Omega-3 FA in colorectal cancer
Dietary omega-3 fatty acids (FAs) were first linked to primary prevention of colorectal cancer (CRC) in large epidemiological studies, after which observational data in humans linked omega-3 FA status to the prognosis of CRC. In addition, preclinical evidence indicates that these fatty acids could be useful in its treatment. Since a randomised, controlled trial in patients with familial adenomatous polyposis showed the preventative efficacy of eicosapentaenoic acid (EPA) during the early stages of intestinal tumorigenesis, new preclinical and clinical evidence has provided support for the use of omega-3 FAs as adjuvant therapy in CRC, more than for prevention. Various mechanisms have been described to explain the anti-inflammatory and anti-cancer activity of omega-3 FAs, many of which have been shown to occur in CRC models.
In in vivo and in vitro models, omega-3 FAs have been observed to modulate cyclooxygenase (COX) metabolism and reduce production in tumours of various prostanoids, including prostaglandin E2 (PGE2), while increasing production of the mediators involved in inflammation resolution (e.g. resolvins), which could have anti-cancer properties. COX-2 expression is high in over 90% of CRCs and associated with high concentrations of PGE2, which lead to tumorigenic proliferation, migration and invasion, and also favour an immunosuppressive environment beneficial to tumour growth. It has been demonstrated that omega-3 FAs are incorporated into the plasma membrane of cancer cells, where they alter the composition and fluidity of the lipid rafts; these can result in inhibition of the transduction signal, limiting the survival of the cancer cell and promoting apoptosis. They are also incorporated into the membranes of non-cancer cells in the tumour environment and can alter their phenotype. In addition, omega-3 FAs down-regulate the signalling pathways that promote CRC (Wnt/ß-catenin, MAPK/ERK and PI3K-PTEN), while the accumulation of omega-3 FAs in CRC cells increases lipid peroxidation and cellular oxidative stress. Omega-3 FAs also exert their anti-CRC activity by interacting with G-protein-coupled receptors, thus activating pro-apoptotic signalling. These receptors are expressed in non-epithelial cells such as adipocytes and macrophages and their activation can alter the polarisation of macrophages and reduce inflammation, which is potentially important for omega-3 FA anti-cancer activity.
Due to the diversity of probable molecular targets for omega-3 FAs, preclinical studies on their already established potential against CRC have focussed on pharmacodynamic parameters related to relevant aspects in cancer, such as proliferation, apoptosis and cellular migration. In CRC models, omega-3 FAs have anti-proliferative and pro-apoptotic effects. However, there have been few clinical trials in humans and most of the clinical data that link post-diagnostic results in CRC with omega-3 FA consumption are observational. A study on the relationship between dietary consumption of marine-origin omega-3 FA (EPA, docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA)) and the course of diagnosed CRC showed that individuals with higher consumption had a lower risk of CRC-related mortality after diagnosis. In a retrospective study, patients whose omega-3 FA consumption was in the top quartile had higher disease-free survival rates than those in the lower quartile. The VITAL study, which gathered information not just on consumption but also on the use of omega-3 FA supplementation, showed that fish-oil supplement consumers (≥ 4 day per weeks for ≥ 3 years) had a 49% lower risk than non-consumers.
The only double-blind, randomised, placebo-controlled intervention study on patients with metastatic CRC to have been reported is the EMT study, in which EPA or placebo were administered daily before surgery to patients due to undergo liver metastasis resection (for an average of 30 days). In the first 18 months after the resection, patients treated with EPA had better overall and disease-free survival rates.
Eleven studies have focussed on the perioperative use of enteral or parenteral nutrition, including omega-3 FA in patients with CRC. Overall, including omega-3 FA in perioperative nutrition was associated with fewer post-surgical complications, lower levels of proinflammatory cytokines and shorter hospitalisation times.
The EMT2 study will provide information on the effect of EPA on overall survival in CRC after liver metastasis resection surgery (ClinicalTrials.gov; NCT03428477).
Future investigation should be oriented towards: a) defining the contribution of omega-3 FAs in tumour immunology, as opposed to their direct effects on cells; b) understanding the different mechanisms of action of EPA and DHA, and studying whether joint administration is more beneficial than just taking one of them; c) establishing predictive CRC response biomarkers to omega-3 FAs; d) better understanding the effect of omega-3 FAs on the efficacy and toxicity of standard chemotherapy and new biological therapies; and e) studying the effects of purified formulations of omega-3 FA on survival biomarkers and cachexia in advanced CRC.
Volpato M, Hull MA. Omega-3 polyunsaturated fatty acids as adjuvant therapy of colorectal cancer. Cancer Metastasis Rev. 2018 Jul 3. doi: 10.1007/s10555-018-9744-y. [Epub ahead of print]