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Cellular and Molecular Biology

Glycometabolic reprogramming-mediated proangiogenic phenotype enhancement of cancer-associated fibroblasts in oral squamous cell carcinoma: role of PGC-1α/PFKFB3 axis

British Journal of Cancer volume 127, pages 449–461 (2022)Cite this article

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Abstract

Background

Angiogenesis is a key rate-limiting step in the process of tumour progression. Cancer-associated fibroblasts (CAFs), the most abundant component OSCC stroma, play important roles in pro-angiogenesis. Recently, the stroma “reverse Warburg effect” was proposed, and PFKFB3 has been brought to the forefront as a metabolic enzyme regulating glycometabolism. However, it remains unclear whether glycometabolism reprogramming is involved in promoting the angiogenesis of CAFs.

Methods

CAFs and paracancerous fibroblasts (PFs) were isolated from OSCC and adjacent tissues. We detected the pro-angiogenesis and glycometabolism phenotype of three pairs of fibroblasts. Targeted blockage of PFKFB3 or activation of PGC-1α signal was used to investigate the effect of glycolysis on regulating angiogenesis of CAFs in vitro and vivo.

Results

CAFs exhibited metabolic reprogramming and enhanced proangiogenic phenotype compared with PFs. Inhibition of PFKFB3-dependent glycolysis impaired proangiogenic factors (VEGF-A, PDGF-C and MMP9) expression in CAFs. Furthermore, CAFs proangiogenic phenotype was regulated by glycometabolism through the PGC-1α/PFKFB3 axis. Consistently, PGC-1α overexpression or PFKFB3 knockdown in CAFs slowed down tumour development by reducing tumour angiogenesis in the xenograft model.

Conclusion

CAFs of OSCC are characterised with glycometabolic reprogramming and enhanced proangiogenic phenotypes. Our findings suggest that activating PGC-1α signalling impairs proangiogenic phenotype of CAFs by blocking PFKFB3-driven glycolysis.

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Fig. 1: Tumour stroma glycolysis phenotype is positively correlated with tumour microvessel density.
Fig. 2: CAFs of OSCC promote proliferation, migration and tube formation of HUVECs.
Fig. 3: CAFs of OSCC undergo glycometabolism reprogramming.
Fig. 4: Inhibition of PFKFB3-dependent glycolysis can impair proangiogenic phenotype of CAFs.
Fig. 5: PGC-1α/PFKFB3 axis regulates the proangiogenic phenotype in CAFs.
Fig. 6: PGC-1α overexpression or PFKFB3 inhibition suppressed proangiogenic phenotype of CAFs in vivo.

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Data availability

The datasets generated during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors are grateful to Xiang Du for his support and help. And we would like to thank Ruiqi Li (The State Key Laboratory Breeding Base of Basic Science of Stomatology, Wuhan University) for her help in the experimental research.

Funding

This study was supported by grants from the National Natural Science Foundation of China (Grant number: 81972547 to ZS); Chinese Fundamental Research Funds for the Central Universities (2042021kf0184 to EJ).

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Author notes

  1. These authors contributed equally: Xiang Li, Erhui Jiang.

Authors and Affiliations

  1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China

    Xiang Li, Erhui Jiang, Hui Zhao, Yang Chen, Yuming Xu, Chunyu Feng, Ji Li & Zhengjun Shang

  2. Department of Oral and Maxillofacial-Head and Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China

    Erhui Jiang & Zhengjun Shang

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Contributions

The authors contributed in the following way: designed and performed the research: XL; write the manuscripts: XL, EJ and HZ; data analysis: YX and YC; perform experiments: CF and JL; supervised the research: ZS.

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Correspondence to Zhengjun Shang.

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The authors declare no competing interests.

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Study of OSCC tissue samples was in accordance with the Ethics Committee of School and Hospital of Stomatology at Wuhan University (2019LUNSHENZIA70). Written informed consents were obtained from all patients participated. Animal works were approved by the Ethical Committee on Animal Experiments of the Animal Care Committee of Wuhan University (S07921020L).

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Li, X., Jiang, E., Zhao, H. et al. Glycometabolic reprogramming-mediated proangiogenic phenotype enhancement of cancer-associated fibroblasts in oral squamous cell carcinoma: role of PGC-1α/PFKFB3 axis. Br J Cancer 127, 449–461 (2022). https://doi.org/10.1038/s41416-022-01818-2

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