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Anoikis resistant gastric cancer cells promote angiogenesis and peritoneal metastasis through C/EBPβ-mediated PDGFB autocrine and paracrine signaling

Oncogene volume 40, pages 5764–5779 (2021)Cite this article

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A Correction to this article was published on 19 January 2022

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Abstract

Anoikis is a type of programmed cell death induced by loss of anchorage to the extracellular matrix (ECM). Anoikis resistance (AR) is crucial for the survival of metastatic cancer cells in blood, lymphatic circulation and distant organs. Compared to ordinary cancer cells, anoikis resistant cancer cells undergo various cellular and molecular alterations, probably characterizing the cells with unique features not limited to anoikis resistance. However, the molecular mechanisms connecting anoikis resistance to other metastatic properties are still poorly understood. Here, the biological interaction between anoikis resistance and angiogenesis as well as their involvement into peritoneal metastasis of gastric cancer (GC) were investigated in vitro and in vivo. The prognostic value of key components involved in this interaction was evaluated in the GC cohort. Compared to ordinary GC cells, GCAR cells exhibited stronger metastatic and pro-angiogenic traits corresponding to elevated PDGFB secretion. Mechanistically, transcription factor C/EBPβ facilitated PDGFB transcription by directly binding to and interacting with PDGFB promoter elements, subsequently increasing PDGFB secretion. Secreted PDGFB promoted the survival of detached GC cells through a C/EBPβ-dependent self-feedback loop. Moreover, secreted PDGFB promoted angiogenesis in metastases via activation of the MAPK/ERK signaling pathway in vascular endothelial cells. Both C/EBPβ activation level and PDGFB expression were significantly elevated in GC and correlated with metastatic progression and poor prognosis of patients with GC. Overall, interaction between GCAR cells and vascular endothelial cells promotes angiogenesis and peritoneal metastasis of GC based on C/EBPβ-mediated PDGFB autocrine and paracrine signaling. C/EBPβ-PDGFB-PDGFRβ-MAPK axis promises to be potential prognostic biomarkers and therapeutic targets for peritoneal metastasis of GC.

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Fig. 1: GCAR cells manifest a more vigorous metastatic and pro-angiogenic trait.
Fig. 2: GCAR cells manifest stronger pro-angiogenic potential.
Fig. 3: GCAR cells promote angiogenesis through elevated secretion of PDGFB.
Fig. 4: Transcription factor C/EBPβ mediates secretion of PDGFB in gastric cancer.
Fig. 5: GCAR cells derived PDGFB promotes angiogenesis through MAPK/ERK signaling pathway.
Fig. 6: GCAR cells promote its anoikis resistance through a PDGFB-dependent autocrine pattern.
Fig. 7: C/EBPβ/PDGFB/PDGFRβ axis triggers angiogenesis and peritoneal metastasis in vivo.
Fig. 8: Elevated C/EBPB activation level and PDGFB expression correlate with poor prognosis of patients with gastric cancer.

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Data availability

All raw and processed RNA sequencing data of HUVEC was deposited to NCBI Genome Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) under the accession numbers: GSE176441.

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Acknowledgements

We are particularly grateful to Dr. Chong Sun (German Cancer Research Center, Heidelberg, Germany) for rigorous guidance.

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Author notes

  1. These authors contributed equally: Shangce Du, Zhi Yang, Xiaofeng Lu.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, P.R. China

    Shangce Du, Zhi Yang, Xiaofeng Lu, Min Zhao, Heng Yu, Xinya Zhu, Hong Chen, Linseng Shi & Wenxian Guan

  2. Department of Gastrointestinal Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, P.R. China

    Shangce Du, Zhi Yang, Xiaofeng Lu, Ji Miao, Xingzhou Wang, En Xu, Xuefeng Xia & Wenxian Guan

  3. Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany

    Suhail Yousuf

  4. Faculty of Medicine, University of Heidelberg, Heidelberg, Germany

    Wenxi Li

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Contributions

SD, ZY, EX, MZ, WL, JM, XW and HY performed the experiments; XZ, HC and LS analysed data; WG, XX and XL provided the samples; SD and SY wrote the paper; WG and SY commented on the study and revised the paper; SD, WG, XX and XL designed the research.

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Correspondence to En Xu, Xuefeng Xia or Wenxian Guan.

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The use of human samples was approved by the Ethics Committee of the Nanjing Drum Tower Hospital of Nanjing University Medical School. Written informed consents were obtained from all patients. The study was performed according to the guideline expressed in the Declaration of Helsinki.

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Du, S., Yang, Z., Lu, X. et al. Anoikis resistant gastric cancer cells promote angiogenesis and peritoneal metastasis through C/EBPβ-mediated PDGFB autocrine and paracrine signaling. Oncogene 40, 5764–5779 (2021). https://doi.org/10.1038/s41388-021-01988-y

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