Integrin α9β1 promotes malignant tumor growth and metastasis by potentiating epithelial-mesenchymal transition

Gupta, Shiv K.; Oommen, Saji; Aubry, Marie‐Christine; Williams, Brian P.; Vlahakis, Nicholas E.

doi:10.1038/onc.2012.41

Cited by 49 publications

(40 citation statements)

References 39 publications

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“…22 Upregulated expression of αvβ3 is also observed in TGF-β-induced EMT in murine mammary epithelial cells. 23 Moreover, colon cancer cells transfected with α9β1 display an EMT phenotype, 24 and pancreatic cancer cells plated on collagen I show EMT-like change mediated through integrin α2β1. 25 …”

Section: Introductionmentioning

confidence: 99%

Binding of αvβ1 and αvβ6 integrins to tenascin-C induces epithelial–mesenchymal transition-like change of breast cancer cells

et al. 2013

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Tenascin-C (TNC), a large hexameric extracellular glycoprotein, is a pleiotropic molecule with multiple domains binding to a variety of receptors mediating a wide range of cellular functions. We earlier reported that TNC induces epithelial–mesenchymal transition (EMT)-like change in breast cancer cells. In the present study, we clarified TNC receptor involvement in this process. Among integrins previously reported as TNC receptors, substantial expression of αv, α2, β1 and β6 subunits was detected by quantitative PCR and immunoblotting in MCF-7 cells. Integrin β6 mRNA was remarkably upregulated by transforming growth factor (TGF)-β1 treatment, and protein expression was prominently increased by additional exposure to TNC. Immunofluorescent labeling demonstrated integrin αvβ6 accumulation in focal adhesions after TNC treatment, especially in combination with TGF-β1. The α2 and β1 subunits were mainly localized at cell–cell contacts, αv being found near cell cluster surfaces. Immunoprecipitation showed increase in αvβ1 heterodimers, but not α2β1, after TNC treatment. Activated β1 subunits detected by an antibody against the Ca2+-dependent epitope colocalized with αv in focal adhesion complexes, associated with FAK phosphorylation at tyrosine 925. Neutralizing antibodies against αv and β1 blocked EMT-like change caused by TNC alone. In addition, anti-αv and combined treatment with anti-β1 and anti-αvβ6 inhibited TGF-β1/TNC-induced EMT, whereas either of these alone did not. Integrin subunits αv, β1 and β6, but not α2, bound to TNC immobilized on agarose beads in a divalent cation-dependent manner. Treatments with neutralizing antibodies against β1 and αvβ6 reduced αv subunit bound to the beads. Immunohistochemistry of these receptors in human breast cancer tissues demonstrated frequent expression of β6 subunits in cancer cells forming scattered nests localized in TNC-rich stroma. These findings provide direct evidence that binding of αvβ6 and αvβ1 integrins to TNC as their essential ligand induces EMT-like change in breast cancer cells.

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Section: Introductionmentioning

confidence: 99%

Binding of αvβ1 and αvβ6 integrins to tenascin-C induces epithelial–mesenchymal transition-like change of breast cancer cells

et al. 2013

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“…Hedgehog, Notch, Wnt, and transforming growth factor (TGF)-β are capable of initiating EMT via up-regulation of a group of transcription factors [19] and a large number of laminins [20] and integrins [21] related to EMT have been identified. However, the precise mechanisms of EMT/MET remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Induction of an EMT-like transformation and MET in vitro

et al. 2013

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BackgroundThe epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) play pivotal roles in metastasis of epithelial cancers. The distinction between them has shed new light on the molecular mechanisms of tumor metastasis. Recently, tumor microenvironment (TM) has been identified as one of the most potent inducers of EMT and MET. TM is characterized by its complexity and flexibility. The purpose of this study was to ascertain the exact effect of each distinct TM component on the evolution hepatocellular carcinoma (HCC) metastasis.MethodsTwo different cell culture models were used. The HCC cell line Bel-7402 was co-cultured with the normal liver cell line HL-7702 or with the retinal vascular endothelial cell line RF/6A in double-layer six-well plates, imitating the direct interaction between tumor-host cells and tumor cells. Bel-7402 was also cultured in the conditioned medium (CM) of the human lung fibroblast cell line MRC-5, HL-7702 or RF/6A, imitating an indirect interaction. Integrin β1, β3, β4, β7, laminin β3, E-cadherin and Snail levels were measured by quantitative RT-PCR in tumor sepecimens from 42 resected HCC.ResultsWe found that Bel-7402 cells co-cultured with HL-7702 or RF/6A cells were induced to undergo MET. The expression of E-cadherin, α-catenin and β-catenin was up-regulated, accompanied with a strengthened E-cadherin/catenin complex on the membrane of co-cultured Bel-7402 cells. Consequently, the invasion and migration ability of cells was declined. Conversely, Bel-7402 cells cultured in conditioned medium from MRC-5 cells underwent an EMT-like transformation as the cells became elongated with increased invasion and migration ability. Furthermore, we demonstrated that HL-7702 cells could generally inhibit the tumorigenicity and viability of Bel-7402 cells. We also found that integrin β1 expression was negatively associated with capsular formation, and that integrin β4 expression was negatively associated with CK19 expression.ConclusionOur findings highlight the strong influences exerted by TM on tumor progression through EMT and MET by impacting the expression of adhesion molecules, including the E-cadherin/catenin complex, laminins and integrins.

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“…The authors found evidence for an a9b1-b-catenin-E-cadherin complex that dissociated upon a9b1 integrin-ligand interaction and subsequent Src and bcatenin phosphorylation. Further, investigation of small cell lung carcinoma samples from 15 patients showed that high expression of a9b1 could be a prognostic indicator of poor survival and the average survival time for patients with high a9b1 was significantly reduced (Gupta et al, 2012). This finding is important to replicate with a larger set of patients.…”

Section: A9b1 In Cancermentioning

confidence: 88%

“…a9b1 has recently been implicated in epithelial-mesenchymal transition (EMT), independently of the known EMT inducer, TGF-b (Gupta et al, 2012). The authors found evidence for an a9b1-b-catenin-E-cadherin complex that dissociated upon a9b1 integrin-ligand interaction and subsequent Src and bcatenin phosphorylation.…”

Section: A9b1 In Cancermentioning

confidence: 96%