Browsing by Author "Ono, Kisho"

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    The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone
    (Elsevier, 2021-02) Okui, Tatsuo; Hiasa, Masahiro; Ryumon, Shoji; Ono, Kisho; Kunisada, Yuki; Ibaragi, Soichiro; Sasaki, Akira; Roodman, G. David; White, Fletcher A.; Yoneda, Toshiyuki; Medicine, School of Medicine
    Bone pain is a common complication of breast cancer (BC) bone metastasis and is a major cause of increased morbidity and mortality. Although the mechanism of BC-associated bone pain (BCABP) remains poorly understood, involvement of BC products in the pathophysiology of BCABP has been proposed. Aggressive cancers secrete damage-associated molecular patterns (DAMPs) that bind to specific DAMP receptors and modulate cancer microenvironment. A prototypic DAMP, high mobility group box 1 (HMGB1), which acts as a ligand for the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), is increased in its expression in BC patients with poor outcomes. Here we show that 4T1 mouse BC cells colonizing bone up-regulate the expression of molecular pain markers, phosphorylated ERK1/2 (pERK) and pCREB, in the dorsal root ganglia (DRGs) innervating bone and induced BCABP as evaluated by hind-paw mechanical hypersensitivity. Importantly, silencing HMGB1 in 4T1 BC cells by shRNA reduced pERK and pCREB and BCABP with decreased HMGB1 levels in bone. Further, administration of a neutralizing antibody to HMGB1 or an antagonist for RAGE, FPS-ZM1, ameliorated pERK, pCREB and BCABP, while a TLR4 antagonist, TAK242, showed no effects. Consistent with these in vivo results, co-cultures of F11 sensory neuron-like cells with 4T1 BC cells in microfluidic culture platforms increased neurite outgrowth of F11 cells, which was blocked by HMGB1 antibody. Our results show that HMGB1 secreted by BC cells induces BCABP via binding to RAGE of sensory neurons and suggest that the HMGB1/RAGE axis may be a potential novel therapeutic target for BCABP.
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    Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81
    (Spandidos Publications, 2023) Okui, Tatsuo; Hiasa, Masahiro; Hasegawa, Kazuaki; Nakamura, Tomoya; Ono, Kisho; Ibaragi, Soichiro; Kanno, Takahiro; Sasaki, Akira; Yoneda, Toshiyuki; Medicine, School of Medicine
    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, in vivo assessment of cancer pain and in vitro 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 Ca2+ 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.