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

Molecular Cancer

Research

Javier Dotor¹  Peter Altevogt²  Xabier Morales³  Saray Garasa³  Elizabeth Salvo³  Rafael Peláez³  Ana Rouzaut⁴ 

[1]DIGNA-Biotech, 31008, Pamplona, Spain

[2]Department of Translational Immunology, German Cancer Research Center, D015, 69120, Heidelberg D, Germany

[3]Oncology, CIMA, 31008, Pamplona, Spain

[4]Oncology, CIMA, 31008, Pamplona, Spain

[5]Department of Biochemistry and Genetics, University of Navarra, 31080, Pamplona, Spain

关键词: Integrin;    TGF-β;    Metastases;    Lymph nodes;    Lymphatic vessels;   

DOI  :  10.1186/1476-4598-13-112

 received in 2014-01-03, accepted in 2014-05-09,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundTransforming Growth Factor beta (TGF-β) acts as a tumor suppressor early in carcinogenesis but turns into tumor promoter in later disease stages. In fact, TGF-β is a known inducer of integrin expression by tumor cells which contributes to cancer metastatic spread and TGF-β inhibition has been shown to attenuate metastasis in mouse models. However, carcinoma cells often become refractory to TGF-β-mediated growth inhibition. Therefore identifying patients that may benefit from anti-TGF-β therapy requires careful selection.MethodsWe performed in vitro analysis of the effects of exposure to TGF-β in NSCLC cell chemotaxis and adhesion to lymphatic endothelial cells. We also studied in an orthotopic model of NSCLC the incidence of metastases to the lymph nodes after inhibition of TGF-β signaling, β3 integrin expression or both.ResultsWe offer evidences of increased β3-integrin dependent NSCLC adhesion to lymphatic endothelium after TGF-β exposure. In vivo experiments show that targeting of TGF-β and β3 integrin significantly reduces the incidence of lymph node metastasis. Even more, blockade of β3 integrin expression in tumors that did not respond to TGF-β inhibition severely impaired the ability of the tumor to metastasize towards the lymph nodes.ConclusionThese findings suggest that lung cancer tumors refractory to TGF-β monotherapy can be effectively treated using dual therapy that combines the inhibition of tumor cell adhesion to lymphatic vessels with stromal TGF-β inhibition.

【 授权许可】

Unknown   
© Salvo et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.