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

BMC Cancer

Oleksandr Ekshyyan³  Tara N Moore-Medlin³  Matthew C Raley⁴  Kunal Sonavane³  Xiaohua Rong³  Michael A Brodt⁴  Fleurette Abreo¹  Jonathan Steven Alexander²  Cherie-Ann O Nathan³ 

[1] Department of Pathology, LSUHSC, Shreveport, LA, USA

[2] Department of Cellular and Molecular Physiology, LSUHSC, Shreveport, LA, USA

[3] Feist-Weiller Cancer Center, LSUHSC, Shreveport, LA, USA

[4] Department of Otolaryngology/Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA

关键词: Lymph node metastasis;    VEGFR-2;    VEGFR-3;    mTOR;    mTOR inhibitors;    Rapamycin;    Head and neck squamous cell carcinoma;   

Others  :  1079670
DOI  :  10.1186/1471-2407-13-320

 received in 2013-04-07, accepted in 2013-06-20,  发布年份 2013

【 摘 要 】

Background

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%. The lymphatic suppressing properties of mTOR inhibitors are not yet well understood.

Methods

Lymphatic 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.

Results

Rapamycin 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.

Conclusions

The 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.

【 授权许可】

   
2013 Ekshyyan et al.; licensee BioMed Central Ltd.

【 图 表 】

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