Theranostics 2022; 12(9):4221-4236. doi:10.7150/thno.69605 This issue

Research Paper

TGFBI secreted by tumor-associated macrophages promotes glioblastoma stem cell-driven tumor growth via integrin αvβ5-Src-Stat3 signaling

Peng Peng1, Hongtao Zhu1, Dan Liu2, Zirong Chen1, Xiaolin Zhang1, Zhongyin Guo1, Minhai Dong1, Lijun Wan1, Po Zhang1, Guohao Liu1, Suojun Zhang1, Fangyong Dong1, Feng Hu1, Fangling Cheng3, Shijun Huang4, Dongsheng Guo1, Bin Zhang5,6,7✉, Xingjiang Yu8✉, Feng Wan1✉

1. Department of Neurosurgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
2. Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
3. Department of Surgery, Hepatic Surgery Center, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
4. Department of Neurosurgery, Shayang County People's Hospital, Jingmen, Hubei, China.
5. Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
6. Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, Wuhan, Hubei, China.
7. The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China.
8. Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Peng P, Zhu H, Liu D, Chen Z, Zhang X, Guo Z, Dong M, Wan L, Zhang P, Liu G, Zhang S, Dong F, Hu F, Cheng F, Huang S, Guo D, Zhang B, Yu X, Wan F. TGFBI secreted by tumor-associated macrophages promotes glioblastoma stem cell-driven tumor growth via integrin αvβ5-Src-Stat3 signaling. Theranostics 2022; 12(9):4221-4236. doi:10.7150/thno.69605. Available from https://www.thno.org/v12p4221.htm

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Abstract

Graphic abstract

Rationale: In the glioblastoma (GBM) microenvironment, tumor-associated macrophages (TAMs) are prominent components and facilitate tumor growth. The exact molecular mechanisms underlying TAMs' function in promoting glioma stem cells (GSCs) maintenance and tumor growth remain largely unknown. We found a candidate molecule, transforming growth factor beta-induced (TGFBI), that was specifically expressed by TAMs and extremely low in GBM and GSC cells, and meanwhile closely related to glioma WHO grades and patient prognosis. The exact mechanism of TGFBI linking TAM functions to GSC-driven tumor growth was explored.

Methods: Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), immunohistochemistry staining (IHC) and public datasets were used to evaluate TGFBI origin and level in GBM. The response of GSCs to recombinant human TGFBI was assessed in vitro and orthotopic xenografts were established to investigate the function and mechanism in vivo.

Results: M2-like TAMs infiltration was elevated in high-grade gliomas. TGFBI was preferentially secreted by M2-like TAMs and associated with a poor prognosis for patients with GBM. TGFBI promoted the maintenance of GSCs and GBM malignant growth through integrin αvβ5-Src-Stat3 signaling in vitro and in vivo. Of clinical relevance, TGFBI was enriched in the serum and CSF of GBM patients and significantly decreased after tumor resection.

Conclusion: TAM-derived TGFBI promotes GSC-driven tumor growth through integrin αvβ5-Src-Stat3 signaling. High serum or CSF TGFBI may serve as a potential diagnostic and prognostic bio-index for GBMs.

Keywords: TGFBI, tumor-associated macrophages (TAMs), glioblastoma (GBM), glioblastoma stem cells (GSCs), integrin αvβ5