Decreased Lymphangiogenesis and Lymph Node Metastasis by mTOR Inhibition in Head and Neck Cancer

Abstract

Despite our improved understanding of cancer, the 5-year survival rate for head and neck squamous cell carcinomas (HNSCC) patients remains relatively unchanged at 50% for the past three decades. HNSCC often metastasize to locoregional lymph nodes, and lymph node involvement represents one of the most important prognostic factors of poor clinical outcome. Among the multiple dysregulated molecular mechanism in HNSCC, emerging basic, preclinical, and clinical findings support the importance of the mTOR signaling route in HNSCC progression. Indeed, we observed here that the activation of mTOR is a widespread event in clinical specimens of HNSCC invading locoregional lymph nodes. We developed an orthotopic model of HNSCC consisting in the implantation of HNSCC cells into the tongues of immunocompromised mice. These orthotopic tumors spontaneously metastasize to the cervical lymph nodes, where the presence of HNSCC cells can be revealed by histological and immunohistochemical evaluation. Both primary and metastatic experimental HNSCC lesions exhibited elevated mTOR activity. The ability to monitor and quantitate lymph node invasion in this model system enabled us to explore whether the blockade of mTOR could impact on HNSCC metastasis. We found that inhibition of mTOR with rapamycin and the rapalog RAD001 diminished lymphangiogenesis in the primary tumors and prevented the dissemination of HNSCC cancer cells to the cervical lymph nodes, thereby prolonging animal survival. These findings may provide a rationale for the future clinical evaluation of mTOR inhibitors, including rapamycin and its analogs, as part of a molecular-targeted metastasis preventive strategy for the treatment of HNSCC patients.

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

“…Cancer cells induce the formation of new lymphatic vessels, which are characterized by discontinuous cell-cell junctions and a lack of pericytes or vascular smooth muscle cells, via secretion of lymphangiogenic growth factors with promotion of tumor cell dissemination to LNs (29,42). Importantly, diminishing lymphangiogenesis in vivo prevents regional LN metastasis and prolongs animal survival times in studies of other cancer types (43,44). Herein, our results show that downregulation of BLACAT2 plays dual antilymphatic metastasis roles, including prevention of lymphangiogenesis and inhibition of cell invasiveness, suggesting that BLA-CAT2 may serve as a potential target for intervention in bladder cancer.…”

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

“…Indirectly, tumor-induced lymphangiogenesis is correlated with metastasis in a number of cancer models, including colorectal, breast, prostate, head and neck cancer, and melanoma [93][94][95][96][97][98][99], and expression of Semaphorin…”

“…The precise molecular events that signal for lymphangiogenesis are poorly understood. Inhibition of the mTOR pathway decreases lymphangiogenesis and metastasis, and prolongs survival in a head and neck cancer animal model [99].…”

Lymphatic Endothelial Differentiation in Pulmonary Lymphangioleiomyomatosis Cells

“…Although there is evidence suggesting that activation of the mTOR pathway stimulates lymphangiogenesis (Kobayashi et al 2007;Patel et al 2011;Luo et al 2012) and hence may underlie LAM cell lymphatic differentiation, a recent study by our group stands against such a possibility (Badri et al 2013). In that study, we examined the TSC1 and TSC2 genes by ultra-deep sequencing in 10 of the 19 late-stage LAM cases included here and found that 2 of those cases had neither TSC2 nor TSC1 mutations identified and no activation of the mTOR signaling cascade.…”