Exosome-Derived ADAM17 Promotes Liver Metastasis in Colorectal Cancer

Abstract

Exosomes derived from cancer cells are deemed important drivers of pre-metastatic niche formation at distant organs, but the underlying mechanisms of their effects remain largely unknow. Although the role of ADAM17 in cancer cells has been well studied, the secreted ADAM17 effects transported via exosomes are less understood. Herein, we show that the level of exosome-derived ADAM17 is elevated in the serum of patients with metastatic colorectal cancer as well as in metastatic colorectal cancer cells. Furthermore, exosomal ADAM17 was shown to promote the migratory ability of colorectal cancer cells by cleaving the E-cadherin junction. Moreover, exosomal ADAM17 overexpression as well as RNA interference results highlighted its function as a tumor metastasis-promoting factor in colorectal cancer in vitro and in vivo. Taken together, our current work suggests that exosomal ADAM17 is involved in pre-metastatic niche formation and may be utilized as a blood-based biomarker of colorectal cancer metastasis.

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

“…By inhibiting ADAM17 activity in liver CSCs, the broad-spectrum inhibitor of metalloenzymes TAPI-2 blocks Notch activation, responsible for a more aggressive phenotype [238]. CSCs derived from lung adenocarcinoma display high levels of MMP2, which contribute to highly invasive and migratory cell capabilities [242]. These few examples emphasize the relevance of ectoprotease inhibitors in targeting and eliminating CSCs.…”

“…Exosomes transfer various molecules from tumour cells to immune cells and neovascular cells, contributing to the escape from immune surveillance and increased angiogenesis, respectively [231,245,246]. DPP4, APN, ADAM17, and MMP2/9 were recently described in EVs derived from solid and haematological tumours [242,[250][251][252][253][254][255][256][257]. For instance, DPP4 + exosomes in AML patients' plasma suppress the proliferation of normal haematopoietic progenitor cells, and, diprotin A, by inhibiting DPP4 activity, reverses the effects of exosome-mediated myelosuppression [251].…”

“…EVs from myeloid tumours (including AML, CML, MDS, and myeloproliferative neoplasms) contain high levels of APN [250]. Patients with metastatic colorectal cancer (CRC) express high serum levels of exosome-derived ADAM17 which contribute to metastasis formation by cleaving Ecadherin junctions in the subsequent premetastatic niche [242]. Moreover, the interaction between the integrin α5β1 on CRC cells and its ligand ADAM17 on exosomes mediates the uptake of exosomes by cancer recipient cells, which can bear relevance during the peritoneal dissemination of CRC [259].…”

Biocompatible exosome-modified fibrin gel accelerates the recovery of spinal cord injury by VGF-mediated oligodendrogenesis

“…Meng et al proved the presence of large amounts of granulocyte–macrophage colony stimulating factor (GM-CSF) in exosomes, which have the potential to enhance the immunomodulatory function [ 44 ]. Sun et al demonstrated that patients with metastatic colorectal cancer had higher serum levels of exosome-derived ADAM17 and that exosomal ADAM17 could facilitate colorectal cancer cell migration by cleaving the E-cadherin junction [ 45 ]. Chen et al showed that neuronal apoptosis induced by necroptotic astrocyte-derived exosomes could be dramatically impaired by blocking pro-BDNF (brain-derived neurotrophic factor), suggesting that necroptotic astrocytes provoked neuronal apoptosis partially through exosome-derived pro-BDNF [ 46 ].…”

Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring

“…EVs are divided into exosomes, oncosomes, microbubbles, and apoptotic bodies according to size, morphology and origin. Exosomes are widely distributed in saliva, blood, bronchoalveolar lavage (BAL) fluid, sputum, and other body fluids [ 40 ]. The cell membrane invaginates, forms endosomes, then forms multivesicular bodies, and finally secretes the bodies to the outside of the cell to become exosomes with a diameter of 30–100 nm.…”