title: Fibrotic microenvironment promotes the metastatic seeding of tumor cells via activating the fibronectin 1/secreted phosphoprotein 1-integrin signaling.
abstract: The seeding of tumor cells is a critical step in the process of metastasis, but whether and how the microenvironment of target organs affects metastatic seeding remain largely unknown. Based on cell and mouse models, we found that the metastatic seeding and outgrowth of tumor cells were significantly enhanced in fibrotic lungs. The conditioned medium from both fibrotic lungs and the fibrotic lung-derived fibroblasts (CM-FLF) had a strong activity to chemoattract tumor cells and to inhibit the apoptosis of tumor cells. Subsequent investigations revealed that the levels of fibronectin 1 (FN1) and secreted phosphoprotein 1 (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.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Mengzhi
authors.initials: M
authors.lastname: Wu
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: Shang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Fang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, Collaborative Innovation Center for Cell Signaling Network, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China.
authors.forename: Shi-Mei
authors.initials: SM
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000556:secondary; D053495:Osteopontin / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D005353:Fibronectins; C506896:Spp1 protein, mouse; D053495:Osteopontin
keywords: FN1; ITGAV; SPP1; fibrotic microenvironment; metastatic seeding