Dataset Information

Combined targeting of TGF-?1 and integrin ?3 impairs lymph node metastasis in a mouse model of non-small-cell lung cancer.

ABSTRACT:

Background

Transforming Growth Factor beta (TGF-?) acts as a tumor suppressor early in carcinogenesis but turns into tumor promoter in later disease stages. In fact, TGF-? is a known inducer of integrin expression by tumor cells which contributes to cancer metastatic spread and TGF-? inhibition has been shown to attenuate metastasis in mouse models. However, carcinoma cells often become refractory to TGF-?-mediated growth inhibition. Therefore identifying patients that may benefit from anti-TGF-? therapy requires careful selection.

Methods

We performed in vitro analysis of the effects of exposure to TGF-? 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-? signaling, ?3 integrin expression or both.

Results

We offer evidences of increased ?3-integrin dependent NSCLC adhesion to lymphatic endothelium after TGF-? exposure. In vivo experiments show that targeting of TGF-? and ?3 integrin significantly reduces the incidence of lymph node metastasis. Even more, blockade of ?3 integrin expression in tumors that did not respond to TGF-? inhibition severely impaired the ability of the tumor to metastasize towards the lymph nodes.

Conclusion

These findings suggest that lung cancer tumors refractory to TGF-? monotherapy can be effectively treated using dual therapy that combines the inhibition of tumor cell adhesion to lymphatic vessels with stromal TGF-? inhibition.

SUBMITTER: Salvo E

PROVIDER: S-EPMC4049383 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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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.

Salvo Elizabeth E Garasa Saray S Dotor Javier J Morales Xabier X Peláez Rafael R Altevogt Peter P Rouzaut Ana A

Molecular cancer 20140519

<h4>Background</h4>Transforming 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 a ...[more]

PMID: 24884715

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