Abstract
Activation of peroxisome proliferator-activated receptor gamma (PPARγ) elicits anti-proliferative effects on different tumor cells, including those derived from breast cancer. PPARγ is also expressed in several cells of the breast tumor microenvironment, among which tumor associated macrophages (TAMs) play a pivotal role in tumor progression and metastasis. We explored the ability of synthetic and natural PPARγ ligands to modulate TAM polarization. The ligands included rosiglitazone (BRL-49653), and two docosahexaenoic acid (DHA) conjugates, N-docosahexaenoyl ethanolamine (DHEA) and N-docosahexaenoyl serotonin (DHA-5-HT). Human THP-1 monocytic cells were differentiated into M0, M1 and M2 macrophages that were characterized by qRT-PCR, ELISA and western blotting. A TAM-like phenotypic state was generated by adding two different breast cancer cell conditioned media (BCC-CM) to the cultures. Macrophages exposed to BCC-CM concomitantly exhibited M1 and M2 phenotypes. Interestingly, rosiglitazone, DHEA and DHA-5-HT attenuated cytokine secretion by TAMs, and this effect was reversed by the PPARγ antagonist GW9662. Given the key role played by PPARγ in the crosstalk between cancer cells and TAMs in tumor progression, its activation via endogenous or synthetic ligands may lead to novel strategies that target both epithelial neoplastic cells and the tumor microenvironment.
Highlights
Despite major advances in prevention, screening and treatment, breast cancer remains the leading cause of cancer incidence and mortality in women worldwide, with 2.1 million new cases, accounting for almost one in four diagnosed cancer cases in 2018 [1]
An increasing number of studies point towards the importance of two main dietary n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in breast cancer prevention and treatment [8,9,10,11,12]
Based on the anti-inflammatory and antineoplastic properties found for conjugates of the n-3 long-chain PUFAs [28,29,30,31,33,34,40,41,42], we investigated the effects of two DHA metabolites, docosahexaenoyl ethanolamine (DHEA) and DHA-5-HT, and the synthetic PPARγ ligand rosiglitazone (BRL-49653), on modulating tumor-associated macrophages (TAMs) polarization induced by breast cancer cell conditioned media (BCC-CM)
Summary
Despite major advances in prevention, screening and treatment, breast cancer remains the leading cause of cancer incidence and mortality in women worldwide, with 2.1 million new cases, accounting for almost one in four diagnosed cancer cases in 2018 [1]. An increasing number of studies point towards the importance of two main dietary n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in breast cancer prevention and treatment [8,9,10,11,12]. These molecules serve as structural components of cellular membranes and are assumed to exert antineoplastic activities through alteration of membrane fluidity and cell surface receptor function, modulation of cyclooxygenase (COX) activity and an attenuation of increased cellular oxidative stress [13]. DHA and EPA are endogenously converted to a plethora of bioactive molecules in a condition and tissue-specific manner [22,23,24]
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