Tumor metastasis in an orthotopic murine model of head and neck cancer: possible role of TGF-beta 1 secreted by the tumor cells.
In an orthotopic murine model of head and neck cancer, combined subcutaneous and intratumoral vaccination with recombinant vaccinia virus expressing interleukin-2 (rvv-IL-2) induced significant tumor regression early on therapy. However, its efficacy was restricted by recurrent tumor growth and loco-regional metastases. In this study, we explored the mechanism of tumor metastasis. We compared the levels of expression of a number of molecules involved in tumor metastasis, which included transforming growth factor-beta1 (TGF-beta1), E-cadherin, matrix metalloproteinases (MMPs): MT1-MMP, MMP-2, MMP-9, their tissue inhibitors (TIMPs): TIMP-1/TIMP-2, and pro-angiogenic factors CD31, VEGF-R2, and iNOS between primary and metastatic tumors by real-time RT-PCR and immunohistochemistry. We detected spontaneous lymph node and tongue metastasis. Metastasis was delayed in rvv-IL-2 treated mice. Cultured tumor cells expressed negligible amount of TGF-beta1. Untreated or metastatic tumors, on the other hand, expressed high levels of TGF-beta1 and secreted TGF-beta1 in the sera of tumor-bearing mice. Levels of TGF-beta1 in the sera suddenly jumped at the time when tumor metastasis started. In the metastatic tumors, levels of MT1-MMP, MMP-2, and MMP-9 were significantly elevated (P < 0.001), while levels of TIMP-1/TIMP-2 and E-cadherin were decreased (P < 0.001) compared to control or primary tumors. Levels of CD31, VEGF-R2, and iNOS were also significantly elevated in the metastatic lesions (P < 0.001). The concurrence of high levels of TGF-beta1 in the sera, expression of proteins involved in metastasis and initiation of metastasis suggested possible role of TGF-beta1 in on setting the metastatic cascade in this model.
Dasgupta
Santanu
S
Department of Internal Medicine and the Barrett Cancer Center, University of Cincinnati, Cincinnati, Ohio 45267-0509, USA.
Bhattacharya-Chatterjee
Malaya
M
O'Malley
Bert W
BW
Chatterjee
Sunil K
SK
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D008198:Lymph Nodes / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D014062:Tongue Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014611:Vaccination; D014616:Vaccinia virus / Q000276:immunology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014765:Viral Vaccines
D015820:Cadherins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C508961:Tgfb1 protein, mouse; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014765:Viral Vaccines; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D020782:Matrix Metalloproteinases