfaty

et al. 2023

European Urology Open Science

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Prostate tumor–derived GDF11 accelerates androgen deprivation therapy–induced sarcopenia

Cited by 9 publications

References 48 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

Glucocorticoid signaling delays castration-induced regression in murine models of prostate cancer

Low Alanine Aminotransferase, as a Marker of Sarcopenia and Frailty, Is Associated with Shorter Survival Among Prostate Cancer Patients and Survivors. A Retrospective Cohort Analysis of 4064 Patients

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