The Modulatory Effects of Fatty Acids on Cancer Progression

Abstract

Cancer is the second leading cause of death worldwide and the global cancer burden rises rapidly. The risk factors for cancer development can often be attributed to lifestyle factors, of which an unhealthy diet is a major contributor. Dietary fat is an important macronutrient and therefore a crucial part of a well-balanced and healthy diet, but it is still unclear which specific fatty acids contribute to a healthy and well-balanced diet in the context of cancer risk and prognosis. In this review, we describe epidemiological evidence on the associations between the intake of different classes of fatty acids and the risk of developing cancer, and we provide preclinical evidence on how specific fatty acids can act on tumor cells, thereby modulating tumor progression and metastasis. Moreover, the pro- and anti-inflammatory effects of each of the different groups of fatty acids will be discussed specifically in the context of inflammation-induced cancer progression and we will highlight challenges as well as opportunities for successful application of fatty acid tailored nutritional interventions in the clinic.

Keywords: cancer; diet; fatty acids; inflammation; tumor progression.

Figure 1

A comparative diagram of the chemical structures of the most investigated fatty acids, including their pro-tumor and anti-carcinogenic properties. Abbreviations: iTFA, industrial trans-fatty acid; MUFA, mono-unsaturated fatty acid; n-3 PUFA, omega-3 poly-unsaturated fatty acid; n-6 PUFA, omega-6 poly-unsaturated fatty acid; rTFA, ruminant trans-fatty acid; SCFA, short-chain fatty acid; SFA, saturated fatty acid.

Figure 2

Schematic overview of the relationship between the different fatty acid classes and cancer initiation, progression and metastasis. Cancer risk: iTFAs increase the risk of cancer initiation, while dietary fibers and n-3 PUFAs in general seem to decrease the risk of cancer initiation. For SCFAs, SFAs, rTFAs, MUFAs and n-6 PUFAs information remains controversial. Cancer progression: n-3 PUFAs and SCFAs seem to reduce cancer cell proliferation and stimulate apoptosis/ferroptosis. Opposite, n-6 PUFAs, SFAs and iTFAs predominantly show a stimulatory effect on cancer cell proliferation. The effects of MUFAs and rTFAs on cancer cell proliferation are ambiguous, while rTFAs induce apoptosis. Data for n-6 PUFAs on apoptosis and ferroptosis are contradictory. Alterations in membrane fluidity influence tumor progression and metastasis. SFAs decrease membrane fluidity, whereas MUFAs and PUFAs stimulate membrane fluidity. SCFAs increase gut barrier functioning, decrease systemic inflammation and, by extension, might reduce tumor progression. MUFAs, n-3 PUFAs and rTFAs also reduce systemic inflammation, while SFAs and n-6 PUFAs increase systemic inflammation. Cancer metastasis: SCFAs predominantly reduce metastasis, while iTFAs, SFAs and n-6 PUFAs seem to stimulate metastasis. The role of rTFAs and MUFAs in metastasis development is not yet understood. Abbreviations: iTFAs, industrial trans-fatty acids; MUFAs, mono-unsaturated fatty acids; n-3 and n-6 PUFAs, omega-3 and omega-6 polyunsaturated fatty acids; rTFAs, ruminant trans-fatty acids; SCFAs, short-chain fatty acids; SFA, saturated fatty acids.