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

Publisher: BioMed Central Country of Publication: England NLM ID: 101147698 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-4598 (Electronic) Linking ISSN: 14764598 NLM ISO Abbreviation: Mol Cancer Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2002-

Gene Expression Regulation, Neoplastic*; Carcinoma, Non-Small-Cell Lung/*genetics ; Carcinoma, Non-Small-Cell Lung/*therapy ; Integrin beta3/*genetics ; Lung Neoplasms/*genetics ; Lung Neoplasms/*therapy ; Transforming Growth Factor beta1/*genetics; Animals ; Antibodies, Monoclonal/pharmacology ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Adhesion/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chemotaxis/drug effects ; Coculture Techniques ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Humans ; Integrin beta3/metabolism ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Lymphatic Metastasis ; Mice ; Molecular Targeted Therapy ; Neural Cell Adhesion Molecule L1/antagonists & inhibitors ; Neural Cell Adhesion Molecule L1/genetics ; Neural Cell Adhesion Molecule L1/metabolism ; Platelet Endothelial Cell Adhesion Molecule-1/genetics ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Signal Transduction ; Transforming Growth Factor beta1/antagonists & inhibitors ; Transforming Growth Factor beta1/metabolism ; Xenograft Model Antitumor Assays

Background: 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 anti-TGF-β therapy requires careful selection.
Methods: We 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.
Results: We 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.
Conclusion: These 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.

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0 (Antibodies, Monoclonal)
0 (Integrin beta3)
0 (Neural Cell Adhesion Molecule L1)
0 (Platelet Endothelial Cell Adhesion Molecule-1)
0 (RNA, Small Interfering)
0 (Transforming Growth Factor beta1)

Date Created: 20140603 Date Completed: 20150112 Latest Revision: 20211021

20231215

PMC4049383

10.1186/1476-4598-13-112

24884715