Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis

Abstract

Tumor lymphangiogenesis is now known to play a causal role in lymph node metastasis, and thus its inhibition would have great significance for the prevention of lymph node metastasis in cancer therapy. VEGF-C has recently been identified as a key molecule that involved in tumor lymphangiogenesis and lymphatic metastasis. However, the expressional regulation of VEGF-C is not fully understood. We investigated the role of mTOR, which is a downstream kinase of the phosphatidylinositol 3-kinase/Akt pathway, and the MAPK family (MEK1/2, p38, and JNK) in the regulation of VEGF-C and VEGF-A expression in B13LM cells, a lymphatic metastasis-prone pancreatic tumor cell line. We also investigated the antilymphangiogenic effect of rapamycin, a specific inhibitor of mTOR in vivo using male BALB/c nu/nu mice. VEGF-C expression was inhibited by the inhibitors for mTOR, p38, and JNK, but not by the inhibitor for MEK1/2, whereas VEGF-A expression was inhibited by all four of these inhibitors. The serum starvationinduced expression of VEGF-C was inhibited by rapamycin, whereas that of VEGF-A was incompletely inhibited. The metastatic experiment in vivo demonstrated that the number and the area of lymphatic vessels in the primary tumors were significantly decreased by rapamycin. Finally, the lymph node metastasis was significantly suppressed in rapamycin-treated mice. Our results suggest that mTOR, p38, and JNK play important roles in VEGF-C expression, and that rapamycin has an antilymphangiogentic effect and exerts the expected inhibition of lymphatic metastasis.

RNAi targeting urokinase‐type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo

“…49,51 Moreover, the cytoplasmic signaling molecule, p38 MAPK and JNK, are critically involved in the transcriptional activation of the VEGF-C gene. 52,53 Mountain et al recently reported that the downregulation of VEGF-D expression by interleukin-1 beta in cardiac microvascular endothelial cells is mediated by MAPKs (ERK1/2 and JNK pathways) and protein kinase C a/b1 (PKC a/b1). 54 Therefore, the mechanism that u-PAR activates the downstream pathways (such as MAPKs pathways) through its interaction with different integrins, provides probably an explanation for the downregulation of mRNA expression of VEGF-C, VEGF-D and VEGFR-3 by RNAi targeting u-PAR in our study.…”

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

“…Rapamycin has been shown to inhibit mammalian lymphangiogenesis but not angiogenesis in vitro (Kobayashi et al, 2007). A previous study investigating the effects of rapamycin in zebrafish organogenesis established that treatment with 400 nM rapamycin impaired intestinal development without adverse effects on vasculogenesis (Makky et al, 2007).…”

“…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.…”