Dataset Information

Reducing tumor invasiveness by ramucirumab and TGF-β receptor kinase inhibitor in a diffuse-type gastric cancer patient-derived cell model.

ABSTRACT:

Background

Diffuse-type gastric cancer (GC) is known to be more aggressive and relatively resistant to conventional chemotherapy. Hence, more optimized treatment strategy is urgently needed in diffuse-type GC.

Methods

Using a panel of 10 GC cell lines and 3 GC patient-derived cells (PDCs), we identified cell lines with high EMTness which is a distinct feature for diffuse-type GC. We treated GC cells with high EMTness with ramucirumab alone, TGF-β receptor kinase inhibitor (TEW-7197) alone, or in combination to investigate the drug's effects on invasiveness, spheroid formation, EMT marker expression, and tumor-induced angiogenesis using a spheroid-on-a-chip model.

Results

Both TEW-7197 and ramucirumab treatments profoundly decreased invasiveness of EMT-high cell lines and PDCs. With a 3D tumor spheroid-on-a-chip, we identified versatile influence of co-treatment on cancer cell-induced blood vessel formation as well as on EMT progression in tumor spheroids. The 3D tumor spheroid-on-a-chip demonstrated that TEW-7197 + ramucirumab combination significantly decreased PDC-induced vessel formation.

Conclusions

In this study, we showed TEW-7197 and ramucirumab considerably decreased invasiveness, thus EMTness in a panel of diffuse-type GC cell lines including GC PDCs. Taken together, we confirmed that combination of TEW-7197 and ramucirumab reduced tumor spheroid and GC PDC-induced blood vessel formation concomitantly in the spheroid-on-a-chip model.

SUBMITTER: Lee SY

PROVIDER: S-EPMC8525100 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Reducing tumor invasiveness by ramucirumab and TGF-β receptor kinase inhibitor in a diffuse-type gastric cancer patient-derived cell model.

Lee Song-Yi SY Byeon Seonggyu S Ko Jihoon J Hyung Sujin S Lee In-Kyoung IK Jeon Noo Li NL Hong Jung Yong JY Kim Seung Tae ST Park Se Hoon SH Lee Jeeyun J

Cancer medicine 20210920 20

<h4>Background</h4>Diffuse-type gastric cancer (GC) is known to be more aggressive and relatively resistant to conventional chemotherapy. Hence, more optimized treatment strategy is urgently needed in diffuse-type GC.<h4>Methods</h4>Using a panel of 10 GC cell lines and 3 GC patient-derived cells (PDCs), we identified cell lines with high EMTness which is a distinct feature for diffuse-type GC. We treated GC cells with high EMTness with ramucirumab alone, TGF-β receptor kinase inhibitor (TEW-719 ...[more]

PMID: 34542244

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Project description:BackgroundCore fucosylation (addition of fucose in α-1,6-linkage to core N-acetylglucosamine of N-glycans) catalyzed by fucosyltransferase 8 (FUT8) is critical for signaling receptors involved in many physiological and pathological processes such as cell growth, adhesion, and tumor metastasis. Transforming growth factor-β (TGF-β)-induced epithelial-mesenchymal transition (EMT) regulates the invasion and metastasis of breast tumors. However, whether receptor core fucosylation affects TGF-β signaling during breast cancer progression remains largely unknown.MethodIn this study, gene expression profiling and western blot were used to validate the EMT-associated expression of FUT8. Lentivirus-mediated gain-of-function study, short hairpin RNA (shRNA) or CRISPR/Cas9-mediated loss-of-function studies and pharmacological inhibition of FUT8 were used to elucidate the molecular function of FUT8 during TGF-β-induced EMT in breast carcinoma cells. In addition, lectin blot, luciferase assay, and in vitro ligand binding assay were employed to demonstrate the involvement of FUT8 in the TGF-β1 signaling pathway. The role of FUT8 in breast cancer migration, invasion, and metastasis was confirmed using an in vitro transwell assay and mammary fat pad xenograft in vivo tumor model.ResultsGene expression profiling analysis revealed that FUT8 is upregulated in TGF-β-induced EMT; the process was associated with the migratory and invasive abilities of several breast carcinoma cell lines. Gain-of-function and loss-of-function studies demonstrated that FUT8 overexpression stimulated the EMT process, whereas FUT8 knockdown suppressed the invasiveness of highly aggressive breast carcinoma cells. Furthermore, TGF-β receptor complexes might be core fucosylated by FUT8 to facilitate TGF-β binding and enhance downstream signaling. Importantly, FUT8 inhibition suppressed the invasive ability of highly metastatic breast cancer cells and impaired their lung metastasis.ConclusionsOur results reveal a positive feedback mechanism of FUT8-mediated receptor core fucosylation that promotes TGF-β signaling and EMT, thus stimulating breast cancer cell invasion and metastasis.

Dataset Information

Reducing tumor invasiveness by ramucirumab and TGF-β receptor kinase inhibitor in a diffuse-type gastric cancer patient-derived cell model.

Background

Methods

Results

Conclusions

Publications

Reducing tumor invasiveness by ramucirumab and TGF-β receptor kinase inhibitor in a diffuse-type gastric cancer patient-derived cell model.

Similar Datasets

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