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Effect of dietary omega-3 fatty acids on castrate-resistant prostate cancer and tumor-associated macrophages

Prostate Cancer and Prostatic Diseases volume 23, pages 127–135 (2020)Cite this article

Subjects

Abstract

Background

M2-like macrophages are associated with the pathogenesis of castrate-resistant prostate cancer (CRPC). We sought to determine if dietary omega-3 fatty acids (ω-3 FAs) delay the development and progression of CRPC and inhibit tumor-associated M2-like macrophages.

Methods

MycCap cells were grown subcutaneously in immunocompetent FVB mice. Mice were castrated when tumors reached 300 mm2. To study effects of dietary ω-3 FAs on development of CRPC, ω-3 or ω-6 diets were started 2 days after castration and mice sacrificed after early regrowth of tumors. To study ω-3 FA effects on progression of CRPC, tumors were allowed to regrow after castration before starting the diets. M2 (CD206+) macrophages were isolated from allografts to examine ω-3 FA effects on macrophage function. Omega-3 fatty acid effects on androgen-deprived RAW264.7 M2 macrophages were studied by RT-qPCR and a migration/ invasion assay.

Results

The ω-3 diet combined with castration lead to greater MycCap tumor regression (tumor volume reduction: 182.2 ± 33.6 mm3) than the ω-6 diet (tumor volume reduction: 148.3 ± 35.2; p = 0.003) and significantly delayed the time to CRPC (p = 0.006). Likewise, the ω-3 diet significantly delayed progression of established castrate-resistant MycCaP tumors (p = 0.003). The ω-3 diet (as compared to the ω-6 diet) significantly reduced tumor-associated M2-like macrophage expression of CSF-1R in the CRPC development model, and matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor (VEGF) in the CRPC progression model. Migration of androgen-depleted RAW264.7 M2 macrophages towards MycCaP cells was reversed by addition of docosahexaenoic acid (ω-3).

Conclusions

Dietary omega-3 FAs (as compared to omega-6 FAs) decreased the development and progression of CRPC in an immunocompetent mouse model, and had inhibitory effects on M2-like macrophage function. Clinical trials are warranted evaluating if a fish oil-based diet can delay the time to castration resistance in men on androgen deprivation therapy, whereas further preclinical studies are warranted evaluating fish oil for more advanced CRPC.

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Acknowledgements

We thank Howard B. Klein for his generous support.

Funding

This work was supported by the National Institute of Health (P50CA92131 to WJA; RO1CA231219 to WJA and PC and P30CA016042 and used the flow cytometry core of the CCSG shared resource) and Department of Defense Prostate Cancer Research Program (PC141593 to PL).

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Authors and Affiliations

  1. Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Pei Liang, Susanne M. Henning, Johnny Guan & William J. Aronson

  2. Department of Medicine Statistics Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Tristan Grogan & David Elashoff

  3. Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA

    Pinchas Cohen

  4. VA Medical Center Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    William J. Aronson

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  1. Pei Liang
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Correspondence to William J. Aronson.

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Liang, P., Henning, S.M., Guan, J. et al. Effect of dietary omega-3 fatty acids on castrate-resistant prostate cancer and tumor-associated macrophages. Prostate Cancer Prostatic Dis 23, 127–135 (2020). https://doi.org/10.1038/s41391-019-0168-8

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