Fibroblast growth factor signals regulate transforming growth factor‐β‐induced endothelial‐to‐myofibroblast transition of tumor endothelial cells via Elk1

Akatsu, Yuichi; Takahashi, Naoya; Yoshimatsu, Yasuhiro; Kimuro, Shiori; Muramatsu, Tomoki; Katsura, Akihiro; Maishi, Nako; Suzuki, Hiroshi; Inazawa, Johji; Hida, Kyoko; Miyazono, Kohei; Watabe, Tetsuro

doi:10.1002/1878-0261.12504

Cited by 43 publications

(40 citation statements)

References 53 publications

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“…Recently, FGF2 was shown to not only inhibit TGF-β-induced endothelial-to-myofibroblast transition (End-MyoT) mediated via the transcription factor ELK1, but also promoted the formation of active fibroblastic cells with migratory and proliferative characteristics. This revealed the opposing and cooperative action between FGF and TGF-β signaling during the modulation of different mesenchymal cell phenotypes (Akatsu et al, 2019). In mouse embryos with ECs deficient in β-catenin, the cardiac cushion had fewer cells, suggesting that β-catenin in ECs is needed for efficient EndMT and invasion of the mesenchymal cells into the cardiac jelly to form cardiac septa and valves.…”

Section: Interplay With Other Signaling Pathways That Mediate or Regumentioning

confidence: 99%

TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering

Ma¹,

Sánchez‐Duffhues²,

Goumans³

et al. 2020

Front. Cell Dev. Biol.

178

129

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Endothelial to mesenchymal transition (EndMT) is a complex biological process that gives rise to cells with multipotent potential. EndMT is essential for the formation of the cardiovascular system during embryonic development. Emerging results link EndMT to the postnatal onset and progression of fibrotic diseases and cancer. Moreover, recent reports have emphasized the potential for EndMT in tissue engineering and regenerative applications by regulating the differentiation status of cells. Transforming growth factor β (TGF-β) engages in many important physiological processes and is a potent inducer of EndMT. In this review, we first summarize the mechanisms of the TGF-β signaling pathway as it relates to EndMT. Thereafter, we discuss the pivotal role of TGF-β-induced EndMT in the development of cardiovascular diseases, fibrosis, and cancer, as well as the potential application of TGF-β-induced EndMT in tissue engineering.

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Section: Interplay With Other Signaling Pathways That Mediate or Regumentioning

confidence: 99%

TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering

Ma¹,

Sánchez‐Duffhues²,

Goumans³

et al. 2020

Front. Cell Dev. Biol.

178

129

View full text Add to dashboard Cite

show abstract

“…Conversely, recent studies demonstrated that ECs resist specific conversion to alpha-SMA+ myofibroblast-like cells when the cells are challenged with TGFβ through secretion of bFGF [83]. TGFβ and bFGF could oppose and cooperate with each other during EndMT via Elk1 [84]. These data suggest that EndMT is another mechanism producing TEC heterogeneity.…”

Section: Heterogeneity Of Tecsmentioning

confidence: 99%

Tumor Endothelial Heterogeneity in Cancer Progression

Maishi

Annan

Kojima

et al. 2019

Cancers

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Tumor blood vessels supply nutrients and oxygen to tumor cells for their growth and provide routes for them to enter circulation. Thus, angiogenesis, the formation of new blood vessels, is essential for tumor progression and metastasis. Tumor endothelial cells (TECs) that cover the inner surfaces of tumor blood vessels reportedly show phenotypes distinct from those of their normal counterparts. As examples, TECs show cytogenetic abnormalities, resistance to anticancer drugs, activated proliferation and migration, and specific gene expression patterns. TECs contain stem-like cell populations, which means that the origin of TECs is heterogeneous. In addition, since some abnormal phenotypes in TECs are induced by factors in the tumor microenvironment, such as hypoxia and tumor cell-derived factors, phenotypic diversity in TECs may be caused in part by intratumoral heterogeneity. Recent studies have identified that the interaction of tumor cells and TECs by juxtacrine and paracrine signaling contributes to tumor malignancy. Understanding TEC abnormality and heterogeneity is important for treatment of cancers. This review provides an overview of the diversity of TECs and discusses the interaction between TECs and tumor cells in the tumor microenvironment.

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“…2 We recently reported that transforming growth factor-β (TGF-β) induced the transition from tumor ECs (TECs) to α-smooth muscle actin (αSMA)-positive mesenchymal cells (myofibroblasts), which induced tumor formation more potently than αSMA-negative TEC-derived mesenchymal cells. 5 In addition to formation of CAFs during EndMT, loss of the endothelial barrier of the tumor vasculature can be observed, suggesting an important role of EndMT in facilitating metastatic dissemination. Thus, effective targeting of EndMT is likely to result in the development of novel anti-cancer therapies.…”

Section: Introductionmentioning

confidence: 99%

TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation

et al. 2020

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The tumor microenvironment (TME) consists of various components including cancer cells, tumor vessels, cancer‐associated fibroblasts (CAFs), and inflammatory cells. These components interact with each other via various cytokines, which often induce tumor progression. Thus, a greater understanding of TME networks is crucial for the development of novel cancer therapies. Many cancer types express high levels of TGF‐β, which induces endothelial‐to‐mesenchymal transition (EndMT), leading to formation of CAFs. Although we previously reported that CAFs derived from EndMT promoted tumor formation, the molecular mechanisms underlying these interactions remain to be elucidated. Furthermore, tumor‐infiltrating inflammatory cells secrete various cytokines, including TNF‐α. However, the role of TNF‐α in TGF‐β‐induced EndMT has not been fully elucidated. Therefore, this study examined the effect of TNF‐α on TGF‐β‐induced EndMT in human endothelial cells (ECs). Various types of human ECs underwent EndMT in response to TGF‐β and TNF‐α, which was accompanied by increased and decreased expression of mesenchymal cell and EC markers, respectively. In addition, treatment of ECs with TGF‐β and TNF‐α exhibited sustained activation of Smad2/3 signals, which was presumably induced by elevated expression of TGF‐β type I receptor, TGF‐β2, activin A, and integrin αv, suggesting that TNF‐α enhanced TGF‐β‐induced EndMT by augmenting TGF‐β family signals. Furthermore, oral squamous cell carcinoma‐derived cells underwent epithelial‐to‐mesenchymal transition (EMT) in response to humoral factors produced by TGF‐β and TNF‐α‐cultured ECs. This EndMT‐driven EMT was blocked by inhibiting the action of TGF‐βs. Collectively, our findings suggest that TNF‐α enhances TGF‐β‐dependent EndMT, which contributes to tumor progression.

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Fibroblast growth factor signals regulate transforming growth factor‐β‐induced endothelial‐to‐myofibroblast transition of tumor endothelial cells via Elk1

Cited by 43 publications

References 53 publications

TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering

TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering

Tumor Endothelial Heterogeneity in Cancer Progression

TNF‐α enhances TGF‐β‐induced endothelial‐to‐mesenchymal transition via TGF‐β signal augmentation

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