{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:43:29Z","timestamp":1790437409666,"version":"4.1.0"},"reference-count":25,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Robert Bosch Stiftung","doi-asserted-by":"publisher","award":["DA572(11-4)"],"award-info":[{"award-number":["DA572(11-4)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Matrix metalloproteinases (MMPs) play a crucial role in tumour initiation, progression, and metastasis, including peritoneal carcinosis (PC) formation. MMPs serve as biomarkers for tumour progression in colorectal cancer (CRC), and MMP overexpression is associated with advanced-stage metastasis and poor survival. However, the molecular mechanisms of PC from CRC remain largely unclear. Methods: We investigated the role of MMPs during peritoneal colonisation by CRC cell lines in a human ex vivo peritoneum model and in patient-derived CRC and corresponding PC samples. MMP2 and MMP9 were inhibited using the small-molecule inhibitors batimastat and the specific MMP2\/9 inhibitor III. Results: MMP2 and MMP9 were strongly upregulated in patient-derived samples and following peritoneal colonisation by CRC cells in the ex vivo model. MMP inhibition with batimastat reduced colonisation of HT29 and Colo205 cells by 36% and 68%, respectively (p = 0.0073 and p = 0.0002), while MMP2\/9 inhibitor III reduced colonisation by 50% and 41%, respectively (p = 0.0003 and p = 0.0051). Fibronectin cleavage was enhanced in patient-derived samples of PC and during peritoneal colonisation in the ex vivo model, and this was inhibited by MMP2\/9 inhibition. Conclusion: MMPs were upregulated in patient-derived samples and during peritoneal attachment of CRC cell lines in our ex vivo model. MMP2\/9 inhibition prevented fibronectin cleavage and peritoneal colonisation by CRC cells. MMP inhibitors might thus offer a potential treatment strategy for patients with PC.<\/jats:p>","DOI":"10.3390\/cancers14153760","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T21:41:37Z","timestamp":1659476497000},"page":"3760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Pharmacologic Targeting of MMP2\/9 Decreases Peritoneal Metastasis Formation of Colorectal Cancer in a Human Ex Vivo Peritoneum Culture Model"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5978-3992","authenticated-orcid":false,"given":"Jana","family":"Koch","sequence":"first","affiliation":[{"name":"Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany"},{"name":"University of T\u00fcbingen, 72074 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2437-0394","authenticated-orcid":false,"given":"Dina","family":"M\u00f6nch","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany"},{"name":"University of T\u00fcbingen, 72074 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Maa\u00df","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany"},{"name":"University of T\u00fcbingen, 72074 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Mangold","sequence":"additional","affiliation":[{"name":"Robert Bosch Centre for Tumour Diseases (RBCT), Department of General and Visceral Surgery, Robert Bosch Hospital, 70376 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8089-3969","authenticated-orcid":false,"given":"Miodrag","family":"Gu\u017evi\u0107","sequence":"additional","affiliation":[{"name":"University of Regensburg, 93059 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"M\u00fcrdter","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany"},{"name":"University of T\u00fcbingen, 72074 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Leibold","sequence":"additional","affiliation":[{"name":"Robert Bosch Centre for Tumour Diseases (RBCT), Department of General and Visceral Surgery, Robert Bosch Hospital, 70376 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc-H.","family":"Dahlke","sequence":"additional","affiliation":[{"name":"Robert Bosch Centre for Tumour Diseases (RBCT), Department of General and Visceral Surgery, Robert Bosch Hospital, 70376 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Renner","sequence":"additional","affiliation":[{"name":"Robert Bosch Centre for Tumour Diseases (RBCT), Department of General and Visceral Surgery, Robert Bosch Hospital, 70376 Stuttgart, Germany"},{"name":"University Medical Centre Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.soc.2018.02.006","article-title":"Evolving Treatment Strategies and Outcomes in Advanced Gastric Cancer with Peritoneal Metastasis","volume":"27","author":"Dahdaleh","year":"2018","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1200\/JCO.2003.04.187","article-title":"Randomized Trial of Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy versus Systemic Chemotherapy and Palliative Surgery in Patients with Peritoneal Carcinomatosis of Colorectal Cancer","volume":"21","author":"Verwaal","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1097\/SLA.0b013e3182197102","article-title":"Hyperthermia and Intraperitoneal Chemotherapy for the Treatment of Peritoneal Carcinomatosis: An Experimental Study","volume":"254","author":"Klaver","year":"2011","journal-title":"Ann. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Turner, K.M., Morris, M.C., Sohal, D., Sussman, J.J., Wilson, G.C., Ahmad, S.A., and Patel, S.H. (2022). Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Summary of Key Clinical Trials. J. Clin. Med., 11.","DOI":"10.3390\/jcm11123406"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/S1470-2045(20)30599-4","article-title":"Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy versus Cytoreductive Surgery Alone for Colorectal Peritoneal Metastases (PRODIGE 7): A Multicentre, Randomised, Open-Label, Phase 3 Trial","volume":"22","author":"Elias","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/S2468-1253(19)30239-0","article-title":"Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients with Locally Advanced Colon Cancer (COLOPEC): A Multicentre, Open-Label, Randomised Trial","volume":"4","author":"Klaver","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S1470-2045(20)30322-3","article-title":"Second-Look Surgery plus Hyperthermic Intraperitoneal Chemotherapy versus Surveillance in Patients at High Risk of Developing Colorectal Peritoneal Metastases (PROPHYLOCHIP\u2013PRODIGE 15): A Randomised, Phase 3 Study","volume":"21","author":"Glehen","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s00018-017-2663-1","article-title":"The Peritoneal \u201cSoil\u201d for a Cancerous \u201cSeed\u201d: A Comprehensive Review of the Pathogenesis of Intraperitoneal Cancer Metastases","volume":"75","author":"Uruski","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1158\/0008-5472.CAN-07-5167","article-title":"Loss of E-Cadherin Promotes Ovarian Cancer Metastasis via Alpha 5-Integrin, Which Is a Therapeutic Target","volume":"68","author":"Sawada","year":"2008","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"366","DOI":"10.3390\/cancers6010366","article-title":"The Role of Matrix Metalloproteinases in Colorectal Cancer","volume":"6","author":"Said","year":"2014","journal-title":"Cancers"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1038\/bjc.2012.80","article-title":"MMP-2 and MMP-9 in Normal Mucosa Are Independently Associated with Outcome of Colorectal Cancer Patients","volume":"106","author":"Langers","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_12","first-page":"1391","article-title":"An Ex Vivo Model Using Human Peritoneum to Explore Mesh-Tissue Integration","volume":"6","author":"Falk","year":"2017","journal-title":"Biol. Open"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Klein, C.A., Zohlnh\u00f6fer, D., Petat-Dutter, K., and Wendler, N. (2003). Gene Expression Analysis of a Single or Few Cells. Curr. Protoc. Mol. Biol.","DOI":"10.1002\/0471142727.mb25b08s61"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4977","DOI":"10.1038\/s41467-020-18701-4","article-title":"Interleukin-6 Trans-Signaling Is a Candidate Mechanism to Drive Progression of Human DCCs during Clinical Latency","volume":"11","author":"Grujovic","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"M\u00f6nch, D., Koch, J., Maa\u00df, A., Janssen, N., M\u00fcrdter, T., Renner, P., Fallier-Becker, P., Sola\u00df, W., Schwab, M., and Dahlke, M.-H. (2021). A Human Ex Vivo Coculture Model to Investigate Peritoneal Metastasis and Innovative Treatment Options. Pleura Peritoneum, 6.","DOI":"10.1515\/pp-2021-0128"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1172\/JCI33775","article-title":"The Initial Steps of Ovarian Cancer Cell Metastasis Are Mediated by MMP-2 Cleavage of Vitronectin and Fibronectin","volume":"118","author":"Kenny","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1073\/pnas.93.7.2749","article-title":"Batimastat, a Potent Matrix Mealloproteinase Inhibitor, Exhibits an Unexpected Mode of Binding","volume":"93","author":"Botos","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Pezeshkian, Z., Nobili, S., Peyravian, N., Shojaee, B., Nazari, H., Soleimani, H., Asadzadeh-Aghdaei, H., Ashrafian Bonab, M., Nazemalhosseini-Mojarad, E., and Mini, E. (2021). Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer. Cancers, 13.","DOI":"10.3390\/cancers13246226"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Quintero-Fabi\u00e1n, S., Arreola, R., Becerril-Villanueva, E., Torres-Romero, J.C., Arana-Arg\u00e1ez, V., Lara-Riegos, J., Ram\u00edrez-Camacho, M.A., and Alvarez-S\u00e1nchez, M.E. (2019). Role of Matrix Metalloproteinases in Angiogenesis and Cancer. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01370"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1007\/s00018-011-0763-x","article-title":"Matrix Metalloproteinases in Tumorigenesis: An Evolving Paradigm","volume":"68","author":"Hua","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.neuroscience.2010.03.064","article-title":"Inhibition of Metalloproteinases Derived from Tumours: New Insights in the Treatment of Human Glioblastoma","volume":"168","author":"Gabelloni","year":"2010","journal-title":"Neuroscience"},{"key":"ref_22","first-page":"1103","article-title":"Knockdown of MMP-1 Inhibits the Progression of Colorectal Cancer by Suppressing the PI3K\/Akt\/C-myc Signaling Pathway and EMT","volume":"43","author":"Wang","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/BF00210790","article-title":"Phase I Trial of a Novel Matrix Metalloproteinase Inhibitor Batimastat (BB-94) in Patients with Advanced Cancer","volume":"14","author":"Low","year":"1996","journal-title":"Investig. New Drugs"},{"key":"ref_24","first-page":"1899","article-title":"Phase I Study of Intraperitoneal Metalloproteinase Inhibitor BB94 in Patients with Malignant Ascites","volume":"4","author":"Beattie","year":"1998","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/S0748-7983(97)93077-8","article-title":"Phase I\/II Trial of Batimastat, a Matrix Metalloproteinase Inhibitor, in Patients with Malignant Ascites","volume":"23","author":"Parsons","year":"1997","journal-title":"Eur. J. Surg. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/15\/3760\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:01:08Z","timestamp":1760140868000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/15\/3760"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,2]]},"references-count":25,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["cancers14153760"],"URL":"https:\/\/doi.org\/10.3390\/cancers14153760","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,2]]}}}