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Translational Therapeutics

Aspirin reduces the incidence of metastasis in a pre-clinical study of Braf mutant serrated colorectal neoplasia

British Journal of Cancer volume 124, pages 1820–1827 (2021)Cite this article

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Abstract

Background

Aspirin reduces the incidence of conventional adenomas driven by APC mutation and thus colorectal cancer. The effect of aspirin on the ~20% of colorectal cancers arising via BRAF mutation is yet to be established.

Methods

BrafV637E/+;Villin-CreERT2/+ mice were allocated to a control (n = 86) or aspirin-supplemented (n = 83) diet. After 14 months the incidence of murine serrated lesions, carcinoma and distant metastases were measured by histological examination. RNA was extracted from carcinomas from each cohort and subjected to sequencing to identify differentially expressed genes and molecular pathways.

Results

Aspirin did not reduce the incidence of murine serrated lesions or carcinoma when compared to control, however, did significantly reduce lesion size (P = 0.0042). Among the mice with carcinoma there was a significant reduction in the incidence of distant metastasis with aspirin treatment (RR 0.69, 95% CI 0.48–0.90, P = 0.0134). Key pathways underlying metastasis of carcinoma cells include NOTCH, FGFR and PI3K signalling, were significantly downregulated in carcinomas sampled from mice on an aspirin-supplemented diet.

Conclusions

Aspirin reduces the incidence of metastatic Braf mutant carcinoma, although this is not due to a reduction in primary disease. The reduction in metastasis could be attributed to a delay or prevention of molecular changes within the primary site driving metastatic growth.

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Fig. 1: Morphology of serrated neoplasia in Braf mutant mice.
Fig. 2: Characteristics of tumours in control and aspirin treated Braf mutant mice.
Fig. 3: Analysis of RNA sequencing data from primary carcinomas collected from mice with (n = 6, dark grey) and without (n = 10, light grey) synchronous metastasis at sacrifice.
Fig. 4: RNA sequencing analysis of primary carcinomas collected from mice on an aspirin diet (n = 8, blue) and mice on a control diet that had synchronous metastasis (n = 6, dark grey) at time of sacrifice.

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Acknowledgements

We gratefully acknowledge the generous support of the Garry Whyte Sea Angel PAF.

Author information

Authors and Affiliations

  1. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

    Alexandra M. Kane, Cheng Liu, Lochlan J. Fennell, Diane M. McKeone, Catherine E. Bond, Barbara A. Leggett & Vicki L. J. Whitehall

  2. Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

    Alexandra M. Kane, Cheng Liu, Lochlan J. Fennell, Barbara A. Leggett & Vicki L. J. Whitehall

  3. Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, QLD, Australia

    Alexandra M. Kane & Vicki L. J. Whitehall

  4. Envoi Specialist Pathologists, Brisbane, QLD, Australia

    Cheng Liu

  5. Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology and Translational Research Institute, Brisbane, QLD, Australia

    Pamela M. Pollock

  6. Flinders University, Adelaide, SA, Australia

    Graeme Young

  7. Department of Gastroenterology and Hepatology, The Royal Brisbane and Women’s Hospital, Queensland Health, Brisbane, QLD, Australia

    Barbara A. Leggett

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  1. Alexandra M. Kane
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Contributions

A.K., P.P., G.Y., B.L. and V.W. conceptualised and designed the study. A.K., C.L., L.F., D.M. and C.B. contributed to methodology and experiments. A.K. and L.F. analysed data. A.K. drafted manuscript. B.L. and V.W. supervised the study.

Corresponding author

Correspondence to Alexandra M. Kane.

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Ethics approval

All studies were approved by the QIMR Berghofer Animal Ethics Committee (P2178).

Data availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding information

Funding for this research was provided by a Cancer Council Queensland grant (grant number 1100701). This work was supported by Cancer Council Queensland, National Health and Medical Research Council of Australia.

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Kane, A.M., Liu, C., Fennell, L.J. et al. Aspirin reduces the incidence of metastasis in a pre-clinical study of Braf mutant serrated colorectal neoplasia. Br J Cancer 124, 1820–1827 (2021). https://doi.org/10.1038/s41416-021-01339-4

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