Diagnosis and Prognosis of Prostate Cancer from Circulating Matrix Metalloproteinases and Inhibitors.
Statistics worldwide indicate that prostate cancer (PCa) has high prevalence and lethality, with three-quarters of cases among 65-year-oldsters . 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 .
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 .
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.  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.  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.  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.  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.  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.  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.  obtained the same conclusions as Incorvaia et al.  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. , 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.  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.  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.  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  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.  also found higher levels of TIMP-1 (but not TIMP-2) in patients with PCa.
Serum MMP-7 was investigated by Szarvas et al.  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.  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.  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.  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 , 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 .
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.
Conflicts of Interest
No potential conflicts of interest exist.
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.
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).
 Epidemiology: epidemic rates of cancer incidence in Latin America," Nature Reviews Clinical Oncology, vol. 10, no. 6, p. 304, 2013.
 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.
 E. I. Deryugina and J. P. Quigley, "Matrix metalloproteinases and tumor metastasis," Cancer and Metastasis Reviews, vol. 25, no. 1, pp. 9-34, 2006.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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; email@example.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.  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.  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.  To compare levels of Cross-sectional osteopontin (OPN), MMP-2, MMP-9, and TIMP-1. Cicco et al.  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.  To compare TIMP-1 Descriptive levels of castrated metastatic Pca patients with noncastrated (responsive to androgen ablation therapy). Incorvaia et al.  To compare levels of Cohort MMP-2 and 9 in individuals with PCa with bone metastases in relation to healthy individuals. Jung et al.  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.  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.  To evaluate TIMP-1 as Survival study a predictor of survival in castrated PCa patients. Prior et al.  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.  patients who underwent prostate biopsy. Salminen et al.  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.  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.  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  1562C-T polymorphism of the MMP-9 gene with its plasma levels. Kanoh et al.  To correlate the Cross-sectional serum levels of MMP- 2 and PSA with the different stages of PCa. Gohji et al.  To compare MMP-2 Cross-sectional levels between individuals with and without PCa. Authors and title Material and sample Analysis method Baker et al.  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.  Test: plasma (EDTA) ELISA of 29 PCa patients. Control: 10 healthy men with PSA <1.5 ng/ ml. Castellano et al.  Test: plasma ELISA (heparin) of 96 patients with PCa. Control: 92 individuals with BPH and 125 healthy subjects. Cicco et al.  Serum of 162 PCa ELISA carriers for MMP-2 and 9 and plasma (EDTA) for TIMP-1 and 2. Gong et al.  Test: serum of 39 ELISA castrated metastatic PCa patients. Control: 24 noncastrated metastatic PCa patients. Incorvaia et al.  Test: plasma (EDTA) ELISA of 35 patients with breast cancer and 44 with PCa with bone metastases. Control: 57 healthy patients. Jung et al.  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.  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.  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.  Test: serum of 34 PCa ELISA patients. Control: 79 patients without PCa. Gonzalez Rodriguez et Test: serum of 32 ELISA al.  patients with positive biopsy (PCa group). Control: 58 patients with negative biopsy. Salminen et al.  Test: serum of 35 ELISA individuals with PCa with bone metastasis. Control: 49 individuals with PCa without bone metastasis. Szarvas et al.  Test: serum of 93 ELISA individuals with localized PCa and 13 PCa cases with bone metastasis. Control: 19 healthy individuals. Zhang et al.  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  (heparin) of 90 patients submitted to prostatic biopsy with positive results for PCa. Control: 135 with negative biopsy for PCa. Kanoh et al.  Test: serum of 51 PCa ELISA patients. Control: serum of 39 BPH. Gohji et al.  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.  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.  No difference between mean MMP-13 values among test and control groups at any test period. Castellano et al.  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.  Patients with serum levels of MMP-2 < 206 ng/ml had a higher risk of PCa progression. Gong et al.  Higher TIMP-1 serum levels in castrated PCa patients. Incorvaia et al.  MMP-2 and MMP-9 significantly higher in PCa patients with bone metastases than in the control group. Jung et al.  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.  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.  Lower survival rates among individuals with higher levels of TIMP-1 in both groups. Prior et al.  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.  9 levels between groups. Salminen et al.  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.  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.  Increased expression and enzymatic activity of MMP-9 compared to the other groups. Gil-Ugarteburu et al. No correlation  between the gene polymorphism and plasma concentration of MMP-9. Kanoh et al.  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.  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|
|Date:||Jan 1, 2018|
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