- Titel
- Extravesicular TIMP-1 is a non-invasive independent prognostic marker and potential therapeutic target in colorectal liver metastases
- Zitierfähige Url:
- https://nbn-resolving.org/urn:nbn:de:bsz:14-qucosa2-911955
- Quellenangabe
- Oncogene
Erscheinungsjahr: 2022
Jahrgang: 41
Seiten: 1809-1820
E-ISSN: 1476-5594 - Erstveröffentlichung
- 2022
- Abstract (EN)
- Molecular reprogramming of stromal microarchitecture by tumour-derived extracellular vesicles (EVs) is proposed to favour pre-metastatic niche formation. We elucidated the role of extravesicular tissue inhibitor of matrix metalloproteinase-1 (TIMP1EV) in pro-invasive extracellular matrix (ECM) remodelling of the liver microenvironment to aid tumour progression in colorectal cancer (CRC). Immunohistochemistry analysis revealed a high expression of stromal TIMP1 in the invasion front that was associated with poor progression-free survival in patients with colorectal liver metastases. Molecular analysis identified TIMP1EV enrichment in CRC-EVs as a major factor in the induction of TIMP1 upregulation in recipient fibroblasts. Mechanistically, we proved that EV-mediated TIMP1 upregulation in recipient fibroblasts induced ECM remodelling. This effect was recapitulated by human serum-derived EVs providing strong evidence that CRC release active EVs into the blood circulation of patients for the horizontal transfer of malignant traits to recipient cells. Moreover, EV-associated TIMP1 binds to HSP90AA, a heat-shock protein, and the inhibition of HSP90AA on human-derived serum EVs attenuates TIMP1EV-mediated ECM remodelling, rendering EV-associated TIMP1 a potential therapeutic target. Eventually, in accordance with REMARK guidelines, we demonstrated in three independent cohorts that EV-bound TIMP1 is a robust circulating biomarker for a non-invasive, preoperative risk stratification in patients with colorectal liver metastases.
- Andere Ausgabe
- Link zum Artikel der zuerst in der Zeitschrift „Oncogene” bei Springer Nature erschienen ist.
DOI: 10.1038/s41388-022-02218-9 - Verweis
- Ergänzendes Material ist unter folgendem Link zu finden.
Link: https://www.nature.com/articles/s41388-022-02218-9#Sec14 - Freie Schlagwörter (DE)
- Metastasierung, Prädiktive Marker, Prognostische Marker
- Freie Schlagwörter (EN)
- Metastasis, Predictive markers, Prognostic markers
- Klassifikation (DDC)
- 610
- Verlag
- Springer Nature, London
- Förder- / Projektangaben
- Roland-Ernst-Foundation (DFG)
ID: 5/15 - Deutsche Forschungsgemeinschaft ID: KA 3511/3-1
- Version / Begutachtungsstatus
- publizierte Version / Verlagsversion
- URN Qucosa
- urn:nbn:de:bsz:14-qucosa2-911955
- Veröffentlichungsdatum Qucosa
- 04.06.2024
- Dokumenttyp
- Artikel
- Sprache des Dokumentes
- Englisch
- Lizenz / Rechtehinweis
CC BY 4.0