More recently, however, Robitaille et al reported the results of a placebo-controlled phase IIb study evaluating the effect of the long-chain omega-3 FA dietary supplement MAG-EPA on prostate cancer proliferation. The authors showed that a daily dose of three grams of MAG-EPA for 7 weeks quadrupled the levels of eicosapentaenoic fatty acid in prostate tissue compared to placebo. But, the dietary supplement had no effect on the primary outcome - prostate cancer proliferation based on Ki-67 expression. (Published March 22, 2024 in the journal Communications Medicine). Why do we often (and almost always) get different results under identical or comparable research conditions? The answer is clear - we do not know and cannot take into account all the factors influencing the final result. In this aspect, studies that identify mechanisms that can explain the presence or absence of an effect are always interesting.
Of great interest is the fact that the anticancer effects of omega-3 FAs depend on the tumor microenvironment, and not on a direct effect on tumor cells, namely, they have an inhibitory effect on the function of M2-like macrophages. In a mouse model of prostate cancer, the effects of ω-3 diet on cancer growth inhibition were dependent on the presence of GPR120 in non-tumor cells of the body, but were independent of the presence of GPR120 in cancer cells. To test this hypothesis, Pei Liang, Suzanne M. Henning and co-authors took mice with prostate cancer transplants (MycCap) and transplanted them with bone marrow from healthy mice or mice with a damaged GPR120 receptor gene and then fed them an ω-3 or ω-6 diet LCD. The authors found that the ω-3 diet inhibited MycCap allograft growth only when recipient mice were injected with bone marrow from healthy donor mice. Further reasoning by the authors led to the assumption that dietary ω-3 FAs inhibit the progression of prostate cancer due to their effects on bone marrow-derived immune cells that migrate into the tumor microenvironment and they turned out to be tumor-infiltrating M2-like macrophages with the GPR120 receptor.
Talking briefly about the microenvironment of prostate cancer, it contains various cellular components, mainly tumor-associated macrophages, cancer-associated fibroblasts, myeloid suppressor cells, which play a decisive role in oncogenesis, progression and metastasis of prostate cancer. Moreover, they significantly mediate resistance to conventional treatments, including antiandrogen therapy, chemotherapy, and immunotherapy. Therapeutic interventions targeting these cellular components have demonstrated promising effects in preclinical models and several clinical studies. Xue-Feng Li, Cigdem Selli et.al. discovered a macrophage-dependent mechanism of enzalutamide resistance. El-Kenawi and colleagues described the mechanism underlying the resistance of prostate tumors to hormonal therapy. It involves the accumulation of cholesterol by macrophages in tumors and its transfer to cancer cells, where cholesterol acts as an androgen precursor and leads to the activation of androgen receptors, causing cancer cell growth. But attempts to reduce the number of macrophages in cancer patients in clinical trials have failed, largely due to serious side effects.
Combining dietary therapy targeting GPR120 in the microenvironment with tumor-targeting therapy may therefore be beneficial. These preclinical results provide a rationale for clinical trials evaluating ω-3 FAs as a potential therapy for prostate cancer through inhibition of functional M2-like macrophages GPR120.
What do the results currently provide to patients in practical application? Should we wait for the research results, or should we now focus our diet on ω-3 FA? From the standpoint of evidence-based medicine, the answer is clear – wait for the results! But while the results of future studies on this issue are begun and summed up, for many patients time may run out forever. So you will have to decide personally, after discussing with your treating oncologist.
Clinical trials are warranted to evaluate whether a fish oil diet can delay the development of castration resistance in men receiving androgen deprivation therapy, while further studies are needed to evaluate the effect of fish oil on prostate cancer progression.
In summary, current research points to many unique factors that influence PC. However, questions remain because dieting is a complex and long-term behavior. Ultimately, a key unanswered question remains: is it possible to develop an evidence-based diet for PC patients that achieves the triple effect, slows PC growth, improves quality of life, and is practical to implement with high acceptance rates?
As public opinion about diet constantly changes, new questions arise about dietary regimens and supplements and their relationship to PC. Does the inflammatory potential of certain diets play any role in PC risk? Can restricting carbohydrates affect tumor growth? Are fasting-mimicking diets, which are effective in treating type 2 diabetes and metabolic syndrome, and for weight control in patients with PC, safe?
In addition, the search for a dietary supplement with a preventive effect on PC has not yet yielded positive results [2]. Although clear evidence for recommended use is lacking, the search for supplements to prevent PC continues using omega-3 fatty acids.
By targeting bone marrow-derived immune cells with functional GPR120 that migrate into the M2 microenvironment in GFP+ tumor-infiltrating CD206+ macrophages, which are known to be associated with prostate cancer progression, was reduced only when M2-like macrophages. Thus, host bone marrow cells with functional GPR120 are required for the anticancer effects of dietary ω-3 FAs, and the key target of the ω-3 diet is M2-like CD206+ macrophages. And the key target of the ω-3 diet is M2-like CD206+ macrophages.
Only M2-like macrophages were reduced in number in the ω-3 diet groups compared to the ω-6 diet. Likewise, gene expression of M2 markers in GFP+ tumor-infiltrating CD206+ macrophages, which are known to be associated with prostate cancer progression, was reduced only when M2-like macrophages had functional GPR120. Thus, host bone marrow cells with functional GPR120 are required for the anticancer effects of dietary ω-3 FAs, and the key target of the ω-3 diet is M2-like macrophages.
GPR120 is a receptor involved in the modulation of metabolism, endocrine and immune functions, and is a receptor for long-chain polyunsaturated fatty acids.
Involvement of tumor-associated macrophages and dependence on GPR120 in the tumor microenvironment.
Although research linking diet and cancer is not new, recent research suggests that dietary factors and obesity are associated with both the risk and outcome of prostate cancer, thereby opening up additional prospects for disease control.
In numerous preclinical models, including animal models, dietary ω-3 fatty acids (FAs) from fish oil delayed the development and progression of androgen-sensitive and castrate-resistant prostate cancer (PCa). However, epidemiological studies in humans report varying results regarding the effect of FA on the risk of developing this cancer. In a prospective study of men with prostate cancer who were undergoing active surveillance, higher eicosapentaenoic acid levels in prostate tissue were associated with a lower likelihood of developing aggressive prostate cancer on subsequent biopsies. Similarly, a preprostatectomy study reported a reduction in proliferation (Ki-67 index) and a reduction in genetic risk score in tumor tissue after prostatectomy in men following a low-fat diet and consuming fish oil supplements compared with a so-called Western diet.