Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+)
Neuropeptide-induced modulation of carcinogenesis in a metastatic breast cancer cell line (MDA-MB-231LUC+)
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DOI：
10.1186/s12935-018-0707-8
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发表时间：
2018-12-22
影响因子：
5.8
通讯作者：
Boada, M. Danilo
中科院分区：
文献类型：
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作者：
Gutierrez, Silvia;Boada, M. Danilo
众所周知，骨转移癌会产生剧痛。有研究表明，这种感知疼痛的程度与疾病进展和预后不良有关。这些数据表明，癌细胞和伤害感受器之间的潜在交互作用不仅会导致疼痛，还会导致癌症的侵袭性，尽管潜在的机制尚未确定。方法采用体外创面愈合实验和胶原细胞侵袭实验，分别观察神经肽（P物质[SP]、降钙素基因相关肽和神经动素A [NKA]）和/或其联合使用对MDA-MB-231（LUC+）迁移和侵袭的剂量依赖性。分别采用western-blot和ELISA法检测NPs对MDA-MB-231（LUC+）细胞培养上清中其受体（SP [NK1]和神经激肽A受体[NK2]， CALCRL和RAMP1）表达和激肽原（高分子量激肽原）释放的影响。采用单因素方差分析、重复测量方差分析或配对t检验检验统计显著性。进行事后检验，并酌情对多重比较进行校正。结果我们的数据显示，NPs强烈地改变了通常用作骨转移癌模型的细胞系（MDA-MB-231(LUC+)）的趋化动力学能力，并增加了这些细胞上它们的受体（NK1R, NK2R， RAMP1和CALCRL）的表达。最后，我们证明NPs还可以通过MDA-MB-231（LUC+）触发HMWK（缓激肽前体）的急性释放，这是一种具有致瘤性和促伤害活性的分子。基于这些观察，我们得出结论，NPs暴露通过增加其迁移和侵入新组织的能力来调节乳腺癌细胞系的侵袭性。此外，这些结果还支持在疾病的初始阶段，周围神经系统的前伤害和癌症促进作用。
BackgroundMetastatic cancer to bone is well-known to produce extreme pain. It has been suggested that the magnitude of this perceived pain is associated with disease progression and poor prognosis. These data suggest a potential cross-talk between cancer cells and nociceptors that contribute not only to pain, but also to cancer aggressiveness although the underlying mechanisms are yet to be stablished.MethodsThe in vitro dose dependent effect of neuropeptides (NPs) (substance P [SP], calcitonin gene-related peptide and neurokinin A [NKA]) and/or its combination, on the migration and invasion of MDA-MB-231(LUC+) were assessed by wound healing and collagen-based cell invasion assays, respectively. The effect of NPs on the expression of its receptors (SP [NK1] and neurokinin A receptors [NK2], CALCRL and RAMP1) and kininogen (high-molecular-weight kininogen) release to the cell culture supernatant of MDA-MB-231(LUC+), were measured using western-blot analysis and an ELISA assay, respectively. Statistical significance was tested using one-way ANOVA, repeated measures ANOVA, or the paired t-test. Post-hoc testing was performed with correction for multiple comparisons as appropriate.ResultsOur data show that NPs strongly modify the chemokinetic capabilities of a cellular line commonly used as a model of metastatic cancer to bone (MDA-MB-231(LUC+)) and increased the expression of their receptors (NK1R, NK2R, RAMP1, and CALCRL) on these cells. Finally, we demonstrate that NPs also trigger the acute release of HMWK (Bradykinin precursor) by MDA-MB-231(LUC+), a molecule with both tumorigenic and pro-nociceptive activity.ConclusionsBased on these observations we conclude that NPs exposure modulates this breast cancer cellular line aggressiveness by increasing its ability to migrate and invade new tissues. Furthermore, these results also support the pro nociceptive and cancer promoter role of the peripheral nervous system, during the initial stages of the disease.