Elevated plasma tissue inhibitor of metalloproteinase‐1 levels predict decreased survival in castration‐resistant prostate cancer patients

Oh, William K.; Vargas, Roberto; Jacobus, Susanna; Leitzel, Kim; Regan, Meredith M.; Hamer, Peter; Pierce, Karen; Brown-Shimer, Sheryl; Carney, Walter P.; Ali, Suhail M.; Kantoff, Philip W.; Lipton, Allan

doi:10.1002/cncr.25394

Cited by 35 publications

(32 citation statements)

References 41 publications

(40 reference statements)

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“…We investigated the potential mechanism by which activates TIMP1 induction in RFP cardiac myocytes. TIMP1 was shown as a downstream target of NF-κB signaling in which TIMP1 induced by the activation of NF-κB signaling in cancer models [21, 22] or under UPR and ER stress [23]. Therefore, we performed the staining for NF-κB p65 subunit as an indicator of NF-κB activation in RFP+/+ cardiac myocytes and found an increase of p65 nuclear and perinuclear staining in cardiac myocytes (Figure 5F).…”

Section: Resultsmentioning

confidence: 99%

Cardiac fibrosis in mouse expressing DsRed tetramers involves chronic autophagy and proteasome degradation insufficiency

Chen

et al. 2016

Oncotarget

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Proteinopathy in the heart which often manifests excessive misfolded/aggregated proteins in cardiac myocytes can result in severe fibrosis and heart failure. Here we developed a mouse model, which transgenically express tetrameric DsRed, a red fluorescent protein (RFP), in an attempt to mimic the pathological mechanisms ofcardiac fibrosis. Whilst DsRed is expressed and forms aggregation in most mouse organs, certain pathological defects are specifically recapitulated in cardiac muscle cells including mitochondria damages, aggresome-like residual bodies, excessive ubiquitinated proteins, and the induction of autophagy. The proteinopathy and cellular injuries caused by DsRed aggregates may be due to impaired or overburdened ubiquitin-proteasome system and autophagy-lysosome systems. We further identified that DsRed can be ubiquitinated and associated with MuRF1, a muscle-specific E3 ligase. Concomitantly, an activation of NF-κB signaling and a strong TIMP1 induction were noted, suggesting that RFP-induced fibrosis was augmented by a skewed balance between TIMP1 and MMPs. Taken together, our study highlights the molecular consequences of uncontrolled protein aggregation leading to congestive heart failure, and provides novel insights into fibrosis formation that can be exploited for improved therapy.

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Section: Resultsmentioning

confidence: 99%

Cardiac fibrosis in mouse expressing DsRed tetramers involves chronic autophagy and proteasome degradation insufficiency

Chen

et al. 2016

Oncotarget

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“…In addition to Figure 1A, studies have shown that TIMP-1 levels in plasma of prostate cancer patients are elevated and the elevated TIMP-1 levels predict for decreased survival of castration-resistant (CR) prostate cancer patients [25,38]. To further assess localization of TIMP-1 in human prostate cancers and determine the potential source(s) of the elevated plasma TIMP-1, we performed immunohistochemistry (IHC) on a panel of human prostate cancer samples and normal prostate tissues.…”

Section: Resultsmentioning

confidence: 99%

TIMP-1 Promotes Accumulation of Cancer Associated Fibroblasts and Cancer Progression

et al. 2013

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Treatment options for late stage prostate and colon cancer are limited and there is an urgent need to develop more effective and targeted novel therapies, which starts with identification and validation of novel therapeutic targets. Recent clinical studies have demonstrated that tissue inhibitor matrix metalloproteinase-1 (TIMP-1) levels are elevated in cancer patient plasma and elevated TIMP-1 levels are associated with worse clinical outcomes. However, it is unknown whether TIMP-1 serves merely as a biomarker of cancer progression or has a functional role in promoting cancer progression and can serve as a cancer therapeutic target, which is the main objective of this study. Here, we show that stroma of human prostate and colon cancer express higher levels of TIMP-1 compared to their normal counterparts and increased expression of TIMP-1 promotes in vivo growth of both cancer types. We demonstrate for the first time that increased TIMP-1 expression stimulates accumulation of cancer associated fibroblasts (CAFs) within prostate and colon cancer tissues and that TIMP-1 enhances prostate CAF proliferation and migration in vitro and promotes ERK1/2 kinase activation in these CAF cells. Our results establish the novel promotive effects of TIMP-1 on cancer progression and on accumulation of CAFs that in turn provides a pro-tumor microenvironment. Together, these results establish the potential of TIMP-1 as a novel target for cancer therapy and the mechanism underlying the pro-tumor activity of TIMP-1.

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“…In addition, TIMP-1 was reported to have anti-apoptotic properties [34], and to have a role as a promotor of cell differentiation [32]. Significantly increased serum TIMP-1 levels and a potential poor prognostic role have been reported in patients with melanoma [35], and patients with a variety of cancer types including breast [36,37], prostate [38], gastric [39], colorectal carcinoma [40], glioblastoma [41], and multiple myeloma [42,43]. In patients with melanoma, levels of TIMP-1 were found to be significantly higher in patients with unresected stage IV disease than in patients with resected stage I/II [35].…”

Section: Discussionmentioning

confidence: 99%

A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma

Tarhini

Lin

Yeku

et al. 2014

Journal of Translational Medicine

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BackgroundE1694 tested GM2-KLH-QS21 vaccine versus high-dose interferon-α2b (HDI) as adjuvant therapy for operable stage IIB-III melanoma. We tested banked serum specimens from patients in the vaccine arm of E1694 for prognostic biomarkers.MethodsAushon Multiplex Platform was used to quantitate baseline serum levels of 115 analytes from 40 patients. Least absolute shrinkage and selection operator proportional hazard regression (Lasso PH) was used to select markers that are most informative for relapse-free survival (RFS) and overall survival (OS). Regular Cox PH models were then fit with the markers selected by the Lasso PH. Survival receiver operating characteristic (ROC) analysis was used to evaluate the ability of the models to predict 1-year RFS and 5-year OS.ResultsFour markers that include Tumor Necrosis Factor alpha Receptor II (TNF-RII), Transforming Growth Factor alpha (TGF-α), Tissue Inhibitor of Metalloproteinases 1 (TIMP-1), and C-reactive protein (CRP) were found to be most informative for the prediction of OS (high levels correlate with worse prognosis). The dichotomized risk score based on the four markers could significantly separate the OS curves (p = 0.0005). When using the four-marker PH model to predict 5-year OS, we achieved an area under the curve (AUC) of 89% (cross validated AUC = 72%). High baseline TNF-RII was also significantly associated with worse RFS. The RFS with high (above median) TNF-RII was significantly lower than low TNF-RII (p = 0.01).ConclusionsThe biomarker signature consisting of TNFR-II, TGF-α, TIMP-1 and CRP is significantly prognostic of survival in patients with high-risk melanoma and warrants further investigation.

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Elevated plasma tissue inhibitor of metalloproteinase‐1 levels predict decreased survival in castration‐resistant prostate cancer patients

Cited by 35 publications

References 41 publications

Cardiac fibrosis in mouse expressing DsRed tetramers involves chronic autophagy and proteasome degradation insufficiency

Cardiac fibrosis in mouse expressing DsRed tetramers involves chronic autophagy and proteasome degradation insufficiency

TIMP-1 Promotes Accumulation of Cancer Associated Fibroblasts and Cancer Progression

A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma

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