Tenascin-C expression in the lymph node pre-metastatic niche in muscle-invasive bladder cancer

• Published in: British journal of cancer Vol. 125; no. 10; pp. 1399 - 1407
• Main Authors: Silvers, Christopher R., Messing, Edward M., Miyamoto, Hiroshi, Lee, Yi-Fen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.11.2021; Nature Publishing Group
• Subjects: 631/67/589/1336; 692/53/2421; Aged; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Bladder cancer; Cancer; Cancer Research; Cell Line, Tumor; Cytokines; Cytokines - metabolism; Drug Resistance; Epidemiology; Extracellular vesicles; Extracellular Vesicles - immunology; Female; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; Invasiveness; Lymph nodes; Lymph Nodes - metabolism; Lymphatic system; Male; Metastases; Metastasis; Molecular Medicine; NF-κB protein; Oncology; Prognosis; Survival Analysis; Tenascin; Tenascin - genetics; Tenascin - metabolism; Tenascin C; Tumors; Up-Regulation; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-021-01554-z

Background Markers of stromal activation at future metastatic sites may have prognostic value and may allow clinicians to identify and abolish the pre-metastatic niche to prevent metastasis. In this study, we evaluate tenascin-C as a marker of pre-metastatic niche formation in bladder cancer patient lymph nodes. Methods Tenascin-C expression in benign lymph nodes was compared between metastatic ( n  = 20) and non-metastatic ( n  = 27) patients with muscle-invasive bladder cancer. Urinary extracellular vesicle (EV) cytokine levels were measured with an antibody array to examine potential correlation with lymph node inflammation. The ability of bladder cancer EVs to activate primary bladder fibroblasts was assessed in vitro. Results Lymph node tenascin-C expression was elevated in metastatic patients vs . non-metastatic patients, and high expression was associated with worse survival. Urinary EVs contained four cytokines that were positively correlated with lymph node tenascin-C expression. Bladder cancer EVs induced tenascin-C expression in fibroblasts in an NF-κB-dependent manner. Conclusions Tenascin-C expression in regional lymph nodes may be a good predictor of bladder cancer metastasis and an appropriate imaging target. It may be possible to interrupt pre-metastatic niche formation by targeting EV-borne tumour cytokines or by targeting tenascin-C directly.