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The formation of tumor-promoting premetastatic microenvironment plays a pivotal role on metastatic progression. Understanding how the primary tumor can promote the formation of premetastatic microenvironment in the lung will aid discovery of a final cure for metastatic breast cancer. The murine 4T1 mammary carcinoma cells were injected into the mammary fat pads of the BALB/c mice. Days 0-14 were considered the premetastatic phase. Lung tissues were examined using hematoxylin-eosin staining and transmission electron microscopy. After intravenous injection of TGFβ1 pretreated 4T1 cells, the relative pulmonary vascular permeability was quantified, the extravasation, survival, and proliferation of tumor cells in premetastatic lungs were evaluated, and the levels of S100A8, S100A9, VEGF, and Angpt2 were detected in tumor-bearing mice. The results showed that during the premetastatic phase, an inflammatory response and inflammation-induced vascular hyperpermeability were established, leading to an abnormal pulmonary microenvironment, which facilitated extravasation of circulating tumor cells, and subsequent survival and proliferation of metastatic tumor cells in a TGFβ-dependent manner. Moreover, the expressions of S100A8, S100A9, VEGF, and Angpt2 were increased, and an induction of these genes by TGFβ was further observed in premetastatic lungs. Thus, this study demonstrated that TGFβ promoted the creation of premetastatic microenvironment by modulating certain crucial inflammatory cytokines and growth factors, and finally enhanced the ability of circulating cells to seed the lung.

Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potential mechanism of this inhibition. In the murine model of breast cancer osseous metastasis, mice that received osthole developed significantly less bone metastases and displayed decreased tumor burden when compared with mice in the control group. Osthole inhibited breast cancer cell growth, migration, and invasion, and induced apoptosis of breast cancer cells. Additionally, it also regulated OPG/RANKL signals in the interactions between bone cells (osteoblasts and osteoclasts) and cancer cells. Besides, it also inhibited TGF-β/Smads signaling in breast cancer metastasis to bone in MDA-231BO cells. The results of this study suggest that osthole has real potential as a therapeutic candidate in the treatment of breast cancer patients with bone metastases.