Ovarian cancer (OC) is the third common malignant tumor of the female reproductive system, has the eighth highest incidence among female cancer,and accounts for 4.4% of cancer-related deaths in females (1). Epithelial cancers account for 90% of all cases and encompass a heterogeneous group of malignancies comprised of five main histotypes: high-grade serous ovarian cancer (HGSOC), endometrioid ovarian cancer (ENOC), clear cell ovarian cancer (CCOC), mucinous ovarian cancer (MOC), and low-grade serous (LGSOC) (2, 3), the most common of which are serous carcinomas (4). Epithelial cancers are typically more aggressive than nonepithelial malignancies since most serous carcinomas are diagnosed at an advanced stage, which accounts for the low survival rates (4). Improving prevention and early detection strategies has improved the outcome, but the prognosis is still not ideal, and the 5-year survival rate is generally approximately 30% for advanced-stage OC (5). This high mortality rate of OC can be attributed to extensive peritoneal metastasis at the time of diagnosis (6, 7). The omentum is mainly composed of adipocytes, which have been considered to promote the initial homing of tumor cells and provide fatty acids to cancer cells, fueling rapid tumor growth (8). Free fatty acids (FFAs) are intermediate products of lipid mobilization that result principally from lipolysis and the breakdown of triglycerides (TGs) (9). In addition to the function of energy sources, FFAs also have the key functions of receptor signaling, gene expression and system energy homeostasis regulation under various physiological conditions (10–12). Serum FFAs include short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), and long-chain fatty acids (LCFAs); in cancer patients, most of FFAs are acetic acid (32%), hexadecanoic acid (40%) and octadecanoic acid (9%). Among them, acetic acid level is lower and hexadecanoic acid/octadecanoic acid is higher in cancer patients than in healthy controls (13).The free fatty acid receptor (FFAR) family is comprised of FFAR1–4, formerly known as GPR40, GPR43, GPR41, and GPR120, respectively; FFAR1 and FFAR4 are both receptors for LCFAs, and FFAR2 and FFAR3 are both receptors for SCFA (14–16). FFARs are expressed in several cancer cells, and their effect depends on the cell type and tumor type. Data on the role of FFARs in OC are limited. Ovarian cell lines and animal models showed that ovarian cells express mRNA for FFAR1 and FFAR4, and FFAR agonist/antagonist affect cell growth (17, 18). Clinical studies of FFAs and prognosis are limited. A previous study showed that serum FFA levels were elevated even when TGs and total cholesterol (TCHO) were normal in tumor patients, especially OC patients (19). In clinical work, we found that in OC patients, the serum FFA level was dramatically decreased after chemotherapy. Here, we wanted to determine the serum FFA levels in OC patients and the role of FFARs in the prognosis of OC.

A previous review showed that overweight (BMI of 25–29.9 kg/m2) and obesity (BMI ≥ 30 kg/m2) appears to increase the risk of OC (23), while our study found that when BMI is within the normal range (BMI of 18.5-24.9 kg/m2), OC has lower BMI than benign ovarian tumor. We found that the FFA level elevated in patients with OC and gradually decreased after chemotherapy, FFAs promote OVCAR3 cell migration, indicating that FFAs play a role during cancer development and progression, which was clearly demonstrated in several studies in related fields. Recent advances in proteomics and metabolomics have deepened our understanding of the role of fatty acid metabolism in determining the fate of cancer cells (24). The TG/FFA cycle participates in various metabolic and physiological processes and provides signaling molecules in cells. Fatty acid metabolism not only supports energy production but also provides necessary substrates for membrane synthesis and metabolic processes through β-oxidation, which is crucial to neogenesis (25, 26).

We found that the FFA level was not related to the pathological type, grade or FIGO stage of OC, while after chemotherapy, the FFA level declined dramatically, which can be explained by the decrease in the number of tumor cells and the diminished requirement of lipid metabolism after chemotherapy since abundant FAs in cancer cells support the rapid growth and proliferation of cancer cells (27).

The roles of FFARs in human cancers and cancer cells are different. In some tumors, FFAR1 and FFAR4 have similar effects, and the activation of FFAR1 and FFAR4 can promote the proliferation and migration of breast cancer cells and enhance the growth of colon cancer cells (28–30). In some tumors, FFAR1 and FFAR4 have the opposite effect; for example, FFAR1 activation inhibits the motile activity of pancreatic cancer and osteosarcoma cells, while FFAR4 activation promotes these activities (31, 32). FFAR1 activation promotes lung cancer and melanoma and prostate cancer, while FFAR4 activation inhibits these processes (33–36). FFAR1 activation inhibits the migration and invasion in fibrosarcoma cells (37), whereas FFAR4 activation stimulates the migration and invasion of esophageal cancer cells (38). FFAR4 activation can promote radiation resistance and chemotherapy resistance (39, 40). FFAR2 and FFAR3 act as tumor suppressors in colon and breast cancer; the loss of FFAR2 promotes colon tumorigenesis (41–43). FFAR2 is expressed in a human cervical cancer cell line and plays a protective role in cervical cancer, leukemia, and oral squamous cell carcinoma (44–46)

Previous studies on the effect of FFARs on OC cells are controversial. One article reported that an FFAR agonist resulted in growth inhibition and was associated with an alteration in energy metabolism, while another article found that an FFAR1 antagonist inhibited the proliferation of OC cells (17, 18). Munkarah et al. found that high-grade serous carcinoma specimens have significantly high expression of FFAR1 than normal ovary specimens and that FFAR1 expression was related to stage; higher expression was noted in advanced-stage disease (18). From the GEPIA data, we found that the mRNA levels of FFAR1/3 were lower in tumors, while those of FFAR2/4 were higher in tumors, but only FFAR1 showed a significant difference. KM plotter analysis showed that in wild-type OC, FFAR1-3 expression is related to a better prognosis, and FFAR4 is related to a poor prognosis; in TP53-mutant OC, FFAR2,4 are related to a poor prognosis, whereas FFAR3 is related to a better prognosis. FFAR2 has opposite effects, while FFAR3 and FFAR4 have similar effects on the prognosis of P53 wild and mutant OC. To our knowledge, FFARs are significant, independent prognostic factors in OC.

Our research has certain limitations. First, the number of cell lines and animal models was limited. Second, we did not assess the protein expression of FFARs in OC tissues, and further study needs to be done.

In summary, we found that serum FFAs were drastically downregulated after chemotherapy and that FFARs may be attractive potential therapeutic targets for OC. Further studies are required to study the mechanism and elucidate the link between the signaling and metabolic cross-talk occurring through FFARs and OC.

In summary, high FFA levels in the serum may be an indicator of OC, and FFARs are related to the prognosis of OC. This study may therefore provide new insight to OC monitoring and prognosis evaluation.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

The studies involving human participants were reviewed and approved by The Medical Ethics Committee of The Affiliated Hospital of Qingdao University (Shandong, China). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was not obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

HZ, XL, and JL collected and organized the data, XZ and HC performed the statistical analysis and generated the figures. LZ wrote the paper. TL designed the study and wrote the paper. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.