Targeting of Alpha-V Integrins Reduces Malignancy of Bladder Carcinoma

Horst, Geertje van der; Bos, Lieke; Mark, Maaike van der; Cheung, Hiu Wing; Heckmann, Bertrand; Clément-Lacroix, Philippe; Lorenzon, Giocondo; Pelger, Rob C.M.; Bevers, Rob F. M.; Pluijm, Gabri van der

doi:10.1371/journal.pone.0108464

Cited by 34 publications

(24 citation statements)

References 55 publications

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“…39 Since then, αV together with β3, β5, β6, or β8 integrins has been widely studied in multiple cancers and numerous studies have shown the correlation of high αV integrin expression with cancer progression. [40][41][42][43][44] Conversely, inhibition of αV integrin is sufficient to block invasive activity in preclinical in vitro and in vivo models- 40,[45][46][47] and has been used as a therapeutic target for metastatic cancers in preclinical and clinical studies. 16,32,48 In this study, we show that αVβ3 heterodimer is found in HER2positive breast cells.…”

Section: Discussionmentioning

confidence: 99%

T-DM1-resistant cells gain high invasive activity via EGFR and integrin cooperated pathways

Endo

Shen

Youssef

et al. 2018

mAbs

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Ado-trastuzumab emtansine (Kadcyla®; T-DM1) is an antibody-drug conjugate developed to treat trastuzumab-resistant disease. Despite initial favorable outcomes, most patients eventually cease to respond due to developing acquired resistance to T-DM1. Currently, there is no targeted therapy to treat T-DM1-resistant disease. To explore novel therapeutic targets to improve therapeutic efficacy of T-DM1, we generated T-DM1-resistant cells using trastuzumab-resistant JIMT1 cells. We found that the loss of human epidermal growth factor receptor 2 confers T-DM1 resistance, which in turn activates a compensatory mechanism that increases epidermal growth factor receptor (EGFR) expression. Upregulation of EGFR increases the protein levels of α5β1 and αVβ3 integrins, resulting in enhanced motility and invasion of T-DM1-resistant cells. This study delineates previously unappreciated relationships between α5β1 and αVβ3 and suggests that specific integrins should be carefully selected as therapeutic targets to treat T-DM1-resistant disease. Specifically, silencing β1 integrin expression by siRNA in T-DM1-resistant cells destabilizes α5, but increases expression of αV, a critical integrin mediating the invasion and metastases in many different cancers. As a consequence, T-DM1-resistant cells gain metastatic potential and become more invasive. This finding is underscored by the fact that β1 integrin blockage induced by an inhibitory antibody, MAB 13, significantly increases invasion of T-DM1-resistant cells. However, the increased cell invasion induced by β1 integrin blockage can be significantly reduced by either EGFR inhibitor or specific siRNA against αV integrin. The discovery of functional cooperation between EGFR and αV integrin in regulating cell growth and invasion provides an opportunity to develop novel therapeutic strategy by dual-targeting EGFR and specific integrin to overcome T-DM1 resistance.

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Section: Discussionmentioning

confidence: 99%

T-DM1-resistant cells gain high invasive activity via EGFR and integrin cooperated pathways

Endo

Shen

Youssef

et al. 2018

mAbs

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“…Concerning the molecular mechanisms involved in the pro-tumourgenic function of HACE1, we demonstrated that HACE1 silencing induced a modification of the transcriptional programme in melanoma cells that was compatible with a decrease in cell movement and migration. Among the genes associated with these effects, ITGAV and ITGB1 were downregulated at the transcriptional level, and their involvement in cell migration has been extensively described [12,22]. Other genes, such as PLAU and SDC4, which promote cell invasiveness [23,24], were also downregulated by HACE1 silencing.…”

Section: Discussionmentioning

confidence: 99%

Uncovering and deciphering the pro-invasive role of HACE1 in melanoma cells

et al. 2018

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HACE1 is an E3 ubiquitin ligase described as a tumour suppressor because HACE1-knockout mice develop multi-organ, late-onset cancers and because HACE1 expression is lost in several neoplasms, such as Wilms' tumours and colorectal cancer. However, a search of public databases indicated that HACE1 expression is maintained in melanomas. We demonstrated that HACE1 promoted melanoma cell migration and adhesion in vitro and was required for mouse lung colonisation by melanoma cells in vivo. Transcriptomic analysis of HACE1-depleted melanoma cells revealed an inhibition of ITGAV and ITGB1 as well changes in other genes involved in cell migration. We revealed that HACE1 promoted the K27 ubiquitination of fibronectin and regulated its secretion. Secreted fibronectin regulated ITGAV and ITGB1 expression, as well as melanoma cell adhesion and migration. Our findings disclose a novel molecular cascade involved in the regulation of fibronectin secretion, integrin expression and melanoma cell adhesion. By controlling this cascade, HACE1 displays pro-tumoural properties and is an important regulator of melanoma cell invasive properties.

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“…CDH2 is commonly up-regulated in various cancers, including colorectal cancer [14], prostate cancer [15], gastric cancer [16], bladder cancer [17] and lung cancer [18]. In addition, it is reported that CDH2 plays a significant part in epithelial-mesenchymal transition (EMT) [19].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-124 Functions as a Tumor Suppressor by Regulating CDH2 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer

Zhao

Wei

et al. 2016

Cell Physiol Biochem

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Background/Aims: Abnormal expression of microRNA-124 (miR-124) was found in non-small cell lung cancer (NSCLC). However, the association between miR-124 and CDH2 has not been reported yet. This study aims to reveal the inhibiting effects of miR-124 on the expression of CDH2 in NSCLC. Methods: Quantitative real-time polymerase chain reaction was used to evaluate the expression of miR-124 and CDH2 in NSCLC tissues. Cell viability, apoptosis and invasion assays were carried out in NSCLC cell lines after transfection. The regulation mechanism was confirmed by luciferase report assay and western blot (WB). Results: Significantly decreased expression of miR-124 was found in NSCLC specimens and cell lines. Overexpression of miR-124 apparently suppressed the proliferation and invasion of NSCLC cell lines in vitro. Luciferase report assay and WB revealed that CDH2 was a target gene of miR-124. Furthermore, results of WB showed that epithelial-mesenchymal transition (EMT) could be inhibited by up-regulation of miR-124. Conclusions: Taken together, our findings present the first evidence that miR-124 could suppress the expression of CDH2 and regulate EMT, which might lead to a potential therapeutic strategy focusing on miR-124 and CDH2 for human lung cancer.

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Targeting of Alpha-V Integrins Reduces Malignancy of Bladder Carcinoma

Cited by 34 publications

References 55 publications

T-DM1-resistant cells gain high invasive activity via EGFR and integrin cooperated pathways

T-DM1-resistant cells gain high invasive activity via EGFR and integrin cooperated pathways

Uncovering and deciphering the pro-invasive role of HACE1 in melanoma cells

MicroRNA-124 Functions as a Tumor Suppressor by Regulating CDH2 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer

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