Yoneda Toshiyuki, Hiasa Masahiro, Okui Tatsuo, Hata Kenji
Department of Biochemistry, Osaka University Graduate School of Dentistry, Osaka, Japan.
Department of Biomaterials and Bioengineerings, University of Tokushima Graduate School of Dentistry, Tokushima, Japan.
J Bone Oncol. 2021 Aug 25;30:100387. doi: 10.1016/j.jbo.2021.100387. eCollection 2021 Oct.
Bone is one of the preferential target organs of cancer metastasis. Bone metastasis is associated with various complications, of which bone pain is most common and debilitating. The cancer-associated bone pain (CABP) is induced as a consequence of increased neurogenesis, reprogramming and axonogenesis of sensory nerves (SNs) in harmony with sensitization and excitation of SNs in response to the tumor microenvironment created in bone. Importantly, CABP is associated with increased mortality, of which precise cellular and molecular mechanism remains poorly understood. Bone is densely innervated by autonomic nerves (ANs) (sympathetic and parasympathetic nerves) and SNs. Recent studies have shown that the nerves innervating the tumor microenvironment establish intimate communications with tumors, producing various stimuli for tumors to progress and disseminate. In this review, our current understanding of the role of SNs innervating bone in the pathophysiology of CABP will be overviewed. Then the hypothesis that SNs facilitate cancer progression in bone will be discussed in conjunction with our recent findings that SNs play an important role not only in the induction of CABP but also the progression of bone metastasis using a preclinical model of CABP. It is suggested that SNs are a critical component of the bone microenvironment that drives the vicious cycle between bone and cancer to progress bone metastasis. Suppression of the activity of bone-innervating SNs may have potential therapeutic effects on the progression of bone metastasis and induction of CABP.
骨骼是癌症转移的优先靶器官之一。骨转移与多种并发症相关，其中骨痛最为常见且使人衰弱。癌症相关骨痛（CABP）是由于感觉神经（SNs）的神经发生增加、重编程和轴突发生，以及在骨中产生的肿瘤微环境作用下SNs的敏化和兴奋共同作用而诱发的。重要的是，CABP与死亡率增加相关，其精确的细胞和分子机制仍知之甚少。骨骼由自主神经（ANs）（交感神经和副交感神经）和SNs密集支配。最近的研究表明，支配肿瘤微环境的神经与肿瘤建立了密切的通讯，产生各种刺激促使肿瘤进展和扩散。在这篇综述中，我们将概述目前对支配骨骼的SNs在CABP病理生理学中作用的理解。然后，结合我们最近的研究结果，即SNs不仅在CABP的诱导中起重要作用，而且在使用CABP临床前模型的骨转移进展中起重要作用，来讨论SNs促进骨中癌症进展的假说。有人提出，SNs是骨微环境的关键组成部分，驱动骨与癌症之间的恶性循环以促进骨转移。抑制支配骨骼的SNs的活性可能对骨转移的进展和CABP的诱导具有潜在的治疗作用。
