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Abstract
BackgroundMetastasis to regional lymph nodes is a common step in the progression of cancer. Recent evidence suggests that tumor production of CXCR4 promotes lymph node metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers.MethodsNitrite/nitrate levels and functional CXCR4 expression were assessed in K1 and B-CPAP papillary thyroid carcinoma (PTC) cells after induction and/or inhibition of NO synthesis. CXCR4 expression was also analyzed in primary human PTC. The relationship between nitrotyrosine levels, which are a biomarker for peroxynitrate formation from NO in vivo, CXCR4 expression, and lymph node status was also analyzed.ResultsProduction of nitrite/nitrate and functional CXCR4 expression in both cell lines was increased by treatment with the NO donor DETA NONOate. The NOS inhibitor L-NAME eliminated this increase. Positive CXCR4 immunostaining was observed in 60.7% (34/56) of PTCs. CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis in human PTC.ConclusionOur data indicate that NO stimulates CXCR4 expression in vitro. Formation of the NO biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in human PTC. NO may induce lymph node metastasis via CXCR4 induction in papillary thyroid carcinoma.
Highlights
Metastasis to regional lymph nodes is a common step in the progression of cancer
Nitric oxide (NO) regulates CXCL12-mediated chemoinvasion To determine the role of NO in cellular response to the CXC chemokine receptor 4 (CXCR4) ligand CXCL12, we examined the effect of LNAME on rhCXCL12- and DETA NONOate-induced invitro Matrigel invasion by K1 and B-CPAP cells (Figure 2). rhCXCL12 produced a dose-dependent increase in invasiveness, which was inhibited in cells pretreated with LNAME
CXCR4 expression is correlated with nitrotyrosine levels and lymph node metastasis We have previously reported that nitrotyrosine formation was detected by immunohistochemistry in all papillary thyroid carcinoma (PTC) [4]
Summary
Metastasis to regional lymph nodes is a common step in the progression of cancer. Recent evidence suggests that tumor production of CXCR4 promotes lymph node metastasis. Nitric oxide (NO) may increase metastatic ability in human cancers. Nitric oxide (NO) is a pleiotropic regulator and inflammatory stimulant, critical to numerous biological processes, including vasodilatation, neurotransmission, and macrophage-mediated immunity [1]. It has both genotoxic and metastasis-promotng properties. Increased NO generation in cancer cells may contribute to tumor hemangiogenesis or lymphangiogenesis by up-regulating vascular endothelial growth factor (VEGF) [2], VEGF-C [3], or VEGF-D [4].
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