Omega-3 polyunsaturated fatty acids as adjuvant therapy of colorectal cancer

Abstract

The majority of evidence linking anti-colorectal cancer (CRC) activity with omega-3 polyunsaturated fatty acids (O3FAs) has focussed on decreased CRC risk (prevention). More recently, preclinical data and human observational studies have begun to make the case for adjuvant treatment of advanced CRC. Herein, we review latest data regarding the effect of O3FAs on post-diagnosis CRC outcomes, including mechanistic preclinical data, evidence that O3FAs have beneficial effects on efficacy and tolerability of CRC chemotherapy, and human epidemiological data linking dietary O3FA intake with CRC outcomes. We also highlight ongoing randomised controlled trials of O3FAs with CRC endpoints and discuss critical gaps in the evidence base, which include limited understanding of the effects of O3FAs on the tumour microenvironment, the host immune response to CRC, and the intestinal microbiome.

Keywords: Cachexia; Chemotherapy; Colorectal cancer; Docosahexaenoic acid; Eicosapentaenoic acid; Omega-3 polyunsaturated fatty acid.

Fig. 1

Potential effects of O3FAs on the crosstalk between cancer cells and the host-derived cell infiltrate in the tumour microenvironment. O3FAs are believed to exert their anti-cancer activity through multiple mechanisms including direct effects on cancer cells, but also inhibition of paracrine signalling between cancer cells themselves or neighbouring stromal cells (including the host innate and acquired immune cell infiltrate, endothelial cells, and fibroblasts). In addition, direct effects on the stromal cell infiltrate may alter pro- or anti-tumorigenic activity of these cells. An example is provided by inhibition of COX-dependent PGE₂ production, which occurs in CRC cells themselves, thereby reducing autocrine (1) and paracrine (2) cell proliferation signalling in malignant epithelial cells, but could also abrogate the immuno-suppressive activity of PGE₂ on host immune surveillance (3) and impair angiogenesis (4). Moreover, O3FAs may inhibit PGE₂ production directly by tumour stromal cells, including myeloid-derived suppressor cells (MDSCs) (5)