Extravesicular TIMP-1 is a non-invasive independent prognostic marker and potential therapeutic target in colorectal liver metastases

Abstract

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.

A prospective cohort study of TIMP1 as prognostic biomarker in gastric and colon cancer

“…In colorectal cancer, TIMP1 predicts the prognosis and is associated with OS (37,10). In patients with colorectal liver metastasis, the invasion front has high expression of stromal TIMP1, which is associated with poor progression free survival (38).…”

Prognostic circulating proteomic biomarkers in colorectal liver metastases

“…Extracellular vesicles initiate and sustain the tumour microenvironment that influences cellular function and the remodelling of the extracellular matrix (ECM) [16] . Extracellular vesicles are upregulated in patients with cancer compared to healthy controls [16] .…”

Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via extracellular vesicles

“… [ 180 ] TIMP-1 Colorectal cancer Cancer-derived EVs transfer TIMP-1 to induced ECM remodelling in the fibroblasts. [ 178 ] LMP1 Epstein-Barr virus (EBV)-associated Nasopharyngeal carcinoma Generate CAFs through NF-κB signalling and change aerobic glycolysis and autophagy in CAFs [ 76 ] PKM2 Gastric cancer Generate CAFs by PKM2 nuclear translocation inducing NF-κB signalling [ 77 ] TGF-β Head and neck squamous cell carcinoma Generate CAFs through activation canonical TGF-β signalling pathway [ 32 ] PKM2 Hypoxic resistant lung cancer cells Induce metabolic reprogramming in CAFs [ 78 ] IGF2 Liver cancer Fluid shear stress-induced cancer cell medium promoted the activation and proliferation of CAFs via activating PI3K/AKT signaling pathway. [ 172 ] α-SMA Lung cancer Cancer-derived EV transfer α-SMA in both lung cancer cell line and fibroblasts.…”