Identification of radiation‐induced EndMT inhibitors through cell‐based phenomic screening

Song, Yeonhwa; Lee, Su-Yeon; Kim, Aram; Kim, Sanghwa; Heo, Jinyeong; Shum, David; Kim, Se-Hyuk; Choi, Inhee; Lee, Yoonjin; Seo, Haeng Ran

doi:10.1002/2211-5463.12552

Cited by 7 publications

(8 citation statements)

References 38 publications

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“…Recently, several drugs in clinical testing have been reported to inhibit EndMT in various animal disease models (Table 1). These drugs inhibit EndMT by targeting various signaling molecules, such as DPP-4 25,96 , Smad 97 , TGF-β [97][98][99] , AMPK 100 , and other proteins 28,[101][102][103][104][105][106] .…”

Section: Drugs With Endmt-inhibiting Effectsmentioning

confidence: 99%

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

et al. 2020

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Endothelial-to-mesenchymal transition (EndMT) involves the phenotypic conversion of endothelial-to-mesenchymal cells, and was first discovered in association with embryonic heart development. EndMT can regulate various processes, such as tissue fibrosis and cancer. Recent findings have shown that EndMT is related to resistance to cancer therapy, such as chemotherapy, antiangiogenic therapy, and radiation therapy. Based on the known effects of EndMT on the cardiac toxicity of anticancer therapy and tissue damage of radiation therapy, we propose that EndMT can be targeted as a strategy for overcoming tumor resistance while reducing complications, such as tissue damage. In this review, we discuss EndMT and its roles in damaging cardiac and lung tissues, as well as EndMT-related effects on tumor vasculature and resistance in anticancer therapy. Modulating EndMT in radioresistant tumors and radiationinduced tissue fibrosis can especially increase the efficacy of radiation therapy. In addition, we review the role of hypoxia and reactive oxygen species as the main stimulating factors of tissue damage due to vascular damage and EndMT. We consider drugs that may be clinically useful for regulating EndMT in various diseases. Finally, we argue the importance of EndMT as a therapeutic target in anticancer therapy for reducing tissue damage.

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Section: Drugs With Endmt-inhibiting Effectsmentioning

confidence: 99%

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

et al. 2020

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“…Within the TME, endothelial cells (ECs) have attracted attention as a key player in cancer progression due to their association with tumor cell angiogenesis, proliferation, and invasion, which have all been linked to the EC-mediated expression of various angiogenic factor receptors and remodeling of the extracellular matrix ( Dudley, 2012 ). In our previous study, we elucidated that the direct interaction between lung cancer cells and ECs induces chemo- and radioresistance by facilitating the endothelial-to-mesenchymal transition (EndMT) in lung cancer cells ( Choi et al, 2018 ; Kim et al, 2019 ; Song et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Expression of HYOU1 via Reciprocal Crosstalk between NSCLC Cells and HUVECs Control Cancer Progression and Chemoresistance in Tumor Spheroids

Lee¹,

Song²,

Choi

et al. 2021

Molecules and Cells

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Among all cancer types, lung cancer ranks highest worldwide in terms of both incidence and mortality. The crosstalk between lung cancer cells and their tumor microenvironment (TME) has begun to emerge as the “Achilles heel” of the disease and thus constitutes an attractive target for anticancer therapy. We previously revealed that crosstalk between lung cancer cells and endothelial cells (ECs) induces chemoresistance in multicellular tumor spheroids (MCTSs). In this study, we demonstrated that factors secreted in response to crosstalk between ECs and lung cancer cells play pivotal roles in the development of chemoresistance in lung cancer spheroids. We subsequently determined that the expression of hypoxia up-regulated protein 1 (HYOU1) in lung cancer spheroids was increased by factors secreted in response to crosstalk between ECs and lung cancer cells. Direct interaction between lung cancer cells and ECs also caused an elevation in the expression of HYOU1 in MCTSs. Inhibition of HYOU1 expression not only suppressed stemness and malignancy, but also facilitated apoptosis and chemosensitivity in lung cancer MCTSs. Inhibition of HYOU1 expression also significantly increased the expression of interferon signaling components in lung cancer cells. Moreover, the activation of the PI3K/AKT/mTOR pathway was involved in the HYOU1-induced aggression of lung cancer cells. Taken together, our results identify HYOU1, which is induced in response to crosstalk between ECs and lung cancer cells within the TME, as a potential therapeutic target for combating the aggressive behavior of cancer cells.

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“…In our previous studies, we established a visual phenomic screening platform to measure radiation-induced EndMT using HUVECs 28 . Herein, this technology was applied to measure TGFβ1-induced EndMT in HUVECs.…”

Section: Resultsmentioning

confidence: 99%

Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model

Song

Kim

Heo

et al. 2021

Sci Rep

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A chronic, local inflammatory milieu can cause tissue fibrosis that results in epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), increased abundance of fibroblasts, and further acceleration of fibrosis. In this study, we aimed to identify potential mechanisms and inhibitors of fibrosis using 3D model-based phenotypic screening. We established liver fibrosis models using multicellular tumor spheroids (MCTSs) composed of hepatocellular carcinoma (HCC) and stromal cells such as fibroblasts (WI38), hepatic stellate cells (LX2), and endothelial cells (HUVEC) seeded at constant ratios. Through high-throughput screening of FDA-approved drugs, we identified retinoic acid and forskolin as candidates to attenuate the compactness of MCTSs as well as inhibit the expression of ECM-related proteins. Additionally, retinoic acid and forskolin induced reprogramming of fibroblast and cancer stem cells in the HCC microenvironment. Of interest, retinoic acid and forskolin had anti-fibrosis effects by decreasing expression of α-SMA and F-actin in LX2 cells and HUVEC cells. Moreover, when sorafenib was added along with retinoic acid and forskolin, apoptosis was increased, suggesting that anti-fibrosis drugs may improve tissue penetration to support the efficacy of anti-cancer drugs. Collectively, these findings support the potential utility of morphometric analyses of hepatic multicellular spheroid models in the development of new drugs with novel mechanisms for the treatment of hepatic fibrosis and HCCs.

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Identification of radiation‐induced EndMT inhibitors through cell‐based phenomic screening

Cited by 7 publications

References 38 publications

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

Expression of HYOU1 via Reciprocal Crosstalk between NSCLC Cells and HUVECs Control Cancer Progression and Chemoresistance in Tumor Spheroids

Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model

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