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

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.

• Authors: Peng Peng, Hongtao Zhu, Dan Liu, Zirong Chen, Xiaolin Zhang, Zhongyin Guo, Minhai Dong, Lijun Wan, Po Zhang, Guohao Liu, Suojun Zhang, Fangyong Dong, Feng Hu, Fangling Cheng, Shijun Huang, Dongsheng Guo, Bin Zhang, Xingjiang Yu, Feng Wan
• Journal: Theranostics (Theranostics) Vol. 12 Issue 9 Pg. 4221-4236 ( 2022) ISSN: 1838-7640 [Electronic] Australia
• PMID: 35673564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Receptors, Vitronectin
• STAT3 Transcription Factor
• STAT3 protein, human
• Transforming Growth Factor beta
• integrin alphaVbeta5

Topics

• Brain Neoplasms (pathology)
• Cell Line, Tumor
• Glioblastoma (metabolism)
• Glioma (metabolism)
• Humans
• Neoplastic Stem Cells (metabolism)
• Receptors, Vitronectin
• STAT3 Transcription Factor (metabolism)
• Transforming Growth Factor beta (metabolism)
• Tumor Microenvironment
• Tumor-Associated Macrophages