Abstract
BackgroundMarkers 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.MethodsTenascin-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.ResultsLymph 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.ConclusionsTenascin-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.
Highlights
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
Primary fibroblast culture expression would be higher in the tumour-free lymph nodes of metastatic We obtained paracarcinoma bladder mucosa sections of grossly normal patients than in those of non-metastatic patients, and second, that high appearance from pN0 bladder cancer patients consented for the study
To identify possible markers of lymph node metastatic niche formation, we first measured the expression of ten prospective fibroblast activation marker genes in primary cancer-associated fibroblasts (CAF) cells cultured from a patient tumour, comparing them to two fibroblast primary cultures derived from paracarcinoma bladder mucosa with grossly normal appearance. (Fig. 1a)
Summary
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. We evaluate tenascin-C as a marker of premetastatic 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. The ability of bladder cancer EVs to activate primary bladder fibroblasts was assessed in vitro. 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. The use of sensitive stromal activation markers to detect pre-metastatic niche formation may help clinicians predict metastatic progression
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