Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Elevated ratio of MMP2/MMP9 activity is associated with poor response to chemotherapy in osteosarcoma

Authors: Pierre Kunz, Heiner Sähr, Burkhard Lehner, Christian Fischer, Elisabeth Seebach, Jörg Fellenberg

Published in: BMC Cancer | Issue 1/2016

Login to get access

Abstract

Background

Matrix metalloproteinases (MMPs) are crucially involved in the regulation of multiple stages of cancer progression. Elevated MMP levels have been associated with the development of metastases and poor prognosis in several types of cancer. However, the role of MMPs in osteosarcoma and their prognostic value is still unclear. Available data are conflicting, most likely due to different technical approaches. We hypothesized that in contrast to total mRNA or protein levels frequently analyzed in previous studies the enzymatic activities of MMPs and their inhibitors the tissue inhibitors of matrix metalloproteinases (TIMPs) are closer related to their biological functions. We therefore aimed to evaluate the reliability of different zymography techniques for the quantification of MMP and TIMP activities in osteosarcoma biopsies in order to investigate their distribution, possible regulation and prognostic value.

Methods

All analyses were done using cryo-conserved osteosarcoma pretreatment biopsies (n = 18). Gene and protein expression of MMPs and TIMPs were analyzed by RT-qPCR and western blot analysis, respectively. Overall MMP activity was analyzed by in situ zymography, individual MMP activities were analyzed by gelatin zymography. Reverse zymography was used to detect and quantify TIMP activities.

Results

Strong overall MMP activities could be detected in osteosarcoma pretreatment biopsies with MMP2 and MMP9 as predominant active MMPs. In contrast to total RNA or protein expression MMP2 and MMP9 activities showed significant quantitative differences between good and poor responders. While MMP9 activity was high in the good responder group and significantly decreased in the poor responder group, MMP2 activity showed a reverse distribution. Likewise, significant differences were detected concerning the activity of TIMPs resulting in a negative correlation of TIMP1 activity with MMP2 activity (p = 0.044) and negative correlations of TIMP2 and TIMP3 with MMP9 activity (p = 0.007 and p = 0.006).

Conclusion

In contrast to mRNA or protein levels MMP and TIMP activities showed significant differences between the analyzed good and poor responder groups. A shift from MMP9 to predominant MMP2 activity is associated with poor response to chemotherapy suggesting that the ratio of MMP2/MMP9 activity might be a valuable and easily accessible marker to predict the response to chemotherapy in osteosarcoma.
Literature
1.
Ferrari S, Smeland S, Mercuri M, Bertoni F, Longhi A, Ruggieri P, Alvegard TA, Picci P, Capanna R, Bernini G, Muller C, Tienghi A, Wiebe T, Comandone A, Bohling T, Del Prever AB, Brosjo O, Bacci G, Saeter G. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol. 2005;23:8845–52.CrossRefPubMed
2.
Provisor AJ, Ettinger LJ, Nachman JB, Krailo MD, Makley JT, Yunis EJ, Huvos AG, Betcher DL, Baum ES, Kisker CT, Miser JS. Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children’s Cancer Group. J Clin Oncol. 1997;15:76–84.CrossRefPubMed
3.
Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment - Where do we stand? A state of the art review. Cancer Treat Rev. 2014;40:523–32.CrossRefPubMed
4.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74.CrossRefPubMed
5.
Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39.CrossRefPubMed
6.
Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 2000;18:1135–49.CrossRefPubMed
7.
Benassi MS, Gamberi G, Magagnoli G, Molendini L, Ragazzini P, Merli M, Chiesa F , Balladelli A, Manfrini M, Bertoni F, Mercuri M, Picci P. Metalloproteinase expression and prognosis in soft tissue sarcomas. Ann Oncol. 2001;12:75–80.CrossRefPubMed
8.
Rundhaug JE. Matrix metalloproteinases, angiogenesis, and cancer: commentary re: A. C. Lockhart et al., Reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. Clin. Cancer Res., 9: 00-00, 2003. Clin Cancer Res. 2003;9:551–4.PubMed
9.
Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol. 1997;74:111–22.PubMed
10.
Boulday G, Fitau J, Coupel S, Soulillou JP, Charreau B. Exogenous tissue inhibitor of metalloproteinase-1 promotes endothelial cell survival through activation of the phosphatidylinositol 3-kinase/Akt pathway. Ann N YAcad Sci. 2004;1030:28–36.CrossRefPubMed
11.
Salzer-Kuntschik M, Brand G, Delling G. [Determination of the degree of morphological regression following chemotherapy in malignant bone tumors]. Pathologe. 1983;4:135–41.PubMed
12.
Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jurgens H, Winkler K. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20:776–90.CrossRefPubMed
13.
Snoek-van Beurden PA, Von den Hoff JW. Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors. Biotechniques. 2005;38:73–83.CrossRefPubMed
14.
McCawley LJ, Matrisian LM. Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today. 2000;6:149–56.CrossRefPubMed
15.
16.
Stetler-Stevenson WG. The role of matrix metalloproteinases in tumor invasion, metastasis, and angiogenesis. Surg Oncol Clin N Am. 2001;10:383–92. x.PubMed
17.
Li H, Zhang K, Liu LH, Ouyang Y, Bu J, Guo HB, Xiao T. A systematic review of matrix metalloproteinase 9 as a biomarker of survival in patients with osteosarcoma. Tumour Biol. 2014;35(6):5487–91.CrossRefPubMed
18.
Uchibori M, Nishida Y, Nagasaka T, Yamada Y, Nakanishi K, Ishiguro N. Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma. Int J Oncol. 2006;28:33–42.PubMed
19.
Kushlinsky NE, Solovyov YN, Babkina IV, Gershtein ES, Bulicheva IV. Matrix metalloproteinases 2, 7, 9 and tissue inhibitor of matrix metalloproteinase-1 in the sera of patients with bone tumors. Bull Exp Biol Med. 2010;149:233–5.CrossRefPubMed
20.
Shen W, Xi H, Wei B, Chen L. The prognostic role of matrix metalloproteinase 2 in gastric cancer: a systematic review with meta-analysis. J Cancer Res Clin Oncol. 2014;140(6):1003–9.CrossRefPubMed
21.
Korpi JT, Hagstrom J, Lehtonen N, Parkkinen J, Sorsa T, Salo T, Laitinen M. Expression of matrix metalloproteinases-2, -8, -13, -26, and tissue inhibitors of metalloproteinase-1 in human osteosarcoma. Surg Oncol. 2011;20:e18–22.CrossRefPubMed
22.
Cho HJ, Lee TS, Park JB, Park KK, Choe JY, Sin DI, Park YY, Moon YS, Lee KG, Yeo JH, Han SM, Cho YS, Choi MR, Park NG, Lee YS, Chang YC. Disulfiram suppresses invasive ability of osteosarcoma cells via the inhibition of MMP-2 and MMP-9 expression. J Biochem Mol Biol. 2007;40:1069–76.PubMed
23.
Tanimura S, Kadomoto R, Tanaka T, Zhang YJ, Kouno I, Kohno M. Suppression of tumor cell invasiveness by hydrolyzable tannins (plant polyphenols) via the inhibition of matrix metalloproteinase-2/-9 activity. Biochem Biophys Res Commun. 2005;330:1306–13.CrossRefPubMed
24.
Talvensaari-Mattila A, Paakko P, Turpeenniemi-Hujanen T. Matrix metalloproteinase-2 (MMP-2) is associated with survival in breast carcinoma. Br J Cancer. 2003;89:1270–5.CrossRefPubMedPubMedCentral
25.
Davidson B, Goldberg I, Gotlieb WH, Kopolovic J, Ben Baruch G, Nesland JM, Reich R. The prognostic value of metalloproteinases and angiogenic factors in ovarian carcinoma. Mol Cell Endocrinol. 2002;187:39–45.CrossRefPubMed
26.
Ruokolainen H, Paakko P, Turpeenniemi-Hujanen T. Expression of matrix metalloproteinase-9 in head and neck squamous cell carcinoma: a potential marker for prognosis. Clin Cancer Res. 2004;10:3110–6.CrossRefPubMed
27.
Kawashima A, Nakanishi I, Tsuchiya H, Roessner A, Obata K, Okada Y. Expression of matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) induced by tumour necrosis factor alpha correlates with metastatic ability in a human osteosarcoma cell line. Virchows Arch. 1994;424:547–52.CrossRefPubMed
28.
Kido A, Tsutsumi M, Iki K, Takahama M, Tsujiuchi T, Morishita T, Tamai S, Konishi Y. Overexpression of matrix metalloproteinase (MMP)-9 correlates with metastatic potency of spontaneous and 4-hydroxyaminoquinoline 1-oxide (4-HAQO)-induced transplantable osteosarcomas in rats. Cancer Lett. 1999;137:209–16.CrossRefPubMed
29.
Foukas AF, Deshmukh NS, Grimer RJ, Mangham DC, Mangos EG, Taylor S. Stage-IIB osteosarcomas around the knee. A study of MMP-9 in surviving tumour cells. J Bone Joint Surg Br. 2002;84:706–11.CrossRefPubMed
30.
Wang J, Shi Q, Yuan TX, Song QL, Zhang Y, Wei Q, Zhou L, Luo J, Zuo G, Tang M, He TC, Weng Y. Matrix metalloproteinase 9 (MMP-9) in osteosarcoma: Review and meta-analysis. Clin Chim Acta. 2014;433C:225–31.CrossRef
31.
Bjornland K, Flatmark K, Pettersen S, Aaasen AO, Fodstad O, Maelandsmo GM. Matrix metalloproteinases participate in osteosarcoma invasion. J Surg Res. 2005;127:151–6.CrossRefPubMed
32.
Kang HG, Kim HS, Kim KJ, Oh JH, Lee MR, Seol SM, Han I. RECK expression in osteosarcoma: correlation with matrix metalloproteinases activation and tumor invasiveness. J Orthop Res. 2007;25:696–702.CrossRefPubMed
33.
Kunz P, Fellenberg J, Moskovszky L, Sapi Z, Krenacs T, Machado I, Poeschl J, Lehner B, Szendroi M, Ruef P, Bohlmann M, Bosch AL, Ewerbeck V, Kinscherf R, Fritzsching B. Improved Survival in Osteosarcoma Patients with Atypical Low Vascularization. Ann Surg Oncol. 2015;22(2):489–96.CrossRefPubMed
34.
Itoh T, Tanioka M, Yoshida H, Yoshioka T, Nishimoto H, Itohara S. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 1998;58:1048–51.PubMed
35.
Chantrain CF, Shimada H, Jodele S, Groshen S, Ye W, Shalinsky DR, Werb Z, Coussens LM, DeClerck YA. Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment. Cancer Res. 2004;64:1675–86.CrossRefPubMed
36.
Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000;2:737–44.CrossRefPubMedPubMedCentral
37.
Fang J, Shing Y, Wiederschain D, Yan L, Butterfield C, Jackson G, Harper J, Tamvakopoulos G, Moses MA. Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc Natl Acad Sci U S A. 2000;97:3884–9.CrossRefPubMedPubMedCentral
Metadata
Title
Elevated ratio of MMP2/MMP9 activity is associated with poor response to chemotherapy in osteosarcoma
Authors
Pierre Kunz
Heiner Sähr
Burkhard Lehner
Christian Fischer
Elisabeth Seebach
Jörg Fellenberg
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2266-5

Other articles of this Issue 1/2016

BMC Cancer 1/2016 Go to the issue

Research article

At least two well-spaced samples are needed to genotype a solid tumor

Research article

Increased long noncoding RNA SNHG20 predicts poor prognosis in colorectal cancer

Research article

Detection of circulating tumor cells using manually performed immunocytochemistry (MICC) does not correlate with outcome in patients with early breast cancer – Results of the German SUCCESS-A- trial

Research article

Is immunohistochemistry of BRAF V600E useful as a screening tool and during progression disease of melanoma patients?

Research article

The prognostic significance of human epidermal growth factor receptor family protein expression in operable pancreatic cancer

Research Article

Differences in predictions of ODE models of tumor growth: a cautionary example
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits