Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling

Sun, Yuanzhen; Fan, Xiaoli; Zhang, Qing; Shi, Xiaoyu; Xu, Guangwei; Zou, Cuimin

doi:10.1177/1010428317712592

Cited by 80 publications

(63 citation statements)

References 32 publications

(54 reference statements)

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“…However, our results also suggest that Fgf2 is not the only Fgf secreted in the tumour microenvironment as Fgfr blocking was more efficient in reducing tumour colonies than eliminating Fgf2 alone, although a direct effect of the aptamer or Fgfr blocker on the epithelial cells cannot be excluded. Indeed, other Fgf s including Fgf1 and Fgf3 have been shown to promote tumour progression in various cancers . We also showed that in our model, CAFs produce more collagen, recruit TAMs, and promote their switch to the pro‐tumorigenic M2 phenotype.…”

Section: Discussionsupporting

confidence: 66%

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

Hegab

Ozaki

Kameyama

et al. 2019

The Journal of Pathology

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Cancer‐associated fibroblasts (CAFs) are known to promote tumourigenesis through various mechanisms. Fibroblast growth factor (FGF)/FGF receptor (FGFR)‐dependent lung cancers have been described. We have developed a mouse model of lung adenocarcinoma that was constructed through the induction of Fgf9 overexpression in type 2 alveolar cells. The expression of Fgf9 in adult lungs resulted in the rapid development of multiple adenocarcinoma‐like tumour nodules. Here, we have characterised the contribution of CAFs and the Fgf/Fgfr signalling pathway in maintaining the lung tumours initiated by Fgf9 overexpression. We found that CAF‐secreted Fgf2 contributes to tumour cell growth. CAFs overexpressed Tgfb, Mmp7, Fgf9, and Fgf2; synthesised more collagen, and secreted inflammatory cell‐recruiting cytokines. CAFs also enhanced the conversion of tumour‐associated macrophages (TAMs) to the tumour‐supportive M2 phenotype but did not influence angiogenesis. In vivo inhibition of Fgfrs during early lung tumour development resulted in significantly smaller and fewer tumour nodules, whereas inhibition in established lung tumours caused a significant reduction in tumour size and number. Fgfr inhibition also influenced tumour stromal cells, as it significantly abolished TAM recruitment and reduced tumour vascularity. However, the withdrawal of the inhibitor caused a significant recurrence/regrowth of Fgf/Fgfr‐independent lung tumours. These recurrent tumours did not possess a higher proliferative or propagative potential. Our results provide evidence that fibroblasts associated with the Fgf9‐induced lung adenocarcinoma provide multiple means of support to the tumour. Although the Fgfr blocker significantly suppressed the tumour and its stromal cells, it was not sufficient to completely eliminate the tumour, probably due to the emergence of alternative (resistance/maintenance) mechanism(s). This model represents an excellent tool to further study the complex interactions between CAFs, their related chemokines, and the progression of lung adenocarcinoma; it also provides further evidence to support the need for a combinatorial strategy to treat lung cancer. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 66%

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

Hegab

Ozaki

Kameyama

et al. 2019

The Journal of Pathology

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“…This data suggests that the CAF may produce soluble factors in the medium to promote NSCLC cell survival under stress of chemotherapy drugs. To further determine the key factors in the CAF‐secreted cytokines involved in NSCLC drug resistance, we screened the expression of IGF2 , SDF‐1 , HGF , VEGF α, FGF , EGF , PDGF , CTGF , Tenascin , TSP‐1 and Fibronectin in the CAF pre‐co‐cultured with or without LCP1 cells and found that IGF2 , VEGFa and EGF were significantly upregulated, especially the IGF2 (Figure C). Moreover, we used the recombinant IGF2 to pre‐treat LCP1 and A549 cells, followed by cisplatin, etoposide and vinorelbine diatrate treatment.…”

Section: Resultsmentioning

confidence: 99%

Reverse of non‐small cell lung cancer drug resistance induced by cancer‐associated fibroblasts via a paracrine pathway

et al. 2018

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The tumor microenvironment orchestrates the sustained growth, metastasis and recurrence of cancer. As an indispensable component of the tumor microenvironment, cancer‐associated fibroblasts (CAF) are considered as an essential synthetic machine producing various tumor components, leading to cancer sustained stemness, drug resistance and tumor recurrence. Here, we developed a sustainable primary culture of lung cancer cells fed with lung cancer‐associated fibroblasts, resulting in enrichment and acquisition of drug resistance in cancer cells. Moreover, IGF2/AKT/Sox2/ABCB1 signaling activation in cancer cells was observed in the presence of CAF, which induces upregulation of P‐glycoprotein expression and the drug resistance of non‐small cell lung cancer cells. Our results demonstrated that CAF cells constitute a mechanism for cancer drug resistance. Thus, traditional chemotherapy combined with insulin‐like growth factor 2 (IGF2) signaling inhibitor may present an innovative therapeutic strategy for non‐small cell lung cancer therapy.

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“…Indeed, mice treated with IFN-␣ showed a weaker response to oncolytic alphavirus M1 treatment (46). These results may be extrapolated to FGFs, as the expression of various FGFs is upregulated in ovarian cancer, breast cancer, prostate cancer, and colon cancer (47)(48)(49)(50)(51). In tumor microenvironments with high FGF levels, replication of oncolytic VSV or coxsackievirus is possibly naturally inhibited.…”

Section: Discussionmentioning

confidence: 97%

Secretome Screening Reveals Fibroblast Growth Factors as Novel Inhibitors of Viral Replication

Asten

Raaben

Nota

et al. 2018

J Virol

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Cellular antiviral programs can efficiently inhibit viral infection. These programs are often initiated through signaling cascades induced by secreted proteins such as type I interferons, IL-6 or TNF-α. Here, we generated an arrayed library of 756 human secreted proteins to perform a secretome screen focused on the discovery of novel modulators of viral entry and/or replication. The individual secreted proteins were tested for their capacity to inhibit infection by two replication-competent recombinant vesicular stomatitis viruses (VSV) with distinct glycoproteins utilizing different entry pathways. Fibroblast growth factor 16 (FGF16) was identified and confirmed as the most prominent novel inhibitor of both VSVs and therefore of viral replication and not entry. Importantly, an antiviral interferon signature was completely absent in FGF16 treated cells. Nevertheless, the antiviral effect of FGF16 is broad as it was evident on multiple cell types and also on infection of Coxsackievirus. In addition, other members of the FGF family also inhibited viral infection. Thus, our unbiased secretome screen revealed a novel protein family capable of inducing a cellular antiviral state. This previously unappreciated role of the FGF family may have implications for the development of new antivirals and the efficacy of oncolytic virus therapy.Viruses infect human cells in order to replicate, while human cells aim to resist infection. Several cellular antiviral programs have therefore evolved to resist infection. Knowledge of these programs is essential for the design of antiviral therapeutics in the future. The induction of antiviral programs is often initiated by secreted proteins such as interferons. We hypothesized that other secreted proteins may also promote resistance to viral infection. Thus we tested 756 human secreted proteins for their capacity to inhibit two pseudotypes of vesicular stomatitis virus (VSV). In this first secretome screen on viral infection we identified fibroblast growth factor 16 (FGF16) as a novel antiviral against multiple VSV pseudotypes as well as Coxsackievirus. Subsequent testing of other FGF family members revealed that FGF signaling generally inhibits viral infection. This finding may lead to the development of new antivirals and may also be applicable to enhance oncolytic virus therapy.

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Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling

Cited by 80 publications

References 32 publications

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

Reverse of non‐small cell lung cancer drug resistance induced by cancer‐associated fibroblasts via a paracrine pathway

Secretome Screening Reveals Fibroblast Growth Factors as Novel Inhibitors of Viral Replication

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