Inhibition of the mammalian target of rapamycin impedes lymphangiogenesis

Abstract

Lymphatic complications are common side effects of mammalian target of rapamycin (mTOR) inhibitor-based immunosuppression in kidney transplantation. Therefore, we investigated whether the mTOR inhibitor rapamycin, besides its known antihemangiogenic effect, also impedes regenerative lymphangiogenesis. In a murine skin flap model, rapamycin impaired recovery of lymphatic flow across surgical incisions resulting in prolonged wound edema in these animals. Importantly, the antilymphangiogenic effect of rapamycin was not related to a general inhibition of wound healing as demonstrated an in vivo Matrigeltrade mark lymphangiogenesis assay and a model of lymphangioma. Rapamycin concentrations as low as 1 ng/ml potently inhibited vascular endothelial growth factor (VEGF)-C driven proliferation and migration, respectively, of isolated human lymphatic endothelial cells (LECs) in vitro. Mechanistically, mTOR inhibition impairs downstream signaling of VEGF-A as well as VEGF-C via mTOR to the p70S6 kinase in LECs. In conclusion, we provide extensive experimental evidence for an antilymphangiogenic activity of mTOR inhibition suggesting that the early use of mTOR inhibitor following tissue injury should be avoided. Conversely, the antilymphangiogenic properties of rapamycin and its derivates may provide therapeutic value for the prevention and treatment of malignancies, respectively.

Neutropenia in Sirolimus Treated Patients of Lymphatic Malformation: A Case Series

“…These classical methods of treatment have their limitations, hence the popularity of incorporating sirolimus in the therapeutic regimen of complex cases had risen. Consequently, the side effects which have been noted in different populations such as bone marrow suppression in kidney transplant patients is now becoming more evident in LM populations treated with the sirolimus [3]. In this case series, we corroborate with what has been reported on sirolimus as an effective therapeutic regimen in the treatment of lymphatic malformation.…”

“…Different therapeutic methods like surgical excision: the first line of treatment; and the non-surgical methods which include sclerotherapy, laser, aspiration, and radiotherapy have been proposed [3]. These classical methods of treatment have their limitations, hence the popularity of incorporating sirolimus in the therapeutic regimen of complex cases had risen.…”

Visualization of embryonic lymphangiogenesis advances the use of the zebrafish model for research in cancer and lymphatic pathologies

“…The mammalian target of rapamycin (mTOR) pathway has recently been identified to function in lymphangiogenesis. mTOR inhibition by rapamycin showed specific anti-lymphangiogenic effects in mammalian experimental systems (Huber et al, 2007;Kobayashi et al, 2007).…”

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“…Some studies have shown that mammalian target of rapamycin inhibitor is a downstream signal of vascular endothelial growth factor C and D, which are essential for lymphatic endothelial cell survival, proliferation, and migration, and that mammalian target of rapamycin inhibitor such as sirolimus can inhibit lymphangiogenesis in vitro. 11,12 Chylous ascites and lymphedema in a renal transplant case were attributed to 19-month use of mammalian target of rapamycin inhibitor (eg. sirolimus), and they were relieved 1 month after switching to cyclosporine.…”