Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in ALK1, a member of the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1 (ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhibit LV formation, and LVs were enlarged in multiple organs in Alk1-depleted mice. These inhibitory effects of ALK-1 signaling were mediated by BMP-9, which decreased the number of cultured lymphatic endothelial cells. Bmp9-deficient mouse embryos consistently exhibited enlarged dermal LVs. BMP-9 also inhibited LV formation during inflammation and tumorigenesis. BMP-9 downregulated the expression of the transcription factor prospero-related homeobox 1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing prospero-related homeobox 1 expression inhibited lymphatic endothelial cell proliferation. Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation.lymphangiogenesis | angiogenesis | blood vascular endothelial cells

The mammalian target of rapamycin (mTOR) pathway is commonly activated in human cancers. The activity of mTOR complex 1 (mTORC1) signaling is supported by the intracellular positioning of cellular compartments and vesicle trafficking, regulated by Rab GTPases. Here we showed that tuftelin 1 (TUFT1) was involved in the activation of mTORC1 through modulating the Rab GTPase-regulated process. TUFT1 promoted tumor growth and metastasis. Consistently, the expression of TUFT1 correlated with poor prognosis in lung, breast and gastric cancers. Mechanistically, TUFT1 physically interacted with RABGAP1, thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promoted mTORC1 signaling. In addition, expression of TUFT1 predicted sensitivity to perifosine, an alkylphospholipid that alters the composition of lipid rafts. Perifosine treatment altered the positioning and trafficking of cellular compartments to inhibit mTORC1. Our observations indicate that TUFT1 is a key regulator of the mTORC1 pathway and suggest that it is a promising therapeutic target or a biomarker for tumor progression.

Although transforming growth factor beta ( TGF ‐β) is known to be involved in the pathogenesis and progression of many cancers, its role in renal cancer has not been fully investigated. In the present study, we examined the role of TGF ‐β in clear cell renal carcinoma (cc RCC ) progression in vitro and in vivo. First, expression levels of TGF ‐β signaling pathway components were examined. Microarray and immunohistochemical analyses showed that the expression of c‐Ski, a transcriptional corepressor of Smad‐dependent TGF‐β and bone morphogenetic protein (BMP) signaling, was higher in cc RCC tissues than in normal renal tissues. Next, a functional analysis of c‐Ski effects was carried out. Bioluminescence imaging of renal orthotopic tumor models demonstrated that overexpression of c‐Ski in human cc RCC cells promoted in vivo tumor formation. Enhancement of tumor formation was also reproduced by the introduction of a dominant‐negative mutant TGF ‐β type II receptor into cc RCC cells. In contrast, introduction of the BMP signaling inhibitor Noggin failed to accelerate tumor formation, suggesting that the tumor‐promoting effect of c‐Ski depends on the inhibition of TGF ‐β signaling rather than of BMP signaling. Finally, the molecular mechanism of the tumor‐suppressive role of TGF ‐β was assessed. Although TGF ‐β signaling did not affect tumor angiogenesis, apoptosis of cc RCC cells was induced by TGF ‐β. Taken together, these findings suggest that c‐Ski suppresses TGF ‐β signaling in cc RCC cells, which, in turn, attenuates the tumor‐suppressive effect of TGF ‐β.