Theranostics 2021; 11(8):3839-3852. doi:10.7150/thno.53749

Research Paper

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17

Anke Zhang1,2*, Yuanzhi Xu1*, Houshi Xu1*, Jie Ren1, Tong Meng3, Yunjia Ni1, Qingwei Zhu1, Wen-Bo Zhang4, Yuan-Bo Pan5, Jiali Jin6, Yunke Bi1, Zhe Bao Wu2✉, Shaojian Lin2✉, Meiqing Lou1✉

1. Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3. Division of Spine, Department of Orthopedics, Tongji Hospital affiliated to Tongji University School of Medicine, Shanghai, China.
4. Department of Neurosurgery, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.
5. Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China.
6. Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, China.
*These authors contributed equally to this work.

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Citation:
Zhang A, Xu Y, Xu H, Ren J, Meng T, Ni Y, Zhu Q, Zhang WB, Pan YB, Jin J, Bi Y, Wu ZB, Lin S, Lou M. Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17. Theranostics 2021; 11(8):3839-3852. doi:10.7150/thno.53749. Available from https://www.thno.org/v11p3839.htm

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Abstract

Background: Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion.

Methods: To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated in vitro and in vivo.

Results: Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization via the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion via the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs.

Conclusion: This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion via M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.

Keywords: pituitary adenoma, macrophages, CCL17, lactate acid, mTOR