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.

Cancer‐associated fibroblasts (CAFs) promote the lymph node metastasis of esophageal squamous cell carcinoma

“…CAFs secrete several signaling molecules, including inflammatory cytokines, growth factors and chemokines, to stimulate cancer cells in the TME, and they remodel the extracellular matrix (ECM) by secreting ECM components . Through these properties, CAFs provide suitable conditions for tumor progression by promoting tumor growth, survival, angiogenesis, inflammation, drug resistance, invasion and metastasis .…”

Limited fibrosis accompanies triple-negative breast cancer metastasis in multiple model systems and is not a preventive target

“…Metastasis formation has been ascribed to both tumor intrinsic and microenvironmental effects of the LPA pathway [ 49 ]. At the intersection of these two phenotypes, fibrosis has been reported as a “soil” for the seeding of metastases [ 50 , 51 ], expansion of micrometastases [ 16 ], promotion of tumor viability [ 10 ], and immune effects [ 17 ], suggesting the hypothesis that LPA-induced fibrosis may be a mechanism of metastasis promotion. This hypothesis was contrary to published data where breast cancer cells with a LPA1 knockdown were metastasis suppressed [ 18 ], suggesting a tumor cell-intrinsic effect, but did not preclude an indirect microenvironmental effect or a transdifferentiation of carcinoma cells to myoepithelial cells [ 11 ].…”

Comprehensive review of Hepatitis B Virus‐associated hepatocellular carcinoma research through text mining and big data analytics

“…The levels of FN1 do not seem to differ significantly between patients with and without HBV integration into FN1 (Ding et al ., ; Sung et al ., ), suggesting that some integration events may not have a direct impact on HCC development (Sung et al ., ) and these genomic sites are perhaps more prone to HBV integration but do not appear to contribute to HCC. Nonetheless, a report showed that activation of FN1 creates a microenvironment to promote the metastatic seeding of tumour cells in lung cancer (Zhang et al ., ). Hence, it is also possible that while FN1 may not have a direct effect on the development of the tumour itself, it may create a microenvironment in adjacent non‐tumour tissues to facilitate tumour metastasis.…”