Utilization of adipocyte-derived lipids and enhanced intracellular trafficking of fatty acids contribute to breast cancer progression

Abstract

BackgroundTo determine whether adipocyte-derived lipids could be transferred into breast cancer cells and investigate the underlying mechanisms of subsequent lipolysis and fatty acid trafficking in breast cancer cells.MethodsA Transwell co-culture system was used in which human breast cancer cells were cultured in the absence or presence of differentiated murine 3 T3-L1 adipocytes. Migration/invasion and proliferation abilities were compared between breast cancer cells that were cultivated alone and those co-cultivated with mature adipocytes. The ability of lipolysis in breast cancer cells were measured, as well as the expression of the rate-limiting lipase ATGL and fatty acid transporter FABP5. ATGL and FABP5 were then ablated to investigate their impact on the aggressiveness of breast cancer cells that were surrounded by adipocytes. Further, immunohistochemistry was performed to detect differential expression of ATGL and FABP5 in breast cancer tissue sections.ResultsThe migration and invasion abilities of cancer cells were significantly enhanced after co-culture with adipocytes, accompanied by elevated lipolysis and expression of ATGL and FABP5. Abrogation of ATGL and FABP5 sharply attenuated the malignancy of co-cultivated breast cancer cells. However, this phenomenon was not observed if a lipid emulsion was added to the culture medium to substitute for adipocytes. Furthermore, epithelial-mesenchymal transaction was induced in co-cultivated breast cancer cells. That may partially due to the stimulation of PPARβ/δ and MAPK, which was resulted from upregulation of FABP5. As evidenced by immunohistochemistry, ATGL and FABP5 also had higher expression levels at the invasive front of the breast tumor, in where the adipocytes abound, compared to the central area in tissue specimens.ConclusionsLipid originating from tumor-surrounding adipocytes could be transferred into breast cancer cells. Adipocyte-cancer cell crosstalk rather than lipids alone induced upregulation of lipases and fatty acid transport protein in cancer cells to utilize stored lipids for tumor progression. The increased expression of the key lipase ATGL and intracellular fatty acid trafficking protein FABP5 played crucial roles in this process via fueling or signaling.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0221-6) contains supplementary material, which is available to authorized users.

RETRACTED ARTICLE: Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression

“…Intriguingly, breast cancer cells strongly overexpressed levels of ATGL, BDH1, HMGCL and HMGCS2, but decreased the level of PDH. This suggests that breast cancer cells mainly depended on the energy supply via oxidation of fatty acids and ketones instead of pyruvate and is consistent with other research [49]. Taken together, the data indicate that breast cancer cells, acting as metabolic parasites, constantly seized energy and biomass from local adipocytes to fuel tumour growth and metastasis.…”

Cancer-associated adipocytes: key players in breast cancer progression

“…Moreover, our results indicated that FABP5 mRNA is highly expressed in adipocytes that were co-cultured with breast cancer cells [66]. FABP5 has also been shown to be overexpressed at the invasive front of the breast tumor and linked to poor survival [86, 87]. Similarly, Wang and colleagues described a novel mechanism in which FFAs were released by adipocytes after lipolysis induced by tumor secretions and were transferred into tumor cells to enhance FFA β-oxidation [3], in which FFA transformation maybe attributed to FABP5 high expression [86].…”

Adipocyte and lipid metabolism in cancer drug resistance

“…cancer cell membrane and cellular organelle constitution (28,29) ; (b) release of endocrine hormones, growth factors, adipokines, and adipocytokines (refs. 30-44 and Table 1); (c) metabolic reprogramming in cancer cells (2, 3); (d) protease production necessary for cancer invasion (45,46); and (e) recruitment of nonadipocyte stromal cells such as inflammatory cells and vascular cells (47,48).…”