Pronociceptive Roles of Schwann Cell–Derived Galectin-3 in Taxane-Induced Peripheral Neuropathy
Year: 2021
Type: article
Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of taxanes such as paclitaxel and docetaxel. Despite the high medical needs, insufficient understanding of the complex mechanism underlying CIPN pathogenesis precludes any endorsed causal therapy to prevent or relieve CIPN. In this study, we report that elevation of plasma galectin-3 level is a pathologic change common to both patients with taxane-treated breast cancer with CIPN and a mouse model of taxane-related CIPN. Following multiple intraperitoneal injections of paclitaxel in mice, galectin-3 levels were elevated in Schwann cells within the sciatic nerve but not in other peripheral organs or cells expressing galectin-3. Consistent with this, paclitaxel treatment of primary cultures of rat Schwann cells induced upregulation and secretion of galectin-3. In vitro migration assays revealed that recombinant galectin-3 induced a chemotactic response of the murine macrophage cell line RAW 264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. By contrast, chemical depletion of macrophages by clodronate liposomes suppressed paclitaxel-induced mechanical hypersensitivity despite the higher level of plasma galectin-3. Deficiency (Galectin-3−/− mice) or pharmacologic inhibition of galectin-3 inhibited paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. In conclusion, we propose that Schwann cell–derived galectin-3 plays a pronociceptive role via macrophage infiltration in the pathogenesis of taxane-induced peripheral neuropathy. Therapies targeting this phenomenon, which is common to patients with CIPN and mouse models, represent a novel approach to suppress taxane-related CIPN. Significance: These findings demonstrate that the elevation of plasma galectin-3 is a CIPN-related pathologic change common to humans and mice, and that targeting galectin-3 is a therapeutic option to delay CIPN progression.
Source: Cancer Research
Authors: Madoka Koyanagi, Satoshi Imai, Mayuna Matsumoto, Yoko Iguma, Nobuko Kawaguchi-Sakita, Takeshi Kotake, Yuki Iwamitsu, Mpumelelo Ntogwa, Ren Hiraiwa, Kazuki Nagayasu, Mamiko Saigo, Takashi Ogihara, Atsushi Yonezawa, Tomohiro Omura, Shunsaku Nakagawa, Takayuki Nakagawa, Kazuo Matsubara
Institutions: Kyoto University Hospital, Kyoto University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Elucidation of oxaliplatin-induced peripheral neuropathy focusing on peripheral blood flow / peripheral temperature regulation mechanism, Identification of determinants of depression pathogenesis and treatment, Drug development for peripheral neuropathy by axonal regeneration targeting Schwann cell differentiation, 抗がん剤誘発末梢神経障害の機序解明とシュワン細胞再髄鞘化を基盤とした治療法の探索, Optogenetic manipulation of primate serotonin system to understand body-emotion integration, G4120871427, The neural basis of modulation in decision-making under negative emotions: Exploring the extended amygdala-basal ganglia circuit., G5721353159, Analysis of mechanisms underlying chemotherapy-induced peripheral neuropathy and screening its prophylactic/therapeutic drugs, Translational Research for development of prophylactic or therapeutic drug for peripheral neuropathy, Possible involvement of Schwann cell in the development of chemotherapy-induced peripheral neuropathy and search for new therapies by drug-repositioning
OpenAlex ID: W3131685531