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.
Highlights
Cancer metastasis is a complex, multi-step process that tumor cells detach from primary site, migrate and invade through extracellular matrix, intravasate into vessels, survive in the bloodstream, extravasate from vessels, seed in target organ and grow to form micro- and macro-metastatic nodules [1, 2]
Fibronectin 1 (FN1) and secreted phosphoprotein 1 (SPP1) secreted by the fibrotic lungderived fibroblasts promoted the chemotaxis and the apoptosis resistance of tumor cells via fibronectin 1 (FN1)/SPP1-Integrin αv (ITGAV) signaling, thereby facilitating the seeding and outgrowth of tumor cells in the lung. These results provide a novel insight into the role of FN1 and SPP1 in the metastatic seeding of tumor cells and implicate the FN1/SPP1-ITGAV signaling as a potential therapeutic target for metastasis
We found that mRNA levels of Fn1 and Spp1 were significantly increased in the fibrotic lungs of both C57BL/6 and BALB/c mice, whereas Cxcl12 was only up-regulated in C57BL/6 but not BALB/c mice and Vtn was down-regulated in both strains (Supplementary Figure S5A)
Summary
Cancer metastasis is a complex, multi-step process that tumor cells detach from primary site, migrate and invade through extracellular matrix, intravasate into vessels, survive in the bloodstream, extravasate from vessels, seed in target organ and grow to form micro- and macro-metastatic nodules [1, 2]. Three studies based on animal models indicate that pulmonary fibrosis may promote the survival and outgrowth of metastatic mammary and lung carcinoma cells in the lungs [8,9,10]. Barkan et al show that the type-I collagen-enriched fibrotic environment www.impactjournals.com/oncotarget in the lung induces the metastatic growth of dormant mammary cancer cell through activation of SRC and focal adhesion kinase [9]. Experimental evidences reveal that collagen crosslinking may create a growthpermissive fibrotic microenvironment that supports metastatic growth by enhancing tumor cell survival [10]. These emerging evidences suggest the significance of fibrotic microenvironment on the outgrowth of tumor cells in the lungs. More extensive investigations are required to explore the impact of fibrotic microenvironment on the seeding of tumor cells and to identify the molecules that mediate the pro-metastasis effect of fibrotic microenvironment
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