Loss of TIMP-1 immune expression and tumor recurrence in localized prostate cancer

Reis, Sabrina T.; Viana, Nayara; Iscaife, Alexandre; Pontes‐Júnior, José; Dip, Nelson; Antunes, Alberto A.; Guimarães, Vanessa Ribeiro; Santana, Isaque; Nahas, William Carlos; Srougi, Miguel; Leite, Kátia R. M.

doi:10.1590/s1677-5538.ibju.2014.0451

Cited by 13 publications

(15 citation statements)

References 19 publications

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“…However, while TIMP downregulation is expected to favor tumor progression, evidence shows that more complex mechanisms are in play; some TIMPs are in fact upregulated, while others are silenced. TIMP-1 overexpression is associated with unfavorable prognosis and early recurrence in multiple cancers including breast and prostate carcinoma (41,42). Conversely, the lack of TIMP-1 expression predicts both a favorable prognosis and tumor responsiveness to chemotherapy in some cancers (43).…”

Section: Matrix Metalloproteinases In Malignancymentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes

Winer

Adams

Mignatti

2018

Molecular Cancer Therapeutics

457

370

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The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis, and metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy. From the 1990s to early 2000s, synthetic inhibitors of MMPs (MMPI) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have antitumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their antimetastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden. .

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Section: Matrix Metalloproteinases In Malignancymentioning

confidence: 99%

Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes

Winer

Adams

Mignatti

2018

Molecular Cancer Therapeutics

457

370

View full text Add to dashboard Cite

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“…The loss of TIMP-1 protein expression was correlated to cancer progression, with MT1-MMP protein expression being identified in the majority of prostate cancer specimens. Once again, a positive correlation with Gleason score was observed [21] . This reinforced an earlier study by the same group (79 prostate cancer patients), which indicated that MT1-MMP expression was higher in patient samples with Gleason scores ≥ 7, though that dataset only exhibited marginal statistical significance [23] .…”

Section: Expression Of Mt-mmps In Prostate Cancer Clinical Tissuesmentioning

confidence: 78%

“…In a further 40 patients, Reis et al [21] also monitored tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) expression together with that of MT1-MMP. TIMPs inhibit some MMPs and other protease enzymes, but not MT1-MMP [22] .…”

Section: Expression Of Mt-mmps In Prostate Cancer Clinical Tissuesmentioning

confidence: 99%

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

Falconer¹,

Loadman²

2017

JCMT

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The membrane-type matrix metalloproteinases (MT-MMPs), an important subgroup of the wider MMP family, demonstrate widespread expression in multiple tumor types, and play key roles in cancer growth, migration, invasion and metastasis. Despite a large body of published research, relatively little information exists regarding evidence for MT-MMP expression and function in metastatic prostate cancer. This review provides an appraisal of the literature describing gene and protein expression in prostate cancer cells and clinical tissue, summarises the evidence for roles in prostate cancer progression, and examines the data relating to MT-MMP function in the development of bone metastases. Finally, the therapeutic potential of targeting MT-MMPs is considered. While MT-MMP inhibition presents a significant challenge, utilisation of MT-MMP expression and proteolytic capacity in prostate tumors is an attractive drug development opportunity. Key words:Matrix metalloproteinase, membrane-type, metastasis, prostate cancer, microenvironment ABSTRACTArticle history:

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“…However, elevated serum MMP7 levels were reported to be significantly associated with metastatic and advanced PCa and was therefore considered to be a biomarker candidate to detect metastatic PCa [ 32 ]. In addition, TIMP1 was found downregulated in adenocarcinoma compared to BPH [ 33 ] and loss of TIMP1 correlated with biochemical recurrence in patients with localized PCa [ 34 ]. These results are in line with our findings and support the idea of regulation of MMP activity by TIMPs as crucial event in PCa growth and progression.…”

Section: Discussionmentioning

confidence: 99%

Protease Expression Levels in Prostate Cancer Tissue Can Explain Prostate Cancer-Associated Seminal Biomarkers—An Explorative Concept Study

Neuhaus

Schiffer²,

Mannello

et al. 2017

IJMS

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Previously, we described prostate cancer (PCa) detection (83% sensitivity; 67% specificity) in seminal plasma by CE-MS/MS. Moreover, advanced disease was distinguished from organ-confined tumors with 80% sensitivity and 82% specificity. The discovered biomarkers were naturally occurring fragments of larger seminal proteins, predominantly semenogelin 1 and 2, representing endpoints of the ejaculate liquefaction. Here we identified proteases putatively involved in PCa specific protein cleavage, and examined gene expression and tissue protein levels, jointly with cell localization in normal prostate (nP), benign prostate hyperplasia (BPH), seminal vesicles and PCa using qPCR, Western blotting and confocal laser scanning microscopy. We found differential gene expression of chymase (CMA1), matrix metalloproteinases (MMP3, MMP7), and upregulation of MMP14 and tissue inhibitors (TIMP1 and TIMP2) in BPH. In contrast tissue protein levels of MMP14 were downregulated in PCa. MMP3/TIMP1 and MMP7/TIMP1 ratios were decreased in BPH. In seminal vesicles, we found low-level expression of most proteases and, interestingly, we also detected TIMP1 and low levels of TIMP2. We conclude that MMP3 and MMP7 activity is different in PCa compared to BPH due to fine regulation by their inhibitor TIMP1. Our findings support the concept of seminal plasma biomarkers as non-invasive tool for PCa detection and risk stratification.

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Loss of TIMP-1 immune expression and tumor recurrence in localized prostate cancer

Cited by 13 publications

References 19 publications

Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes

Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures Into Future Successes

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

Protease Expression Levels in Prostate Cancer Tissue Can Explain Prostate Cancer-Associated Seminal Biomarkers—An Explorative Concept Study

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