Pharmacologic Targeting of MMP2/9 Decreases Peritoneal Metastasis Formation of Colorectal Cancer in a Human Ex Vivo Peritoneum Culture Model.

Autor: Koch J; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.; University of Tübingen, 72074 Tübingen, Germany., Mönch D; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.; University of Tübingen, 72074 Tübingen, Germany., Maaß A; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.; University of Tübingen, 72074 Tübingen, Germany., Mangold A; Robert Bosch Centre for Tumour Diseases (RBCT), Department of General and Visceral Surgery, Robert Bosch Hospital, 70376 Stuttgart, Germany., Gužvić M; University of Regensburg, 93059 Regensburg, Germany., Mürdter T; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.; University of Tübingen, 72074 Tübingen, Germany., Leibold T; Robert Bosch Centre for Tumour Diseases (RBCT), Department of General and Visceral Surgery, Robert Bosch Hospital, 70376 Stuttgart, Germany., Dahlke MH; Robert Bosch Centre for Tumour Diseases (RBCT), Department of General and Visceral Surgery, Robert Bosch Hospital, 70376 Stuttgart, Germany., Renner P; Robert Bosch Centre for Tumour Diseases (RBCT), Department of General and Visceral Surgery, Robert Bosch Hospital, 70376 Stuttgart, Germany.; University Medical Centre Regensburg, 93053 Regensburg, Germany.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Aug 02; Vol. 14 (15). Date of Electronic Publication: 2022 Aug 02.
DOI: 10.3390/cancers14153760
Abstrakt: 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.
Databáze: MEDLINE
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