Koch, Jana and Moench, Dina and Maass, Annika and Mangold, Alina and Guzvic, Miodrag and Muerdter, Thomas and Leibold, Tobias and Dahlke, Marc-H and Renner, Philipp (2022) Pharmacologic Targeting of MMP2/9 Decreases Peritoneal Metastasis Formation of Colorectal Cancer in a Human Ex Vivo Peritoneum Culture Model. CANCERS, 14 (15): 3760. ISSN , 2072-6694
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Simple Summary We investigated the effects of matrix metalloproteinases (MMPs) on the peritoneal attachment of colorectal cancer cells in patient samples and in a human ex vivo peritoneum model. MMP2/9 overexpression and enhanced fibronectin cleavage occurred during peritoneal colonisation, which could be inhibited by specific MMP inhibition, thereby reducing cancer cell attachment. 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY; MATRIX-METALLOPROTEINASE INHIBITOR; CYTOREDUCTIVE SURGERY; PHASE-I; BATIMASTAT; TRIAL; CARCINOMATOSIS; MMP-2; matrix metalloproteinases; peritoneal carcinosis; ex vivo model; colorectal cancer; small molecule inhibitors |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Urologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Feb 2024 06:08 |
| Last Modified: | 14 Feb 2024 06:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57180 |
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