Combined targeting of TGF-β1 and integrin β3 impairs lymph node metastasis in a mouse model of non-small-cell lung cancer

Salvo, Elizabeth; Garasa, Saray; Dotor, Javier; Morales, Xabier; Peláez, Rafael Pila; Altevogt, Peter; Rouzaut, Ana

doi:10.1186/1476-4598-13-112

Cited by 39 publications

(42 citation statements)

References 49 publications

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“…β3 integrin is frequently overexpressed in tumor cells, including lung cancer, melanoma, glioblastoma and breast cancer cells (5,6). Previous studies coupled β3 integrin to epithelial-mesenchymal transition (EMT) and metastasis; β3 integrin inhibition is a therapeutic target to treat TNBC, attenuates TGF-β-mediated EMT and invasion, and inhibits 3-dimensional organoid growth (7).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of β3 integrin by miR-30a-5p modulates cell adhesion and invasion by interrupting Erk/Ets-1 network in triple-negative breast cancer

Liu

Zhao

et al. 2016

International Journal of Oncology

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Integrins are adhesion receptors involved in bidirectional signaling and are crucial for various cellular responses during normal homeostasis and pathological conditions, such as cancer progression and metastasis. In the present study, we demonstrated that blockage of β3 integrin-mediated cell- extracellular matrix interactions restrained triple-negative breast cancer (TNBC) growth, and elevated β3 integrin can trigger the rewiring of Erk/Ets-1 signaling pathways, thereby enhancing cell growth and invasion. Ectopic expression of miRNA has been implicated in the deregulation of integrin expression and activity, blocking of cancer tumor development and progression, and acquisition of metastatic phenotype. miR-30a-5p expression has been implicated in the progression of breast cancer. Overexpression of miR-30a-5p suppressed the proliferation, migration and invasion of breast cancer cells. On the contrary, inhibition of miR-30a-5p promoted the proliferation, migration, and invasion of TNBC cells by suppressing the expression of ERK/Ets-1 signal. An inverse correlation was found between the mRNA expressions of miR-30a-5p and β3 integrin in TNBC samples. Furthermore, bioinformatics analysis revealed the putative miR-30 binding sites in the 3'-UTR of β3 integrin. Results of luciferase assay revealed a strong repression of luciferase activity after transfection with miR‑30a-5p and wild-type 3'-UTR of β3 integrin. In TNBC cells, miR-30a-5p promoted an epithelial phenotype and suppressed invasion by specifically targeting β3 integrin subunit to subsequently interdict the β3 integrin/Erk/Ets-1 network.

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Section: Introductionmentioning

confidence: 99%

Downregulation of β3 integrin by miR-30a-5p modulates cell adhesion and invasion by interrupting Erk/Ets-1 network in triple-negative breast cancer

Liu

Zhao

et al. 2016

International Journal of Oncology

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“…(38–40) TGF-β promotes epithelial mesenchymal transition (EMT) of cancer cells and cancer metastasis through its effects on tumor microenvironment. (40–43) The treatment of 4T1 breast cancer cells with TGF-β resulted in a fibroblast-like mesenchymal phenotype (Fig. 5A), which is a phenomenon in the initiation of invasion and metastases of high-risk breast cancer.…”

Section: Resultsmentioning

confidence: 99%

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging

2016

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The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane–modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging.

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“…Similarly, by inducing collagen III and fibronectin expression, TGF‐β 1 enhanced gastric cancer cell adhesion to mesothelial cells (Lv et al, ). In addition, TGF‐β 1 was found to increase non‐small‐cell lung cancer cell adhesion to lymphatic endothelial cell monolayers through a β 3 integrin‐dependent mechanism (Salvo et al, ). Thus, in addition to the well‐established role of TGF‐β 1 in HCC dissemination through induction of EMT in tumoral hepatocytes, this cytokine may also contribute to HCC metastasis by up‐regulating Gal1 expression and favoring HCC cell adhesion to liver endothelium.…”

Section: Discussionmentioning

confidence: 99%

Galectin-1 Controls the Proliferation and Migration of Liver Sinusoidal Endothelial Cells and Their Interaction With Hepatocarcinoma Cells

et al. 2015

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Galectin-1 (Gal1), a β-galactoside-binding protein elevated in hepatocellular carcinoma (HCC), promotes epithelial-mesenchymal transition (EMT) and its expression correlates with HCC growth, invasiveness, and metastasis. During the early stages of HCC, transforming growth factor β1 (TGF-β1 ) acts as a tumor suppressor; however in advanced stages, HCC cells lose their cytostatic response to TGF-β1 and undergo EMT. Here, we investigated the role of Gal1 on liver endothelial cell biology, and the interplay between Gal1 and TGF-β1 in HCC progression. By Western blot and immunofluorescence, we analyzed Gal1 expression, secretion and localization in HepG2 and HuH-7 human HCC cells, and in SK-HEP-1 human liver sinusoidal endothelial cells (SECs). We used loss-of-function and gain-of-function experiments to down- or up-regulate Gal1 expression, respectively, in HepG2 cells. We cultured SK-HEP-1 cells with conditioned media from HCC cells secreting different levels of Gal1, and demonstrated that Gal1 derived from tumor hepatocytes induced its own expression in SECs. Colorimetric and scratch-wound assays revealed that secretion of Gal1 by HCC cells induced SEC proliferation and migration. Moreover, by fluorescence microscopy we demonstrated that Gal1 promoted glycan-dependent heterotypic adhesion of HepG2 cells to SK-HEP-1 SECs. Furthermore, TGF-β1 induced Gal1 expression and secretion by HCC cells, and promoted HepG2 cell adhesion to SK-HEP-1 SECs through a Gal1-dependent mechanism. Finally, Gal1 modulated HepG2 cell proliferation and sensitivity to TGF-β1 -induced growth inhibition. Our results suggest that Gal1 and TGF-β1 might function coordinately within the HCC microenvironment to regulate tumor growth, invasion, metastasis, and angiogenesis.

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Combined targeting of TGF-β1 and integrin β3 impairs lymph node metastasis in a mouse model of non-small-cell lung cancer

Cited by 39 publications

References 49 publications

Downregulation of β3 integrin by miR-30a-5p modulates cell adhesion and invasion by interrupting Erk/Ets-1 network in triple-negative breast cancer

Downregulation of β3 integrin by miR-30a-5p modulates cell adhesion and invasion by interrupting Erk/Ets-1 network in triple-negative breast cancer

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging

Galectin-1 Controls the Proliferation and Migration of Liver Sinusoidal Endothelial Cells and Their Interaction With Hepatocarcinoma Cells

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