Differential effects of omega‐3 PUFAS on tumor progression at early and advanced stages in TRAMP mice

Abstract

Background: In vitro studies evidenced antitumor effects of omega-3 polyunsaturated fatty acids ([n−3] PUFAs), but their effects on prostate cancer (PCa) remain controversial in epidemiological studies. Here we investigated whether an (n−3) PUFA-enriched diet affects tumor progression in transgenic adenocarcinoma of the mouse prostate (TRAMP), at early (12 weeks age) and advanced stages (20 weeks age).Methods: TRAMP mice were fed with standard rodent diet (C12, C20) or (n−3) PUFA-enriched diet containing 10% fish oil (T12, T20). A group of 8 weeks age animals fed standard diet was also used for comparison (C8). The ventral prostate was processed for histopathological and immunohistochemical analyses and serum samples submitted to biochemical assays.Results: At early stages, (n−3) PUFA increased the frequency of normal epithelium (3.8-fold) and decreased the frequency of high-grade intraepithelial neoplasia (3.3-fold) and in situ carcinoma (1.9-fold) in the gland, maintaining prostate pathological status similar to C8 group. At advanced stages, 50% of the animals developed a large primary tumor in both C20 and T20, and tumor weight did not differ (C20: 2.2 ± 2.4; T20: 2.8 ± 2.9 g). The ventral prostate of T12 and of T20 animals that did not develop primary tumors showed lower cell proliferation, tissue expressions of androgen (AR) and glucocorticoid (GR) receptors, than their respective controls. For these animals, (n−3) PUFA also avoided an increase in the number of T-lymphocytes, collagen fibers, and αSMA immunoreactivity, and preserved stromal gland microenvironment. (n−3) PUFA also lowered serum triglycerides and cholesterol, regulating the lipid metabolism of TRAMP mice.Conclusions: (n−3) PUFAs had a protective effect at early stages of PCa, delaying tumor progression in TRAMP mice, in parallel with reductions in cell proliferation, AR, and GR and maintenance of the stromal compartment of the gland. However, (n−3) PUFAs did not prevent the development of primary tumors for the T20 group, reinforcing the need for further investigation at advanced stages of disease.

Metabolic Alterations in Canine Mammary Tumors

“…It was reported that endogenously synthesized fatty acids are required for cancer cell proliferation [26], and the pharmacological inhibition of fatty acid synthase (FASN) has antitumor effects in cell lines, organoids, and xenograft models [29]. Interestingly, not only endogenous but also exogenous fatty acids obtained through diet have been shown to modulate cancer progression [31], including through the regulation of metabolism [32]. Taken together, this short summary highlights how the rewiring of metabolism is a vulnerability that has been explored as a therapeutic opportunity in several cancers.…”

“…Interestingly, in spheroids from canine mammary adenocarcinoma, the levels of palmitoleate, palmitate, and dihomogamma-linolenic acid are higher compared with adherent cells, suggesting that certain SFAs are required for tumor formation [85]. Polyunsaturated fatty acids (PUFAs) have been investigated because of their antitumoral properties in different cancers [31,32,[86][87][88][89]. Conjugated linoleic acid (CLA), one of the most abundant PUFAs available in the diet, decreases the growth of epithelial and stromal CMT cells through the suppression of COX-2 and the prostaglandin E 2 receptor (EP2) [90].…”

“…In dogs, a clinical trial using long-chain omega-3 fatty acid supplementation through fish oil (eicosapentaenoic acid, EPA; 29 g/kg of diet and DHA 24 g/kg of diet) showed that increased DHA content is associated with longer disease-free intervals and survival in dogs with stage III lymphoma [98]. In TRAMP mice, a DHA-rich diet was able to delay prostate cancer progression [31]. Therefore, this body of evidence suggests the potential antitumoral effects of omega-3 in canine tumors, though its specific role in CMT remains elusive.…”