Melatonin indirectly decreases gastric cancer cell proliferation and invasion via effects on cancer-associated fibroblasts
Introduction
Gastric cancer is one of the most fatal cancers and the third leading cause of cancer deaths worldwide. Despite efforts to develop effective therapies for cancer treatment, the 5-year overall survival rate of patients with gastric cancer remains low [1]. Tumors not only contain cancer cells but also the extracellular matrix (ECM) and various types of stromal cells, such as cancer-associated fibroblasts (CAFs), inflammatory cells, mesenchymal stem cells, and macrophages, which are known as the tumor microenvironment (TME), plays important and diverse roles in tumor progression [2]. The complex interactions between tumor cells and the TME provide new insights for improved understanding of cancer, and strategies for tumor treatment targeting the TME are also being explored [3]. Therefore, further exploration of the role of the TME in gastric cancer could provide a comprehensive understanding of the mechanism of gastric cancer development and help screen more appropriate drugs for gastric cancer treatment.
CAFs are major components of the TME and promote tumor progression through direct cell–cell interactions, cytokines, or as exosomes. Moreover, CAFs are associated with tumor resistance to chemoradiotherapy, and tumor recurrence can affect the prognosis of patients [4,5]. CAFs can influence the progression of gastric cancer cells through cytokines, miRNAs, and other associated factors produced by CAFs, and may induce therapeutic resistance [[6], [7], [8], [9], [10], [11]]. Tumor treatments targeting CAFs have long been a research hotspot. These treatments include reducing the generation of CAFs, reversing the CAF phenotype, and interfering with the upstream and downstream signaling pathways of CAFs. However, owing to the heterogeneity and non-specificity of the CAFs within and among tumors, further screening for more specific and effective drugs is needed [12].
Melatonin is a hormone secreted by the pineal gland and other gastrointestinal tract-associated organs that exhibit pleiotropic effects [13,14]. Low levels of melatonin in the body are associated with a high risk of tumorigenesis in breast, prostate, and endometrial cancers [[15], [16], [17]]. A growing number of in vitro and in vivo experiments are exploring the effect of melatonin on various cancer cell types, and most results suggest that melatonin suppresses cancer cell progression [[18], [19], [20]]. Therefore, some clinical trials have explored the function of melatonin supplementation in terms of survival, side effects of radiation and chemotherapy, and quality of life in patients with cancer, further suggesting the value of additional melatonin use in these patients [[21], [22], [23], [24], [25], [26]]. In gastric cancer, melatonin can inhibit cell proliferation and metastasis by inducing apoptosis, autophagy, and inhibiting epithelial–mesenchymal transition [[27], [28], [29], [30]]. Because of the considerable potential applications of melatonin in cancer therapy and the complex crosstalk between the TME and tumor cells, the role of melatonin in the regulation of the TME, especially CAFs, which is less often reported, requires further in-depth investigation, particularly in gastric cancer.
We hypothesized that melatonin not only affects the proliferation and metastasis of gastric cancer cells directly but also indirectly through its effect on CAFs. This study further deepens the understanding of the mechanism of action of melatonin in gastric cancer and suggests the potential value of melatonin in gastric cancer treatment.
Section snippets
Cell culture and reagents
The human gastric cancer cell lines MGC-803 and SGC-7901 were obtained from the Shanghai Institute of Biological Sciences, Chinese Academy of Sciences (Shanghai, China). Cells were cultured in RPMI 1640 medium or conditioned medium (CM) supplemented with 10% fetal bovine serum (FBS) and 1% antibiotic with 100 U/mL penicillin and 100 μg/mL streptomycin in a humidified incubator at 37 °C with 5% CO2. All cell culture reagents were obtained from Gibco (Invitrogen, Carlsbad, CA, USA). Primary
Melatonin suppresses gastric cancer cell proliferation, migration, and invasion
The CCK-8 assay was performed to estimate the effects of different concentrations of melatonin on MGC-803 cells at different time points. The results showed that the effects of melatonin exhibited a certain concentration-dependent and time-dependent (Fig. 1A). For identifying the suitable treatment time and concentration, the dose response curve was applied, results showed that the IC50 with treatment time point of 24 h, 48 h and 72 h was 4.783 mM, 3.198 mM and 2.69 mM respectively (Fig. 1B).
Discussion
The treatment of gastric cancer faces considerable challenges, especially as advanced gastric cancer cannot be effectively treated by either surgery or chemotherapy and is a malignant tumor with a poor prognosis [31]. Meanwhile, the interaction between tumor cells and CAFs during the development of gastric cancer further contributes to progression and treatment failure. Intervening in the crosstalk between cells may be a more feasible direction for cancer therapy [32]. Melatonin is an endocrine
Conclusion
Melatonin not only inhibits cell proliferation and metastasis by reducing the production of ROS in gastric cancer cells but also inhibits CAF-induced gastric cancer cell progression by reducing the production of MMP2 and MMP9 in CAFs. The direct and indirect inhibitory effects of melatonin on gastric cancer cells are involved in NF-kB signaling pathway-related proteins, and melatonin has great potential for gastric cancer treatment.
Declaration of competing interest
The authors declare that they have no conflict of interest to disclose.
Acknowledgments
This study was supported by the Technology Development Foundation of Pudong District (grant no. PKJ2016-Y54), the National Cultivation Project of Shanghai University of Medicine & Health Sciences (grant no. SFP-18-20-14-005).
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