Miladinovic Tanya, Sharma Manu, Phan Andy, Geres Hana, Ungard Robert G, Linher-Melville Katja, Singh Gurmit
Michael G. DeGroote Institute for Pain Research and Care, Medicine, McMaster University, Hamilton, ON L8S 4M1, Canada,
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4M1, Canada,
J Pain Res. 2019 Mar 18;12:1003-1016. doi: 10.2147/JPR.S191860. eCollection 2019.
Pain is a common and debilitating comorbidity of metastatic breast cancer. The hippocampus has been implicated in nociceptive processing, particularly relating to the subjective aspect of pain. Here, a syngeneic mouse model was used to characterize the effects of peripheral tumors on hippocampal microglial activation in relation to cancer-induced pain (CIP).
Mice were systemically treated with the colony-stimulating factor 1 receptor inhibitor Pexidartinib prior to intrafemoral (IF) or subcutaneous 4T1 carcinoma cell inoculation. Spontaneous and evoked nociceptive responses were quantitated throughout tumor development, and contralateral hippocampi were collected via endpoint microdissection for RNA analysis. Additionally, IF tumor-bearing animals were sacrificed on days 5, 10, 15, and 20 post 4T1 cell inoculation, and brain sections were immunofluorescently stained for Iba1, a marker of activated microglia.
Ablation of these neuroimmune cells with the CSF1R inhibitor Pexidartinib delayed the onset and severity of cancer-induced nociceptive behaviors in IF tumor-bearing animals, adding to the body of literature that demonstrates microglial contribution to the development and maintenance of CIP. Furthermore, in untreated IF tumor-bearing mice, nociceptive behaviors appeared to progress in parallel with microglial activation in hippocampal regions. Immunofluorescent Iba1+ microglia increased in the dentate gyrus and cornu ammonis 1 hippocampal regions in IF tumor-bearing animals over time, which was confirmed at the mRNA level using relevant microglial markers.
This is the first experimental evidence to demonstrate the effects of peripheral tumor-induced nociception on hippocampal microglial activation. The increase in hippocampal microglia observed in the present study may reflect the emotional and cognitive deficits reported by patients with CIP.
疼痛是转移性乳腺癌常见且使人衰弱的合并症。海马体参与伤害性感受处理，尤其与疼痛的主观方面相关。在此，使用同基因小鼠模型来表征外周肿瘤对与癌症诱导性疼痛（CIP）相关的海马小胶质细胞激活的影响。
在股内（IF）或皮下接种4T1癌细胞之前，用集落刺激因子1受体抑制剂培西达替尼对小鼠进行全身治疗。在肿瘤发展过程中对自发和诱发的伤害性反应进行定量，通过终点显微切割收集对侧海马体用于RNA分析。此外，在接种4T1细胞后的第5、10、15和20天处死IF荷瘤动物，并对脑切片进行免疫荧光染色，以检测激活的小胶质细胞的标志物Iba1。
用CSF1R抑制剂培西达替尼消融这些神经免疫细胞可延迟IF荷瘤动物癌症诱导的伤害性行为的发作和严重程度，这进一步证明了小胶质细胞对CIP的发生和维持有作用。此外，在未治疗的IF荷瘤小鼠中，伤害性行为似乎与海马区小胶质细胞的激活平行进展。随着时间的推移，IF荷瘤动物齿状回和海马体的海马角1区中免疫荧光Iba1 +小胶质细胞增加，使用相关小胶质细胞标志物在mRNA水平得到证实。
这是首个证明外周肿瘤诱导性伤害感受对海马小胶质细胞激活影响的实验证据。本研究中观察到的海马小胶质细胞增加可能反映了CIP患者报告的情绪和认知缺陷。
