Nidogen 1‐Enriched Extracellular Vesicles Facilitate Extrahepatic Metastasis of Liver Cancer by Activating Pulmonary Fibroblasts to Secrete Tumor Necrosis Factor Receptor 1

Abstract

In hepatocellular carcinoma (HCC) patients with extrahepatic metastasis, the lung is the most frequent site of metastasis. However, how the lung microenvironment favors disseminated cells remains unclear. Here, it is found that nidogen 1 (NID1) in metastatic HCC cell‐derived extracellular vesicles (EVs) promotes pre‐metastatic niche formation in the lung by enhancing angiogenesis and pulmonary endothelial permeability to facilitate colonization of tumor cells and extrahepatic metastasis. EV‐NID1 also activates fibroblasts, which secrete tumor necrosis factor receptor 1 (TNFR1), facilitate lung colonization of tumor cells, and augment HCC cell growth and motility. Administration of anti‐TNFR1 antibody effectively diminishes lung metastasis induced by the metastatic HCC cell‐derived EVs in mice. In the clinical perspective, analysis of serum EV‐NID1 and TNFR1 in HCC patients reveals their positive correlation and association with tumor stages suggesting the potential of these molecules as noninvasive biomarkers for the early detection of HCC. In conclusion, these results demonstrate the interplay of HCC EVs and activated fibroblasts in pre‐metastatic niche formation and how blockage of their functions inhibits distant metastasis to the lungs. This study offers promise for the new direction of HCC treatment by targeting oncogenic EV components and their mediated pathways.

Nidogen-1 expression is associated with overall survival and temozolomide sensitivity in low-grade glioma patients

“…Moreover, cathepsin degradation of Nid-1 is strongly associated with NSCLC [ 7 ]. Mao et al reported that NID1-enriched extracellular vesicles derived from HCC cells facilitate colonization of tumor cells and extra-hepatic metastasis by activating pulmonary fibroblasts to secrete TNFR1 [ 8 ]. Our study showed that NID1 expression was significantly higher in glioblastoma, anaplastic astrocytoma, and oligodendroglioma compared to the normal brain tissues and cells using glioma datasets from Oncomine, UALCAN, and GEPIA databases.…”

“…Hence, there is an urgent need to identify new and more effective therapeutic targets in gliomas. The abnormally high expression of NID1, which is widely discussed in various types of other cancers including ovarian cancer, non-small cell lung cancer and hepatocellular carcinoma [ 6 – 8 ], in glioma is uncovered through the differently expressed genes (DEGs) analysis between normal and cancer of brain/central nervous system (CNS). However, not many studies on the role of NID1 in glioma are available, and thus we are interested in whether its function in glioma is the same as in other cancer types.…”

“…Serum NID1 levels are elevated in non-small cell lung cancer (NSCLC) patients compared to the healthy controls [ 7 ]. NID1-enriched vesicles secreted by hepatocellular carcinoma (HCC) cells facilitate extrahepatic HCC metastasis [ 8 ]. These findings suggest that NID1 plays a crucial role in tumorigenesis.…”

The Key Role of Exosomes on the Pre-metastatic Niche Formation in Tumors

“…Yokota, Y. et al determined that HuH-7M (highly intrahepatic metastatic cell line) derived exosomal miRNAs (miR-638, miR-663a, miR-3648, and miR-4258) downregulated ECs expression of ZO-1 and vascular endothelial-cadherin (VE-cadherin) and increased vascular permeability to promote intrahepatic tumorigenesis ( Yokota et al, 2021 ). Additionally, Mao, X. et al found that metastatic HCC cell-derived exosomal nidogen 1 (NID1) activated lung fibroblasts to facilitate tumor extrahepatic metastasis via enhancing angiogenesis and pulmonary endothelial permeability ( Mao et al, 2020 ). In melanoma, exosomes highly expressing urokinase plasminogen activator receptor (uPAR) were internalized by ECs, thus enhancing VE-Cadherin, EGFR, and uPAR expression and pro-angiogenic effects ( Biagioni et al, 2021 ).…”

Biomarkers for hepatocellular carcinoma based on body fluids and feces

“…Preclinical trials demonstrated the role of EVs in migration, invasion, and metastasis of HCC. Nidogen 1-enriched EVs have been reported to induce pulmonary fibroblasts to secrete tumor necrosis factor receptor 1, resulting in accelerated extrahepatic metastasis[ 70 ]. Similar findings on the functional role of exosomal miR92a-3p in promoting epithelial-mesenchymal transition and metastasis were found by regulating the Akt/Snail signaling pathway[ 71 ].…”