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Translational Therapeutics

High PGD2 receptor 2 levels are associated with poor prognosis in colorectal cancer patients and induce VEGF expression in colon cancer cells and migration in a zebrafish xenograft model

British Journal of Cancer volume 126, pages 586–597 (2022)Cite this article

Subjects

Abstract

Background

Despite intense research, the prognosis for patients with advanced colorectal cancer (CRC) remains poor. The prostaglandin D2 receptors DP1 and DP2 are explored here as potential therapeutic targets for advanced CRC.

Methods

A CRC cohort was analysed to determine whether DP1 and DP2 receptor expression correlates with patient survival. Four colon cancer cell lines and a zebrafish metastasis model were used to explore how DP1/DP2 receptor expression correlates with CRC progression.

Results

Analysis of the clinical CRC cohort revealed high DP2 expression in tumour tissue, whereas DP1 expression was low. High DP2 expression negatively correlated with overall survival. Other pathological indicators, such as TNM stage and metastasis, positively correlated with DP2 but not DP1 expression. In accordance, the in vitro results showed high DP2 expression in four CC-cell lines, but only one expressed DP1. DP2 stimulation resulted in increased proliferation, p-ERK1/2 and VEGF expression/secretion. DP2-stimulated cells exhibited increased migration in the zebrafish metastasis model.

Conclusion

Our results support DP2 receptor expression and signalling as a therapeutic target in CRC progression based on its expression in CRC tissue correlating with poor patient survival and that it triggers proliferation, p-ERK1/2 and VEGF expression and release and increased metastatic activity in CC-cells.

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Fig. 1: Immunohistochemistry (IHC) images of DP1 and DP2 in colorectal patient tissues.
Fig. 2: The roles of DP1 and DP2 in colorectal cancer patient overall survival.
Fig. 3: Expression of DP1 and DP2 in colon cancer cell lines and colorectal cancer patient tissue.
Fig. 4: Effect of DP2 agonist and antagonist treatment on colon cancer cell migration and proliferation.
Fig. 5: DP2 agonist induced VEGF and HIF-1α expression in colon cancer cells.
Fig. 6: Schematic representation of the experimental process by which zebrafish xenografts were generated.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary information is available on the British Journal of Cancer website.

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Acknowledgements

We would like to acknowledge Kristina Ekstöm-Holka from the Tissue MicroArray Center at Lund University, Malmö, Sweden, for her assistance with IHC. This work was supported by grants to AS from the Swedish Medical Council and Swedish Cancer Foundation and grants to PD, GT, SRS, and LMM by the Royal Physiographic Society in Lund, Sweden.

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Author notes

  1. These authors contributed equally: Pujarini Dash, Souvik Ghatak.

Authors and Affiliations

  1. Division of Cell Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden

    Pujarini Dash, Souvik Ghatak, Geriolda Topi, Shakti Ranjan Satapathy, Lubna M. Mehdawi & Anita Sjölander

  2. Chemical Biology & Therapeutics Group, Department of Experimental Medical Science, Lund University, Lund, Sweden

    Fredrik Ek, Karin Hellman & Roger Olsson

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Contributions

PD and AS designed the study; PD, SG, SRS, GT and LMM carried out the experiments; PD, SG, SRS, GT and AS analysed the data and prepared the manuscript. FE, KH, RO housed and bred the zebrafish. All authors have read the final version of the manuscript.

Corresponding author

Correspondence to Anita Sjölander.

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Ethics approval and consent to participate

Colorectal cancer patient follow-up started on the day of diagnosis and ended on the day of death, migration or December 31, 2000. Information on vital status and the cause of death was obtained from the Swedish Cause of Death Registry until December 31, 2000. The Ethical Committee at Lund University approved this study (LU 52-99 and 367/2005), which was performed in accordance with the Declaration of Helsinki. Informed consent was obtained from all subjects involved in the study. Transgenic zebrafish (Danio rerio), Tg(fli1:EGFP), were handled and used in accordance with the national legislation of Sweden and the European community guidelines for animal studies. All procedures were approved by the Ethical Committee at Malmö-Lund (permit no. M23-15, zebrafish larvae) [31].

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Dash, P., Ghatak, S., Topi, G. et al. High PGD2 receptor 2 levels are associated with poor prognosis in colorectal cancer patients and induce VEGF expression in colon cancer cells and migration in a zebrafish xenograft model. Br J Cancer 126, 586–597 (2022). https://doi.org/10.1038/s41416-021-01595-4

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