Anti-lymphangiogenic properties of mTOR inhibitors in head and neck squamous cell carcinoma experimental models.

Oleksandr Ekshyyan,Fleurette Abreo,Michael A Brodt,Cherie-Ann O Nathan,Kunal Sonavane,Tara N Moore-Medlin,Xiaohua Rong,Jonathan Steven Alexander,Matthew C Raley

doi:10.1186/1471-2407-13-320

Abstract

BackgroundTumor dissemination to cervical lymph nodes via lymphatics represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant predictor of tumor recurrence decreasing survival by 50%. The lymphatic suppressing properties of mTOR inhibitors are not yet well understood.MethodsLymphatic inhibiting effects of rapamycin were evaluated in vitro using two lymphatic endothelial cell (LEC) lines. An orthotopic mouse model of HNSCC (OSC-19 cells) was used to evaluate anti-lymphangiogenic effects of rapamycin in vivo. The incidence of cervical lymph node metastases, numbers of tumor-free lymphatic vessels and those invaded by tumor cells in mouse lingual tissue, and expression of pro-lymphangiogenic markers were assessed.ResultsRapamycin significantly decreased lymphatic vascular density (p = 0.027), reduced the fraction of lymphatic vessels invaded by tumor cells in tongue tissue (p = 0.013) and decreased metastasis-positive lymph nodes (p = 0.04). Rapamycin also significantly attenuated the extent of metastatic tumor cell spread within lymph nodes (p < 0.0001). We found that rapamycin significantly reduced LEC proliferation and was correlated with decreased VEGFR-3 expression in both LEC, and in some HNSCC cell lines.ConclusionsThe results of this study demonstrate anti-lymphangiogenic properties of mTOR inhibitors in HNSCC. mTOR inhibitors suppress autocrine and paracrine growth stimulation of tumor and lymphatic endothelial cells by impairing VEGF-C/VEGFR-3 axis and release of soluble VEGFR-2. In a murine HNSCC orthotopic model rapamycin significantly suppressed lymphovascular invasion, decreased cervical lymph node metastasis and delayed the spread of metastatic tumor cells within the lymph nodes.

Highlights

Tumor dissemination to cervical lymph nodes via lymphatics represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant predictor of tumor recurrence decreasing survival by 50%
HNSCC is characterized by persistent activation of the Akt/mammalian target of rapamycin (mTOR) pathway that triggers a cascade of molecular events central to carcinogenesis including cancer cell survival, cell cycle progression, proliferation, transcription and translation, angiogenesis, invasion, and metastasis [7,8]
Rapamycin significantly decreased intratumoral lymphatic vascular density from 9.1 ± 4.10 in control mice to 5.8 ± 1.18 in rapamycin-treated mice (p = 0.027) as well as the fraction of lymphatic vessels invaded by tumor cells in primary OSC-19 tumors obtained from mouse lingual tissue (Figure 1D)

Summary

Introduction

Tumor dissemination to cervical lymph nodes via lymphatics represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant predictor of tumor recurrence decreasing survival by 50%. MTOR inhibitors depress translation of several mRNAs required for tumor cell cycle progression, proliferation, and angiogenesis suppressing oncogenesis [10,11,12,13,14,15]. Because these pathways are commonly dysregulated in cancer, mTOR represents an attractive anti-tumor target. Dose-limiting toxicities consist of mucositis/stomatitis, asthenia, thrombocytopenia and hyperlipidemia [19]

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Results

Discussion

Conclusion