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The present study demonstrated two novel findings. To the best of our knowledge, it is the first study to demonstrate that regulated upon activation, normal T-cell expressed and secreted (RANTES), produced by breast tumor-associated monocyte-derived dendritic cells (TADCs) following breast cancer cell exposure to phthalate esters, may contribute to the progression of cancer via enhancement of cancer cell proliferation, migration and invasion. Furthermore, the present study revealed that didymin, a dietary flavonoid glycoside present in citrus fruits, was able to reverse phthalate ester-mediated breast cancer aggravation. MDA-MB-231 cells were treated with butyl benzyl phthalate (BBP), di-n-butyl phthalate (DBP) or di-2-ethylhexyl phthalate (DEHP). Subsequently, the conditioned medium (CM) was harvested and cultured with monocyte-derived dendritic cells (mdDCs). Cultures of MDA-MB-231 cells with the conditioned medium of BBP-, DBP- or DEHP-MDA-MB-231 tumor-associated mdDCs (BBP-, DBP- or DEHP-MDA-TADC-CM) demonstrated enhanced proliferation, migration and invasion. Exposure of the MDA-MB-231 cells to DBP induced the MDA-TADCs to produce the inflammatory cytokine RANTES, which subsequently induced MDA-MB-231 cell proliferation, migration and invasion. Depleting RANTES reversed the effects of DBP-MDA-TADC-mediated MDA-MB-231 cell proliferation, migration and invasion. In addition, didymin was observed to suppress phthalate-mediated breast cancer cell proliferation, migration and invasion. The present study suggested that didymin was capable of preventing phthalate ester-associated cancer aggravation.

Phthalates are used as plasticizers in the manufacture of flexible vinyl, which is used in food contact applications. Phthalates have been demonstrated to have an adverse impact on human health, particularly in terms of cancer development. In the present study, we showed for the first time that benzyl butyl phthalate (BBP) potentiates the effect of tumor‑associated dendritic cells (TADCs) on the chemoresistance of breast cancer. Specific knockdown analysis revealed that S100A9 is the major factor responsible for the chemoresistance of doxorubicin/cyclophosphamide induced by BBP-stimulated TADCs in breast cancer. BBP exposure also increased tumor infiltrating myeloid-derived suppressor cell (MDSC) secretion of S100A8/A9, thereby exacerbating the resistance of breast cancer to doxorubicin with cyclophosphamide. In addition, BBP also stimulated the production of CXCL1/GROα by TADCs, which increased the angiogenesis of breast cancer in a mouse model. Inhibition of CXCL1/GROα by a neutralizing antibody, decreased the BBP-induced angiogenesis induced by BBP after chemotherapy in the mouse model. These results, for the first time, provide evidence that BBP influences the efficacy of chemotherapy by remodeling the tumor microenvironment of breast cancer.

Bone metastasis in lung cancer results in an unfavorable outcome for patients by not only impairing the quality of life, yet also increasing the cancer-related death rates. In the present study, we discuss a novel treatment strategy that may benefit these patients. Human CD14+ monocytes treated with macrophage-colony stimulating factor (M-CSF)/receptor activator of nuclear factor κB ligand (RANKL) differentiated into osteoclasts, whereas syringetin (SGN), a flavonoid derivative found in both grapes and wine, suppressed the osteoclastogenesis in vitro in a dose-dependent manner. In addition, SGN inhibited osteoclast formation induced by human lung adenocarcinoma A549 and CL1-5 cells. The associated signaling transduction pathway in osteoclastogenesis and SGN inhibition was found to be via the AKT/mammalian target of rapamycin (mTOR) signaling pathway. Blocking AKT and mTOR by respective inhibitors significantly decreased lung adenocarcinoma-mediated osteoclastogenesis. Moreover, SGN regulated the lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts by suppressing the stimulatory effect of lung adenocarcinoma on M-CSF and RANKL production in osteoblasts, and reversing the inhibitory effect of the lung adenocarcinoma on OPG production in osteoblasts. The present study has two novel findings. It is the first to illustrate lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts, leading to osteolytic bone metastasis. It also reveals that SGN, a flavonoid derivative, directly inhibits osteoclastogenesis and reverses lung adenocarcinoma-mediated osteoclastogenesis. In conclusion, the present study suggests that SGN, a natural compound, prevents and treats bone metastasis in patients with lung cancer.

Several of the soluble inflammatory molecules such as cytokines and chemokines are involved in the regulation of cancer behaviors. Tumor necrosis factor (TNF)‑like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily and is a ligand of fibroblast growth factor inducible 14 (Fn14). TWEAK/Fn14 signaling pathways promote tumor progression in several types of human cancer. In the present study, we investigated the role of TWEAK through bioinformatic assay, in vitro experiments, and serum levels in patients with non‑small cell lung cancer (NSCLC). Our results indicated that TWEAK expression in normal tissues was higher than that in lung cancer tissues. In contrast, relatively higher Fn14 expression was detected in lung cancer tissues compared to normal tissues. Recombinant TWEAK treatment did not enhance and inhibit the proliferation and migration of human NSCLC cell lines including A549, H1299, CL1‑0 and CL1‑5. In addition, the serum concentration of TWEAK in normal controls was significantly higher than that in NSCLC patients. However, the TWEAK levels did not show significant difference in regards to TNM stage, cell type and metastasis status in the sera of NSCLC patients. In summary, the present study suggests that a low serum level of TWEAK may be a feature of NSCLC, and the role of TWEAK‑mediated pathways warrant further investigation.

Lung cancer is the leading cause of cancer-associated mortality worldwide and is also associated with a poor prognosis. As in numerous other types of cancer, galectins have been demonstrated to be involved in the progression of lung cancer. Galectins belong to a superfamily of lectins, which are carbohydrate-binding proteins. There are at least 15 members in the galectin family, however, only galectin-1, -2, -3, -4, -7, -8, -9, -10, -12, and -13 are found in humans. Galectins are able to mediate interactions between cells, including homotypic and heterotypic interactions; they also facilitate the bindings between cells and extracellular matrix components. These cell-cell and cell-matrix interactions, as well as the galectin signaling on the cell surface, are able to modulate signaling pathways and thereby influence cellular functions and behaviors. Galectin-1, -3, -4, -7, -8 and -9 are associated with lung cancer. These galectins are associated with tumor invasion, migration, metastasis and progression, and may serve important roles in the tumor microenvironment of lung cancer. The majority of galectins are associated with the progression of lung cancer, with the exception of galectin-9, which is associated with enhanced anticancer immunity. Therefore, galectins may be potential targets for developing novel lung cancer therapies.

The bone is the most common metastatic site of breast cancer. Bone metastasis causes pain, pathologic frac- tures, and severely reduces the quality of life. Breast cancer causes osteolytic bone metastasis, which is dependent on osteo - clast-mediated bone resorption. While current treatments rely on palliative anti-resorptive agents, there is a need to develop a drug based on potential alternative therapies. This study is the first to determine that wedelolactone (WDL), a natural coumarin isolated from plants, can inhibit breast cancer- mediated osteoclastogenesis. Osteoclasts were generated from human CD14 + monocytes cultured with M-CSF/RANKL and WDL suppressed human osteoclast differentiation and activity in vitro in a dose-dependent manner. Moreover, WDL inhibited the upregulation of osteoclasts stimulated by MDA-MB-231 breast cancer cells. The activity of WDL on osteoclasts and breast cancer-mediated osteoclastogenesis was associated with the inhibition of Akt/mammalian target of the rapamycin signaling pathway (mTOR). Blocking Akt and mTOR by specific inhibitors significantly decreased osteoclast differenti - ation and bone resorption. Furthermore, WDL regulated breast cancer-enhanced interaction of osteoblasts and osteoclasts by decreasing M-CSF expression in MDA-MB-231-stimulated osteoblasts. Thus, this study suggests that WDL may be a poten - tial natural agent for preventing and treating bone destruction in patients with bone metastasis due to breast cancer.