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Diagnosis and Prognosis of Prostate Cancer from Circulating Matrix Metalloproteinases and Inhibitors.

1. Introduction

Statistics worldwide indicate that prostate cancer (PCa) has high prevalence and lethality, with three-quarters of cases among 65-year-oldsters [1]. Serum prostate specific antigen (PSA) levels are measured for early detection, staging, and monitoring despite not being a specific marker for PCa, rising in cases of prostatitis or benign prostatic hyperplasia (BPH) [2, 3].

Biochemical evidence indicates that serum proteinases, namely, matrix metalloproteinases (MMPs), play key roles in the pathophysiology of this malignancy. MMPs are zincor calcium-dependent endopeptidases that degrade various components of extracellular matrix, mainly collagen, elastin, laminin, fibronectin, and proteoglycans, being involved in tumorigenesis and metastasis to favor migration of tumor cells besides being proangiogenic [3].

Twenty-four MMPs have been identified, including collagenases (MMP-1, 8, 13, and 18), gelatinases (MMP-2 and 9), stromelysins (MMP-3 and 10), matrilisins (MMP-7 and 26), and membrane-type MMPs (MMP-14, 15, 16, 17, 24, and 25), among other types. They are found in all tissues and in plasma, being secreted mostly as pro-MMPs activated by the urokinase-plasminogen/plasmin system of cell membranes. In parallel and with regulatory and antagonistic action, four tissue inhibitors of MMPs (TIMPs) were described: TIMP-1, 2, 3, and 4. Hyperexpression of TIMP-1, 2 and 3 normally accompanies the course of tumor growth [2].

Studies performed so far on MMPs/TIMPs to assess risk for PCa seem to yield inconclusive results, with data on specificity and sensitivity being scarce. In this context, this minireview aimed at identifying studies that correlated circulating MMPs and TIMPs with PCa, focusing on reports that aimed at having them tested as serum/plasma biomarkers and describing accuracy scores, when available. A bibliographic survey was carried out in February and March 2017, using the following key words: metalloproteinases OR inhibitors of metalloproteinases OR MMPs OR TIMPs AND prostate cancer. The following quantitative studies were identified in the following primary databases: CINAHL, 20; EMBASE, 141; Google Scholar, 500; Library COCHRANE, 0; LILACS, 52; MEDLINE, 1859; SCOPUS, 201; and Web of Science, 129, and also in the following secondary sources of information: CAPES theses and dissertations database, 749; SCIELO, 29; PROQUEST, 1318; and Tripdatabase, 295. This search, after excluding replicates, produced a total of 17 reports addressing association of plasma/serum MMPs and/or TIMPs with PCa (Figure 1), which were obtained, analyzed, and systematized as depicted in Table 1.

There is a higher prevalence of studies on MMP-2 and MMP-9. In 1998, Gohji et al. [20] accumulated evidence of the correlation between the higher serum levels of MMP-2 and tumor extension. The authors measured MMP-2 by ELISA in the serum of 98 PCa patients, with 76 BPH carriers and 70 healthy men. Serum levels of MMP-2 were significantly higher in the PCa group than in the healthy and BPH counterparts and even higher in patients with metastatic PCa. In line, Kanoh et al. [19] measured by ELISA serum MMP-2 and PSA levels of 51 PCa patients and of 39 BPH carriers. The result consisted of increasing serum levels of both along with disease progression. Very high values of MMP-2 (>950 ng/ml) and PSA (>300ng/ml) were observed when bone metastases was observed. Those authors advocate that MMP-2 can be coupled to PSA for prognostic purposes in PCa.

In this same sense, the study by Morgia et al. [11] investigated the use of MMPs as circulating biomarkers for the diagnosis and prognosis of PCa. Levels of MMP-2, 9, and 13 were significantly higher among PCa patients than in healthy or HPB subjects. The authors concluded that serum MMPs can be used as adjuvant biomarkers (combined with PSA) for the diagnosis (MMP-13) and prognosis (MMP-2 and MMP-9) of PCa. In addition, Prior et al. [13] also measured MMP-2 (and others, including PSA) in serum (and urine) of 113 men, stating that MMP-2 assessed in combination with PSA increases sensitivity for the diagnosis of PCa.

Likewise, Zhang et al. [17] investigated enzyme activity by zymography of MMPs-2, among others, in the serum of healthy men (n = 20), with BPH (n = 26), with localized PCa (n = 10), and with metastatic PCa (n = 15). The results indicated significant differences in enzyme activity between groups for MMP-9 but not for MMP-2. Thus, unlike previous studies, it was concluded that only serum levels of MMP-9 would be correlated with the presence of malignancy and metastases.

Incorvaia et al. [9] measured serum MMP-2 and 9 in patients with breast and prostate cancer, with and without bone metastases. Regarding PCa, both MMPs were significantly higher in patients with PCa compared to control subjects, but being indistinguishable between subjects with and without bone metastases, conversely to Kanoh et al. Therefore, it was concluded that MMPs (mainly MMP-2) display low accuracy for the diagnosis of bone metastatic PCa. Salminem et al. [15] obtained the same conclusions as Incorvaia et al. [9] on the accuracy of MMP-2 and 9 in the diagnosis of bone metastatic PCa, compared to the accuracy of PSA and alkaline phosphatase, contraindicating the testing of these MMPs for diagnostic purpose. Likewise, MMP-9 was the target of Gil-Ugarteburu et al. [18], which correlated MMP-9 plasma concentrations of 235 patients (measured by ELISA) with the 1562C/T polymorphism of the promoter region of the gene. Among the findings, the authors did not identify differences in the circulating concentrations of MMP-9 in the derived subgroups or any correlation with the polymorphism investigated.

In contrast, Castellano et al. [6] evidenced that serum levels of MMP-9 and its activator, osteopontin, declined significantly 6 months after prostatectomy. They also identified a correlation between serum MMP-9 and PSA and Gleason staging values. De Cicco et al. [7] quantified MMP2, MMP-9, TIMP-1, and TIMP-2 among other molecules in the plasma of 162 men diagnosed with PCa, having found only a significant association between low MMP-2 values (less than 206 ng/ml) and an worsened disease progression (corrected HR = 1.7 and CI = 95%).

Gonzalez Rodrigues et al. [14] found unsatisfactory results when serum MMP-9 was determined by ELISA in 100 patients with indication for prostate biopsy (prospective cohort study). Of these, 32 were diagnosed with PCa with 52% classified with Gleason greater than or equal to 7. No significant difference in MMP-9 levels was found between groups with PCa and benign or uncertain histological results. No association was found between MMP-9 levels and PSA or Gleason scores.

Concerning other varieties of MMPs, Jung et al. in 1997 [10] performed ELISA assessments for plasma MMP-1, 3, and TIMP-1 on 19 nonmetastatic PCa, 18 metastatic, and 29 HPB patients, along with 35 healthy men. No difference was found in the MMP-1 means across groups. The mean concentration of MMP-3 and TIMP-1 in metastatic patients was significantly higher than in the other groups, with 10 out of the 18 metastatic cases displaying remarkably high levels of TIMP-1. They concluded that TIMP-1 can be correlated with the PCa condition. Previously, Baker et al. [4] also found higher levels of TIMP-1 (but not TIMP-2) in patients with PCa.

Serum MMP-7 was investigated by Szarvas et al. [16] using ELISA in 93 patients with focal PCa at the preoperative stage, along with 13 patients with bone metastases and 19 normal individuals. No statistically significant difference was found between PCa carriers and normal individuals. However, MMP-7 levels were significantly elevated in patients with metastatic PCa compared to focal counterparts, with specificity and sensitivity of 69 and 92%, respectively, when a cutoff point of 3.7 ng/ml was adopted.

Plasma TIMP-1 was also the subject of Oh et al. [12] in a cohort study with mean follow-up of 6.6 years. Based on 362 samples from hormone-resistant and castrated patients with metastatic PCa, patients with higher levels of plasma TIMP-1 had the lowest survival (19 versus 43 months). Values of PSA, alkaline phosphatase, and Gleason scores were also considered. Plasma TIMP-1 was shown as the best predictor of survival in patients with these characteristics and independently of other classic markers.

Bonaldi et al. [5] correlated serum levels of e-cadherin and MMP-13 on PCa patients with serum levels of total PSA, free PSA, total testosterone, and clinical evolution, measured before onset of treatment as well as three and six months afterwards. The same was done in a parallel control group. At baseline, e-cadherin titers were lower in the PCa group than in the control group while for MMP-13, differences were not noticed. With treatment, authors identified only positive correlation between PSA and e-cadherin levels in the third month of treatment. Gong et al. [8] compared circulating TIMP-1 in hormone-resistant PCa patients who underwent orchiectomy with patients responsive to hormone therapy. In the first group, plasma TIMP-1 was significantly higher.

Thus, with regard to MMPs as circulating biomarkers to diagnose and monitor PCa, we conclude that very few studies were conducted in this matter, having rendered contradictory and inconclusive data. Nonetheless, the premise of differential levels in circulating MMPs among PCa patients for a diagnostic purpose seems worth investigating in light of evidence already existent for other neoplastic entities [21], with emphasis on what concerns MMP-2, 7, and 9 and TIMP-1 in the opinion of the authors of this minireview.

Although having reviewed seventeen scientific papers, it was not possible to meta-analyze results due to methodological heterogeneities and poor description of central tendency scores. Only five articles reported mean values for the plasma/serum markers assessed, three of which for MMP-2 and MMP-9 while the others for MMP-7 and TIMP-1 each. Specificity and sensitivity were only described in 1 study [13].

Considering that the current screening diagnosis, based on serum PSA dosage and rectal examination, has a limited accuracy (mainly specificity) for differentiation of PCa from other prostatic diseases and considering the fragility of the results pointed out in this review, more studies with the aim of confirming (or excluding) MMPs and TIMPs as elective biomarkers for PCa should be welcomed, either for diagnosis, prognosis, or therapeutic referral.

https://doi.org/10.1155/2018/7681039

Conflicts of Interest

No potential conflicts of interest exist.

Authors' Contributions

William Khalil El-Chaer executed the bibliographical research and systematized the data obtained. William Khalil El-Chaer and Otovio Toledo Nobrega analyzed and interpreted results as well as prepared the original manuscript. Clayton Franco Moraes critically revised the manuscript.

Acknowledgments

The research was supported with grants from CNPq (no. 445692/2014) and FAPDF (193.001.240/2016), with a fellowship for productivity in research to O.T. Nobrega (CNPq).

References

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[2] R. Visse and H. Nagase, "Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure function, and biochemistry," Circulation Research, vol. 92, no. 8, pp. 827-839, 2003.

[3] E. I. Deryugina and J. P. Quigley, "Matrix metalloproteinases and tumor metastasis," Cancer and Metastasis Reviews, vol. 25, no. 1, pp. 9-34, 2006.

[4] A. H. Baker, D. R. Edwards, and G. Murphy, "Metalloproteinase inhibitors: biological actions and therapeutic opportunities," Journal of Cell Science, vol. 115, no. 19, pp. 3719-3727, 2002.

[5] C. M. Bonaldi, L. A. Azzalis, V. B. Junqueira et al., "Plasma levels of E-cadherin and MMP-13 in prostate cancer patients: correlation with PSA, testosterone and pathological parameters," Tumori Journal, vol. 101, no. 2, pp. 185-188, 2015.

[6] G. Castellano, G. Malaponte, M. C. Mazzarino et al., "Activation of osteopontin/matrix metalloproteinaes-9 pathway correlates with prostate cancer progression," Clinical Cancer Research, vol. 14, no. 22, pp. 7470-7480, 2008.

[7] C. De Cicco, L. Ravasi, L. Zorzino et al., "Circulating levels of VCAM and MMP-2 may help identify patients with more aggressive prostate cancer," Current Cancer Drug Targets, vol. 8, no. 3, pp. 199-206, 2008.

[8] Y. Gong, U. D. Chippada-Venkata, M. D. Galsky, J. Huang, and W. K. Oh, "Elevated circulating tissue inhibitor of metalloproteinase 1 (TIMP-1) levels are associated with neuroendocrine differentiation in castration resistant prostate cancer," The Prostate, vol. 75, no. 6, pp. 616-627, 2015.

[9] L. Incorvaia, G. Badalamenti, G. Rini et al., "MMP-2, MMP-9 and activin A blood levels in patients with breast cancer or prostate cancer metastatic to the bone," Anticancer Research, vol. 27, pp. 1519-1525, 2007.

[10] K. Jung, L. Nowak, M. Lein, F. Priem, D. Schnorr, and S. A. Loening, "Matrix metalloproteinases 1 and 3, tissue inhibitor of metalloproteinase-1 and the complex of metalloproteinase-1/tissue inhibitor in plasma of patients with prostate cancer," International Journal of Cancer, vol. 74, no. 2, pp. 220-223, 1997.

[11] G. Morgia, M. Falsaperla, G. Malaponte et al., "Matrix metalloproteinases as diagnostic (MMP-13) and prognostic (MMP-2, MMP-9) markers of prostate cancer," Urological Research, vol. 33, no. 1, pp. 44-50, 2005.

[12] W. K. Oh, R. Vargas, S. Jacobus et al., "Elevated plasma tissue inhibitor of metalloproteinase-1 levels predict decreased survival in castration-resistant prostate cancer patients," Cancer, vol. 117, no. 3, pp. 517-525, 2011.

[13] C. Prior, F. Guillen-Grima, J. E. Robles et al., "Use of a combination of biomarkers in serum and urine to improve detection of prostate cancer," World Journal of Urology, vol. 28, no. 6, pp. 681-686, 2010.

[14] I. Gonzalez Rodriguez, M. Rivas del Fresno, R. Gil Ugarteburu et al., "Expresion de metaloproteasa de matriz 9 en el cancer de prostata: experiencia preliminar," Archivos Espanoles de Urologia, vol. 63, no. 2, pp. 119-124, 2010.

[15] E. K. Salminen, M. J. Kallioinen, M. A. Ala-Houala et al., "Survival markers related to bone metastases in prostate cancer," Anticancer Research, vol. 26, pp. 4879-4884, 2006.

[16] T. Szarvas, M. Becker, F. VomDorp et al., "Elevated serum matrix metalloproteinase 7 levels predict poor prognosis after radical prostatectomy," International Journal of Cancer, vol. 128, no. 6, pp. 1486-1492, 2011.

[17] L. Zhang, J. Shi, J. Feng, H. Klocker, C. Lee, and J. Zhang, "Type IV collagenase (matrix metalloproteinase-2 and -9) in prostate cancer," Prostate Cancer and Prostatic Diseases, vol. 7, no. 4, pp. 327-332, 2004.

[18] I. G. R. Gil-Ugarteburu, M. Rivas del Fresno, P. Benito Garcia, A. Fenandez Somoano, and A. Tardon Garcia, "Plasmatic variations of metalloproteinase 9 (MMP-9) due to functional polymorphism in prostate cancer," Urology, vol. 80, no. 3, p. S276, 2012.

[19] Y. Kanoh, T. Akahoshi, T. Ohara et al., "Expression of matrix metalloproteinase-2 and prostate-specific antigen in localized and metastatic prostate cancer," Anticancer Research, vol. 22, no. 3, p. 1813, 2002.

[20] K. Gohji, N. Fujimoto, I. Hara et al., "Serum matrix metalloproteinase-2 and its density in men with prostate cancer as a new predictor of disease extension," International Journal of Cancer, vol. 79, no. 1, pp. 96-101, 1998.

[21] F. L. Fonseca, B. C. A. Alves, L. A. Azzalis, and T. M. Belardo, "Matrix metalloproteases as biomarkers of disease," Methods in Molecular Biology, vol. 1579, pp. 299-311, 2017.

William Khalil El-Chaer, (1) Clayton Franco Moraes, (1,2) and Otavio Toledo Nobrega

(1) University of Brasilia (UnB), 70910-900 Brasilia, DF, Brazil

(2) Catholic University of Brasilia (UCB-DF), 71966-700 Brasilia, DF, Brazil

Correspondence should be addressed to Otavio Toledo Nobrega; otnobrega@gmail.com

Received 18 April 2018; Accepted 11 June 2018; Published 10 July 2018

Academic Editor: Carmela R. Balistreri

Caption: Figure 1: Rationale of the selection of articles.
Table 1: Summary of the 17 articles revised.

Authors and title         Objective of the             Design
                                study

Baker et al. [4]          To measure serum       Prospective cohort
                              levels of
                            collagenases,
                          stromelysins, and
                           TIMP-1 and 2 in
                         patients with PCa,
                        before treatment and
                        6 and 12 months after
                              starting.

Bonaldi et al. [5]       To dose e-cadherin      Prospective cohort
                          and MMP-13 at the
                        diagnosis of PCa and
                        three and six months
                          after treatment,
                         comparing with the
                           control group.

Castellano et al. [6]   To compare levels of       Cross-sectional
                         osteopontin (OPN),
                          MMP-2, MMP-9, and
                               TIMP-1.

Cicco et al. [7]              Correlate            Cross-sectional
                         preoperative serum
                         levels of 6 markers
                        (including MMPs-2 and
                        9 and TIMPs-1 and 2)
                         with tumor staging,
                         Gleason score, and
                            disease-free
                              survival.

Gong et al. [8]           To compare TIMP-1          Descriptive
                         levels of castrated
                           metastatic Pca
                            patients with
                            noncastrated
                           (responsive to
                          androgen ablation
                              therapy).

Incorvaia et al. [9]    To compare levels of           Cohort
                           MMP-2 and 9 in
                        individuals with PCa
                        with bone metastases
                           in relation to
                        healthy individuals.

Jung et al. [10]        To compare levels of       Cross-sectional
                          MMP/1, MMP/3, and
                        TIMP/1 as well as the
                        MMP-1/TIMP-1 ratio of
                            subjects with
                         metastatic PCa and
                         with nonmetastatic
                                PCa.

Morgia et al. [11]        To measure plasma            Cohort
                        levels of MMPs-2, 9,
                        and 13 of TIMP-1, and
                          of the enzymatic
                         activity of MMPs-2
                          and 9 in patients
                        with metastatic PCa,
                         nonmetastatic PCa,
                        BPH, and healthy, at
                        diagnosis and 90 days
                           after starting
                             treatment.

Oh et al. [12]          To evaluate TIMP-1 as      Survival study
                           a predictor of
                        survival in castrated
                            PCa patients.

Prior et al. [13]           To determine          Diagnostic study
                            sensitivity,
                          specificity, and
                        predictive values for
                        MMP-2 as a biomarker
                              for PCa.

Gonzalez Rodriguez et     To dose MMP-9 in         Cross-sectional
al. [14]                    patients who
                         underwent prostate
                               biopsy.

Salminen et al. [15]       To evaluate the       Cross-sectional and
                         prognostic value of         prognostic
                         MMP-2 and MMP-9 in
                        PCa with and without
                          bone metastasis,
                         comparing with ALP
                              and PSA.

Szarvas et al. [16]       To compare serum         Cross-sectional
                         levels of MMP-7 in        and prognostic
                        PCa patients with and
                         without metastasis
                          and to assess its
                          prognostic value.

Zhang et al. [17]        To search mRNA and        Cross-sectional
                        enzymatic activity of
                           MMP-2 and 9 in
                        prostatic tissue and
                        serum of PCa patients
                          (with and without
                        metastasis) comparing
                        with BPH and healthy
                               group.

Gil-Ugarteburu et al.     To correlate the       Prospective cohort
[18]                    1562C-T polymorphism
                          of the MMP-9 gene
                           with its plasma
                               levels.

Kanoh et al. [19]         To correlate the         Cross-sectional
                        serum levels of MMP-
                         2 and PSA with the
                         different stages of
                                PCa.

Gohji et al. [20]         To compare MMP-2         Cross-sectional
                           levels between
                        individuals with and
                            without PCa.

Authors and title        Material and sample       Analysis method

Baker et al. [4]          Test: serum of 19             ELISA
                          individuals with
                        metastatic PCa and 16
                          with PCa without
                        metastases. Control:
                          21 patients with
                        rheumatoid arthritis
                           and 57 healthy
                          subjects without
                        rheumatoid arthritis.

Bonaldi et al. [5]       Test: plasma (EDTA)            ELISA
                         of 29 PCa patients.
                         Control: 10 healthy
                        men with PSA <1.5 ng/
                                 ml.

Castellano et al. [6]       Test: plasma                ELISA
                           (heparin) of 96
                         patients with PCa.
                             Control: 92
                        individuals with BPH
                           and 125 healthy
                              subjects.

Cicco et al. [7]          Serum of 162 PCa              ELISA
                         carriers for MMP-2
                          and 9 and plasma
                        (EDTA) for TIMP-1 and
                                 2.

Gong et al. [8]           Test: serum of 39             ELISA
                        castrated metastatic
                           PCa patients.
                             Control: 24
                            noncastrated
                           metastatic PCa
                              patients.

Incorvaia et al. [9]     Test: plasma (EDTA)            ELISA
                         of 35 patients with
                        breast cancer and 44
                         with PCa with bone
                            metastases.
                         Control: 57 healthy
                              patients.

Jung et al. [10]         Plasma (heparin) of            ELISA
                          47 patients with
                         prostate cancer, 29
                         with no metastasis
                        (T2, 3pN0M0), and 18
                        with metastasis (T2,
                           3, 4pN1, 2M1).
                         Control: 35 healthy
                        subjects and 29 with
                                BPH.

Morgia et al. [11]       Plasma (heparin) of            ELISA
                          40 patients with
                         prostate cancer, 20
                         with no metastasis
                             and 20 with
                             metastasis.
                         Control: 20 healthy
                        patients and 20 with
                                BPH.

Oh et al. [12]           Test: plasma (EDTA)            ELISA
                        of 362 castrated PCa
                        patients; sample was
                          divided into two
                         groups: one with 60
                            (pilot group)
                         individuals with a
                        follow-up time of 5.8
                         years and the other
                          with 302 (primary
                         group) participants
                           followed by 6.6
                               years.

Prior et al. [13]       Test: serum of 34 PCa           ELISA
                             patients.
                        Control: 79 patients
                            without PCa.

Gonzalez Rodriguez et     Test: serum of 32             ELISA
al. [14]                    patients with
                        positive biopsy (PCa
                               group).
                        Control: 58 patients
                        with negative biopsy.

Salminen et al. [15]      Test: serum of 35             ELISA
                        individuals with PCa
                        with bone metastasis.
                             Control: 49
                        individuals with PCa
                            without bone
                             metastasis.

Szarvas et al. [16]       Test: serum of 93             ELISA
                          individuals with
                        localized PCa and 13
                         PCa cases with bone
                            metastasis.
                         Control: 19 healthy
                            individuals.

Zhang et al. [17]       Test: serum of 15 PCa        RT-PCR and
                            patients with            zymography
                          metastasis and 10
                         without metastasis.
                           Control: 26 BPH
                           patients and 20
                              healthy.

Gil-Ugarteburu et al.       Test: plasma                ELISA
[18]                       (heparin) of 90
                        patients submitted to
                        prostatic biopsy with
                        positive results for
                                PCa.
                          Control: 135 with
                         negative biopsy for
                                PCa.

Kanoh et al. [19]       Test: serum of 51 PCa           ELISA
                             patients.
                        Control: serum of 39
                                BPH.

Gohji et al. [20]         Test: serum of 98             ELISA
                        individuals with PCa
                          without previous
                             treatment.
                        Control: serum of 76
                        individuals with BPH
                           and 70 healthy.

Authors and title            Conclusion

Baker et al. [4]             Increase of
                          collagenases and
                         TIMP-1 in patients
                         with metastatic PCa
                          compared to those
                         without metastases
                        and in the former in
                           relation to the
                        control group with or
                         without rheumatoid
                             arthritis.
                         Reduction of TIMP-1
                           and collagenase
                        levels 6 months after
                             treatment.
                        After 12 months, the
                              levels of
                        collagenases remained
                         low; however, those
                        of TIMP-1 returned to
                        pretreatment values.

Bonaldi et al. [5]      No difference between
                         mean MMP-13 values
                           among test and
                        control groups at any
                            test period.

Castellano et al. [6]   Differences of MMP-9
                         and TIMP-1 (but not
                           MMP-2) between
                         groups; significant
                        increase of MMP-9 and
                         reduction of TIMP-1
                          in the CaP group
                           relative to the
                           healthy and BPH
                         control; decreased
                        serum levels of MMP-9
                          six months after
                               radical
                           prostatectomy.

Cicco et al. [7]         Patients with serum
                        levels of MMP-2 < 206
                         ng/ml had a higher
                             risk of PCa
                            progression.

Gong et al. [8]          Higher TIMP-1 serum
                         levels in castrated
                            PCa patients.

Incorvaia et al. [9]       MMP-2 and MMP-9
                        significantly higher
                        in PCa patients with
                        bone metastases than
                        in the control group.

Jung et al. [10]        Mean MMP-1 and TIMP-
                            1 scores were
                        significantly higher
                        in the metastatic PCa
                          group than in the
                         nonmetastatic PCa,
                          BPH, and healthy
                         subjects groups. 10
                         of the 18 patients
                         with metastatic PCa
                        presented high levels
                             of TIMP-1.

Morgia et al. [11]      Plasma levels of MMP-
                         2, 9, and 13 higher
                         at diagnosis in the
                           PCa group with
                         metastasis than in
                          the other groups,
                        with reduction after
                        treatment. Decreased
                          TIMP-1 in the PCa
                        group with metastasis
                         in relation to the
                          healthy group but
                         without significant
                         difference between
                               groups.

Oh et al. [12]          Lower survival rates
                          among individuals
                        with higher levels of
                           TIMP-1 in both
                               groups.

Prior et al. [13]        Increased levels of
                        MMP-2 among subjects
                        with PCa compared to
                          the group without
                          PCa. Sensitivity:
                         24.1%; specificity:
                         78.6%; PPV: 31.8%;
                        NPV: 71.4%. Cutoff of
                         718.36 ng-ml (mean
                          level of MMP-2 in
                         those without PCa).

Gonzalez Rodriguez et   No difference in MMP-
al. [14]                  9 levels between
                               groups.

Salminen et al. [15]      No differences in
                         MMP-2 and 9 levels
                           between groups.
                        MMP-2 and 9 presented
                        low accuracy for the
                          diagnosis of bone
                        metastasis in PCa and
                         were not associated
                           with survival.

Szarvas et al. [16]      Higher serum levels
                           of MMP-7 in PCa
                        patients with distant
                             metastasis;
                         specificity of 69%
                         and sensitivity of
                        92% for detection of
                             metastasis.

Zhang et al. [17]       Increased expression
                            and enzymatic
                          activity of MMP-9
                        compared to the other
                               groups.

Gil-Ugarteburu et al.      No correlation
[18]                      between the gene
                          polymorphism and
                        plasma concentration
                              of MMP-9.

Kanoh et al. [19]       MMP/2 and PSA levels
                           associated with
                           metastatic PCa;
                        higher levels of MMP-
                         2 (>950 ng/ml) and
                         PSA (>300 ng/ml) in
                            PCa with bone
                             metastasis.

Gohji et al. [20]       Higher levels of MMP-
                        2 in the PCa than in
                         the control group.

BPH = benign prostate hyperplasia; MMP = matrix metalloproteinase; NPV
= negative predictive value; PCa = prostate cancer; PPV = positive
predictive value; TIMP = tissue inhibitor of metalloproteinase.
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Author:Chaer, William Khalil El-; Moraes, Clayton Franco; Nobrega, Otavio Toledo
Publication:Journal of Aging Research
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Geographic Code:3BRAZ
Date:Jan 1, 2018
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