Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan.
Department of Medicine, Hematology Oncology, Indiana University School of Medicine and The Roudebush Veterans Administration, Indianapolis, IN 46202, USA.
Int J Oncol. 2023 Mar;62(3). doi: 10.3892/ijo.2023.5487. Epub 2023 Feb 17.
Breast cancer (BC) bone metastasis causes bone pain (BP), which detrimentally damages the quality of life and outcome of patients with BC. However, the mechanism of BC‑BP is poorly understood, and effective treatments are limited. The present study demonstrated a novel mechanism of BC‑BP using a mouse model of bone pain, in which mouse (EO771) and human (MDA‑MB‑231) BC cells were injected in the bone marrow cavity of tibiae. Western blot analysis using sensory nerves, assessment of cancer pain and calcium flux analysis were performed. These mice developed progressive BC‑BP in tibiae in conjunction with an upregulation of phosphorylated pERK1/2 and cAMP‑response element‑binding protein (pCREB), which are molecular indicators of neuron excitation, in the dorsal root ganglia (DRG) of sensory nerves. Importantly, mice injected with BC cells, in which the expression of the lactic acid transporter monocarboxylate transporter 4 (MCT4) was silenced, exhibited decreased BC‑BP with downregulated expression of pERK1/2 and pCREB in the DRG and reduced circulating levels of lactate compared with mice injected with parental BC cells. Further, silencing of the cell‑surface orphan receptor for lactate, G protein‑coupled receptor 81 (GPR81), in the F11 sensory neuron cells decreased lactate‑promoted upregulation of pERK1/2 and Ca influx, suggesting that the sensory neuron excitation was inhibited. These results suggested that lactate released from BC cells via MCT4 induced BC‑BP through the activation of GPR81 of sensory neurons. In conclusion, the activation of GPR81 of sensory neurons by lactate released via MCT4 from BC was demonstrated to contribute to the induction of BC‑BP, and disruption of the interactions among lactate, MCT4 and GPR81 may be a novel approach to control BC‑BP.
乳腺癌（BC）骨转移导致骨痛（BP），严重损害了 BC 患者的生活质量和预后。然而，BC-BP 的机制尚不清楚，有效的治疗方法也有限。本研究通过小鼠骨痛模型，展示了一种新的 BC-BP 机制，在该模型中，将小鼠（EO771）和人（MDA-MB-231）BC 细胞注入胫骨骨髓腔。使用感觉神经进行 Western blot 分析，评估癌症疼痛和钙通量分析。这些小鼠在胫骨中逐渐发展为 BC-BP，同时感觉神经背根神经节（DRG）中磷酸化的 pERK1/2 和 cAMP 反应元件结合蛋白（pCREB）上调，这是神经元兴奋的分子指标。重要的是，与注射亲本 BC 细胞的小鼠相比，注射沉默乳酸转运体单羧酸转运蛋白 4（MCT4）表达的 BC 细胞的小鼠，其 DRG 中 pERK1/2 和 pCREB 的表达下调，DRG 中乳酸的循环水平降低，BC-BP 减少。此外，在 F11 感觉神经元细胞中沉默细胞表面的乳酸受体孤儿 G 蛋白偶联受体 81（GPR81），降低了乳酸促进的 pERK1/2 和 Ca 内流的上调，表明感觉神经元兴奋被抑制。这些结果表明，BC 细胞通过 MCT4 释放的乳酸通过激活感觉神经元的 GPR81 诱导 BC-BP。总之，通过 MCT4 从 BC 细胞释放的乳酸激活感觉神经元的 GPR81 被证明有助于诱导 BC-BP，破坏乳酸、MCT4 和 GPR81 之间的相互作用可能是控制 BC-BP 的一种新方法。
