Tumor metastasis in an orthotopic murine model of head and neck cancer: Possible role of TGF‐beta 1 secreted by the tumor cells

S Dasgupta, M Bhattacharya‐Chatterjee… - Journal of cellular …, 2006 - Wiley Online Library
S Dasgupta, M Bhattacharya‐Chatterjee, BW O'Malley Jr, SK Chatterjee
Journal of cellular biochemistry, 2006Wiley Online Library
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‐β1 (TGF …
Abstract
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‐β1 (TGF‐β1), 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‐β1. Untreated or metastatic tumors, on the other hand, expressed high levels of TGF‐β1 and secreted TGF‐β1 in the sera of tumor‐bearing mice. Levels of TGF‐β1 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‐β1 in the sera, expression of proteins involved in metastasis and initiation of metastasis suggested possible role of TGF‐β1 in on setting the metastatic cascade in this model. J. Cell. Biochem. © 2005 Wiley‐Liss, Inc.
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