Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
Department of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
Cells. 2022 Jan 23;11(3):381. doi: 10.3390/cells11030381.
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of the four molecular subgroups, Group 3 MB is the most aggressive and has the worst prognosis. To understand the origins of chemoresistance involving IL-6/STAT3 signaling, we used in vitro co-culture systems to investigate the contribution of microglia as a brain tumor microenvironment cellular source of paracrine cytokines that promotes acquired drug resistance in Group 3 MB. MB cells subjected to co-culture with microglia exhibited increased expression of phosphorylated JAK1 and STAT3, which was correlated with enhanced resistance to vincristine. We found that both microglia and MB cells co-cultured with microglia secreted significant quantities of IL-6, indicating that IL-6 is a paracrine and autocrine cytokine able to initiate and sustain STAT3 activity in MB cells. Surprisingly, IL-6R MB cells, which cannot respond to exogenous IL-6 stimuli, were responsive to microglia co-culture induced activation of STAT3 and chemoresistance. Subsequently, we found that MB cells conditioned in vitro with the IL-6 family cytokines, IL-6, OSM, LIF, or IL-11, exhibited enhanced JAK1/STAT3 activity and chemoresistance. Intriguingly, MB cells conditioned with any one of the IL-6 family cytokine secreted multiple IL-6 family cytokines, implicating a feedback network involving multiple cytokines. The IL-6 family cytokine receptors share a common signal transducing β-subunit, gp130, which may be targeted to mitigate tumor chemoresistance. We showed that microglia co-culture failed to induce chemoresistance of gp130 MB cells, and that combination treatment using gp130 inhibitors, or with the JAK inhibitor ruxolitinib, effectively overcame the observed resistance to vincristine in gp130 expressing MB cells. Our in vitro studies highlight the gp130/JAK/STAT pathway as a therapeutic target in combating acquired treatment resistance in Group 3 MB.
髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤。在四个分子亚组中，3 组 MB 是最具侵袭性的，预后最差。为了了解涉及 IL-6/STAT3 信号的化疗耐药的起源，我们使用体外共培养系统来研究小胶质细胞作为脑肿瘤微环境细胞来源的旁分泌细胞因子在促进 3 组 MB 获得性耐药中的作用。与小胶质细胞共培养的 MB 细胞表现出磷酸化 JAK1 和 STAT3 的表达增加，这与长春新碱耐药性增强相关。我们发现小胶质细胞和与小胶质细胞共培养的 MB 细胞都分泌大量的 IL-6，表明 IL-6 是一种旁分泌和自分泌细胞因子，能够在 MB 细胞中启动和维持 STAT3 活性。令人惊讶的是，不能对外源 IL-6 刺激做出反应的 IL-6R MB 细胞对小胶质细胞共培养诱导的 STAT3 激活和化疗耐药性有反应。随后，我们发现体外用 IL-6 家族细胞因子（IL-6、OSM、LIF 或 IL-11）处理的 MB 细胞表现出 JAK1/STAT3 活性增强和化疗耐药性增强。有趣的是，用任何一种 IL-6 家族细胞因子处理的 MB 细胞都会分泌多种 IL-6 家族细胞因子，暗示涉及多种细胞因子的反馈网络。IL-6 家族细胞因子受体共享一个共同的信号转导β亚基 gp130，这可能成为减轻肿瘤化疗耐药性的靶向治疗。我们表明，小胶质细胞共培养不能诱导 gp130 MB 细胞的化疗耐药性，而使用 gp130 抑制剂联合治疗，或与 JAK 抑制剂芦可替尼联合治疗，可有效克服 gp130 表达 MB 细胞对长春新碱的观察到的耐药性。我们的体外研究强调了 gp130/JAK/STAT 途径作为治疗 3 组 MB 获得性治疗耐药的靶点。
