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TGF-beta specifically enhances the metastatic attributes of murine lung adenocarcinoma: implications for human non-small cell lung cancer

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Abstract

Lung cancer is the most frequent and one of the most deadly cancer types and is classified into small cell lung cancer and non-small cell lung cancer (NSCLC). Transforming growth factor beta (TGFβ) regulates a wide array of cell functions and plays a major role in lung diseases, including NSCLC. TGFβ signals through the complex of TGFβ type I and type II receptors, triggering Smad and non-Smad signaling pathways such as PI3K/Akt and MEK1/ERK. We investigated the role of TGFβ1 on the progression of the murine lung adenocarcinoma cell line LP07. Furthermore, we undertook a retrospective study with tissue samples from stage I and II NSCLC patients to assess the clinical pathologic role and prognostic significance of TβRI expression. We demonstrated that although lung cancer cell monolayers responded to TGFβ1 anti-mitogenic effects and TGFβ1 pulse (24 h treatment) delayed tumor growth at primary site; a switch towards malignant progression upon TGFβ1 treatment was observed at the metastatic site. In our model, TGFβ1 modulated in vitro clonogenicity, protected against stress-induced apoptosis and increased adhesion, spreading, lung retention and metastatic outgrowth. PI3K and MEK1 signaling pathways were involved in TGFβ1-mediated metastasis stimulation. Several of these TGFβ responses were also observed in human NSCLC cell lines. In addition, we found that a higher expression of TβRI in human lung tumors is associated with poor patient’s overall survival by univariate analysis, while multivariate analysis did not reach statistical significance. Although additional detailed analysis of the endogenous signaling in vivo and in vitro is needed, these studies may provide novel molecular targets for the treatment of lung cancer.

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Abbreviations

NSCLC:

Non-small cell lung cancer

TGFβ:

Transforming growth factor beta

SCC:

Squamous cell carcinoma

ADC:

Adenocarcinoma

TβRI:

TGFβ type I receptor

TβRII:

TGFβ type II receptor

EMT:

Epithelial to mesenchymal transition

FAK:

Focal adhesion kinase

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Authors and Affiliations

  1. Research Area, Institute of Oncology “Ángel H. Roffo”, Av. San Martín 5481, C1417DTB, Buenos Aires, Argentina

    Paula Fernanda Vázquez, María José Carlini, Lucas Colombo, Elisa Dora Bal de Kier Joffé & Lydia Puricelli

  2. Department of Oncology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY, 10471, USA

    María Cecilia Daroqui

  3. Hospital Italiano de Buenos Aires, Gascón 450, C1181ACH, Buenos Aires, Argentina

    Mercedes Liliana Dalurzo, David Eduardo Smith, Julieta Grasselli & María Guadalupe Pallotta

  4. Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Tel Aviv, Israel

    Marcelo Ehrlich

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  1. Paula Fernanda Vázquez
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  2. María José Carlini
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  3. María Cecilia Daroqui
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  4. Lucas Colombo
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  5. Mercedes Liliana Dalurzo
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  11. Lydia Puricelli
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Correspondence to María José Carlini.

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María José Carlini, Lucas Colombo, Elisa Dora Bal de Kier Joffé and Lydia Puricelli are Members of the National Council of Scientific and Technologic Research (CONICET).

Paula Fernanda Vázquez and María José Carlini have contributed equally to this study.

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Vázquez, P.F., Carlini, M.J., Daroqui, M.C. et al. TGF-beta specifically enhances the metastatic attributes of murine lung adenocarcinoma: implications for human non-small cell lung cancer. Clin Exp Metastasis 30, 993–1007 (2013). https://doi.org/10.1007/s10585-013-9598-1

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