Background: Tumor cell dissemination to cervical lymph nodes via the lymphatic system represents the first step in the metastasis of head and neck squamous cell carcinoma (HNSCC) and is the most significant prognostic factor for tumor recurrence decreasing survival by 50%. The anti-lymphangiogenic properties of mTOR inhibitors are not yet well understood nor have the effects of rapalogues’ on tumor-associated lymphangiogenesis been investigated in HNSCC. Methods: The lymphatic suppressing effects of rapamycin were evaluated in vitro using lymphatic endothelial cell lines (SV-LEC; HMEC-1a). An orthotopic model of HNSCC was used to evaluate anti-lymphangiogenic effects of rapamycin in vivo. OSC-19 cells were injected into the basolateral tongue of SCID mice. After 5 days mice were given daily IP injections of vehicle (control group) or rapamycin at 5 mg/kg. On day 21 after OSC-19 administration mice were sacrificed and tongues, cervical lymph nodes and serum collected. The incidence of cervical lymph node metastasis, the number of tumor-free and tumor-associated lymphatic vessels in mouse lingual tissue, and expression of pro-lymphangiogenic markers were assessed. Results: We found that LEC proliferation was significantly reduced by rapamycin. LEC growth inhibition by rapamycin was linked with decreased expression of VEGFR-3 in both LECs, and in some HNSCC cell lines. Rapamycin significantly lowered the fraction of tumor-associated lymphatic vessels in mouse tongues (p=0.0167) and decreased the number of metastasis-positive lymph nodes (p=0.04). Rapamycin also significantly attenuated the extent of metastatic tumor cell spread within the lymph nodes (p<0.0001). Conclusion: The results of this study demonstrate anti-lymphangiogenic properties of mTOR inhibitors in HNSCC. These findings provide preclinical data showing that rapalogues exert anti-lymphatic effects in head and neck cancer via suppressing ofVEGFR-3 expression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1413. doi:1538-7445.AM2012-1413