The Role Of Fibrotic Lung Microenvironment In Tumor Metastasis And Its Underlying Mechanism

The seeding of tumor cells in target organ is the critical step in the process of metastasis.The microenvironment of target organ plays an important role in the seeding of tumor cells,and consequently regulates the metastasis of tumor cells.In pathological conditions,microenvironment of the organ changes,but whether and how the changed microenvironment affects metastasis of tumor cells remain largely unknown.Therefore,we explored the effect of fibrotic microenvironment on metastasis of tumor cells and its underlying mechanism,based on the pulmonary fibrosis model.Using mouse model,we found that pulmonary fibrosis promoted metastatic seeding of hepatocellular carcinoma and mammary cancer cells to the lung,thus enhancing metastasis of tumor cells.In vitro experiments demonstrated that the conditioned medium from fibrotic lungs had a strong activity to chemoattract tumor cells and to inhibit the apoptosis of tumor cells.Fibroblast is the primary responding cell that is activated during fibrosis.The conditioned medium from fibrotic lung-derived fibroblast(CM-FLF)also had a strong activity to chemoattract tumor cells and to inhibit the apoptosis of tumor cells.Using quantitative PCR and immunohistochemical staining,we found the m RNA and protein level of FN1 and SPP1 were significantly increased in fibrotic lungs.Silencing of FN1 in the fibrotic lung-derived fibroblasts dramatically decreased the chemoattracting activity of CM-FLF,while silencing of FN1 or SPP1 in fibroblasts attenuated the anti-apoptosis activity of CM-FLF.Moreover,the CM-FLF-induced apoptosis resistance or chemotaxis of tumor cells was attenuated when ITGAV,the common receptor of FN1 and SPP1,was silenced by RNA interference or blocked by GRGDS treatment in tumor cells.Consistently,ITGAV silencing or GRGDS treatment significantly inhibited the seeding and outgrowth of tumor cells in fibrotic lungs in vivo.Collectively,we suggest that fibrotic microenvironment may enhance the metastatic seeding of tumor cells in the lung by chemoattracting tumor cells and inhibiting their apoptosis via activating the FN1/SPP1-ITGAV signaling.These findings give a novel insight into the regulatory mechanisms of cancer metastasis and provide a potential target for anti-metastasis therapy.