Carcinogenic effect of arsenic in digestive cancers: a systematic review.

BACKGROUND: The carcinogenic effect of arsenic (As) has been documented in lung, bladder and skin cancers but remains unclear for digestive cancers, although metabolic pathways of As and recent data suggest that it may be an important determinant in these malignancies as well. OBJECTIVE: This study aimed to systematically review the available literature investigating the potential association between As and digestive cancers. METHODS: An extensive search was conducted in Medline Ovid SP, Cochrane, PubMed, Embase.com, Cochrane Library Wiley, Web of Science and Google Scholar. Studies providing original data in humans, with As measurement and analysis of association with digestive cancers including esogastric cancers (esophagus and stomach), hepato-pancreatico-biliary (HPB) cancers (including biliary tract, liver and pancreas) and colorectal cancers were eligible. RESULTS: A total of 35 studies were identified, 17 ecological, 13 case-control and 5 cohort studies. Associations between As and digestive cancers were reported for both risks of incidence and cancer-related mortality. Overall, 43% (3/7) and 48% (10/21) studies highlighted an association between As and the incidence or the mortality of digestive cancers, respectively. CONCLUSIONS: A substantial proportion of studies exploring the potential link between As and digestive cancers suggested an association, particularly in HPB malignancies. These findings emphasize the need to further investigate this topic with dedicated and high-quality studies, as it may have an important impact, including for prevention strategies.

Agalsidase-ß should be proposed as first line therapy in classic male Fabry patients with undetectable α-galactosidase A activity.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A (GLA) gene leading to deficiency of α-galactosidase A (α-gal A). This results in progressive multisystemic glycosphingolipid accumulation, especially globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). Enzyme replacement therapy with two recombinant enzymes, agalsidase-α and -ß is approved for two different dosages. However, little is known about which enzyme is more effective in decreasing the metabolite load in male and female patients with the classic form of the disease. METHODS: In this prospective observational study, 14 consecutive adult Fabry patients (10 males) with a classic GLA-mutation, were switched from agalsidase-α to agalsidase-ß at the respective licensed doses. Lyso-Gb3 levels were measured before the switch and for a period of 12 months after the switch in dried blood spots by tandem mass spectrometry. RESULTS: Mean age at start of the switch was 36.7 ± 14 years. Plasma Lyso-Gb3 levels decreased from 27.2 ± 17.9 ng/mL before the switch to 16.8 ± 10.5 ng/mL after the switch (mean reduction of 30.1%; p = 0.004). The decrease was maximal in the subgroup of 7 male patients with no or very low residual enzyme activity (mean reduction of 40.4%). However, two females with high residual enzyme activity also showed a reduction >30% after the switch. In male patients, the reduction of plasma Lyso-Gb3 correlated negatively with the residual α-gal A activity: r = -0.803; p = 0.009. CONCLUSION: Agalsidase-ß at licensed dose is significantly more effective than agalsidase-α to reduce Lyso-Gb3 levels in classic Fabry patients, and should be used as first line therapy in classic males with no residual enzyme activity.

Basic Science with Preclinical Models to Investigate and Develop Liquid Biopsy: What Are the Available Data and Is It a Fruitful Approach?

The molecular analysis of circulating analytes (circulating tumor-DNA (ctDNA), -cells (CTCs) and -RNA (ctRNA)/exosomes) deriving from solid tumors and detected in the bloodstream-referred as liquid biopsy-has emerged as one of the most promising concepts in cancer management. Compelling data have evidenced its pivotal contribution and unique polyvalence through multiple applications. These data essentially derived from translational research. Therewith, data on liquid biopsy in basic research with preclinical models are scarce, a concerning lack that has been widely acknowledged in the field. This report aimed to comprehensively review the available data on the topic, for each analyte. Only 17, 17 and 2 studies in basic research investigated ctDNA, CTCs and ctRNA/exosomes, respectively. Albeit rare, these studies displayed noteworthy relevance, demonstrating the capacity to investigate questions related to the biology underlying analytes release that could not be explored via translational research with human samples. Translational, clinical and technological sectors of liquid biopsy may benefit from basic research and should take note of some important findings generated by these studies. Overall, results underscored the need to intensify the efforts to conduct future studies on liquid biopsy in basic research with new preclinical models.

Correlation Between Portal Pressure and Indocyanine Green Retention Rate is Unaffected by the Cause of Cirrhosis: A Prospective Study.

BACKGROUND: Accurate estimation of the hepatic functional reserve before liver resection is important to avoid post-hepatectomy liver failure (PHLF). The aim of the present study was to evaluate the association of indocyanine green retention test with portal pressure by the cause of cirrhosis (non-viral vs. viral) and assessed postoperative outcomes including incidence of PHLF in patients with viral and non-viral cirrhosis. METHODS: The cohort includes 50 consecutive patients with liver cirrhosis scheduled for liver resection for primary liver tumors at the Lausanne University Hospital between 2009 and 2018. RESULTS: There were 31 patients with non-viral liver cirrhosis (Non-virus group) and 19 with viral liver cirrhosis (virus group). The indocyanine green retention rate at 15 min (ICG-R15) (p = 0.276), Hepatic Venous Portal Gradient (HVPG; p = 0.301), and postoperative outcomes did not differ between the non-virus group and viral group. ICG-R15 and HVPG showed a significant linear correlation in all patients (Spearman's rank correlation coefficient, ρ = 0.599, p < 0.001), the non-virus group (ρ = 0.555, p = 0.026), and the virus group (ρ = 0.534, p = 0.007). A receiver operating characteristic curve analysis showed that ICG-R15 was a predictor for presence of portal hypertension (PH; HVPG ≥ 12 mmHg) (area under the curve [AUC] = 0.780). The cut-off value of ICG-R15 for predicting the presence of PH was 16.0% with 72.3% of sensitivity and 79.0% of specificity. CONCLUSIONS: The ICG-R15 level was associated with portal pressure in both patients with non-virus cirrhosis and patients with virus cirrhosis and predicts the incidence of PH with relatively good discriminatory ability. CLINICAL TRIAL NUMBER: https://clinicalTrials.gov(ID:NCT00827723) LOCAL ETHICS COMMITTEE NUMBER: CER-VD 251.08.

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells.

Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical complications, reducing the treatment success. Understanding these aberrations helps us to select an adapted treatment strategy that surpasses resistance mechanisms, reverting the treatment insensitivity. In this regard, we investigated the dominant mechanisms of resistance to sunitinib and validated an optimized multidrug combination to overcome this resistance. Human ccRCC cells were exposed to single or chronic treatment with sunitinib to obtain three resistant clones. Upon manifestation of sunitinib resistance, morphometric changes in the cells were observed. At the molecular level, the production of cell membrane and extracellular matrix components, chemotaxis, and cell cycle progression were dysregulated. Molecules enforcing the cell cycle progression, i.e., cyclin A, B1, and E, were upregulated. Mass spectrometry analysis revealed the intra- and extracellular presence of N-desethyl sunitinib, the active metabolite. Lysosomal sequestration of sunitinib was confirmed. After treatment with a synergistic optimized drug combination, the cell metabolic activity in Caki-1-sunitinib-resistant cells and 3D heterotypic co-cultures was reduced by >80%, remaining inactive in non-cancerous cells. These results demonstrate geno- and phenotypic changes in response to sunitinib treatment upon resistance induction. Mimicking resistance in the laboratory served as a platform to study drug responses.

[Isolated left ventricular hypertrophy : is it a Fabry disease?] / Hypertrophie ventriculaire gauche isolée : et si c'était une maladie de Fabry ?

Fabry disease, an X-linked disease, results from a deficiency of the lysosomal enzyme alpha-galactosidase A, which causes glycosphingolipids accumulation in the body. On the basis of the residual enzymatic activity level, a classical, severe multisystemic form and an attenuated cardiac variant form are distinguished. In all cases, patients can develop hypertrophic cardiomyopathy in adulthood, the severity of which is the leading cause of morbidity and mortality of the disease. The cardiomyopathy is usually isolated in the cardiac variant form, the most common form of the disease, and should be suspected in the presence of relatively specific ECG, echocardiographic and MRI characteristics.

La maladie de Fabry est liée au chromosome X et résulte d'un déficit de l'enzyme lysosomale alpha-galactosidase A, responsable de l'accumulation de glycosphingolipides dans l'organisme. On distingue une forme classique, multisystémique, sévère, et une forme atténuée ou variant cardiaque. Dans tous les cas, les adultes peuvent développer une cardiomyopathie hypertrophique (CMH), principale cause de morbi-mortalité de la maladie. Dans la forme variant cardiaque, la plus fréquente de la maladie, la CMH est généralement isolée. Elle peut être suspectée en présence de certaines anomalies ECG, échocardiographiques et/ou IRM, et amener à un dépistage.

Rebound pathway overactivation by cancer cells following discontinuation of PI3K or mTOR inhibition promotes cancer cell growth.

Whilst effects of anti-cancer drugs have been thoroughly explored, little is known about the repercussion of drug cessation. However, this has important clinical relevance since several clinical protocols such as intermittent drug scheduling lead to frequent drug discontinuation. In this study, we have thus investigated the consequences of withdrawal of agents that target the PI3K/AKT/mTOR signaling pathway in cancer cells. We report that washout of kinase inhibitors of mTOR or PI3K inhibitors led to a rapid and sustainable overactivation of AKT. Consequently, proliferation of tumor cells was significantly higher following drug washout in cancer cells that were pre-treated with mTOR or PI3K inhibitors compared to untreated cells. This effect was prevented by the addition of an AKT inhibitor following drug washout. Rebound AKT overactivation induced by mTOR or PI3K inhibitors discontinuation was mediated by IGF-1R, as demonstrated by its prevention in the presence of an IGF-1R inhibitor and by increased IGF-1R phosphorylation in treated cells versus control cells. Taken together, our results show that discontinuation of PI3K or mTOR inhibitors results in AKT overactivation that promotes tumor growth. They further highlight the benefit of adding an AKT inhibitor following cessation of PI3K or mTOR inhibitors.

mTOR in Human Diseases.

The human body regenerates constantly in part under the control of signaling pathways that regulate cell growth [...].

mTOR and Tumor Cachexia.

Cancer cachexia affects most patients with advanced forms of cancers. It is mainly characterized by weight loss, due to muscle and adipose mass depletion. As cachexia is associated with increased morbidity and mortality in cancer patients, identifying the underlying mechanisms leading to cachexia is essential in order to design novel therapeutic strategies. The mechanistic target of rapamycin (mTOR) is a major intracellular signalling intermediary that participates in cell growth by upregulating anabolic processes such as protein and lipid synthesis. Accordingly, emerging evidence suggests that mTOR and mTOR inhibitors influence cancer cachexia. Here, we review the role of mTOR in cellular processes involved in cancer cachexia and highlight the studies supporting the contribution of mTOR in cancer cachexia.

Fine-Tuning Tumor Endothelial Cells to Selectively Kill Cancer.

Tumor endothelial cells regulate several aspects of tumor biology, from delivering oxygen and nutrients to shaping the immune response against a tumor and providing a barrier against tumor cell dissemination. Accordingly, targeting tumor endothelial cells represents an important modality in cancer therapy. Whereas initial anti-angiogenic treatments focused mainly on blocking the formation of new blood vessels in cancer, emerging strategies are specifically influencing certain aspects of tumor endothelial cells. For instance, efforts are generated to normalize tumor blood vessels in order to improve tumor perfusion and ameliorate the outcome of chemo-, radio-, and immunotherapy. In addition, treatment options that enhance the properties of tumor blood vessels that support a host's anti-tumor immune response are being explored. Hence, upcoming anti-angiogenic strategies will shape some specific aspects of the tumor blood vessels that are no longer limited to abrogating angiogenesis. In this review, we enumerate approaches that target tumor endothelial cells to provide anti-cancer benefits and discuss their therapeutic potential.

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors.

BACKGROUND: Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study. METHODS: Cancer cell lines were treated with rapamycin in acidic or physiological conditions and cell proliferation was investigated. The effect of acidity on mTORC1 activity was determined by Western blot. The anticancer efficacy of rapamycin in combination with sodium bicarbonate to increase the intratumoral pH was tested in two different mouse models and compared to rapamycin treatment alone. Histological analysis was performed on tumor samples to evaluate proliferation, apoptosis and necrosis. RESULTS: Exposing cancer cells to acidic pH in vitro significantly reduced the anti-proliferative effect of rapamycin. At the molecular level, acidity significantly decreased mTORC1 activity, suggesting that cancer cell proliferation is independent of mTORC1 in acidic conditions. In contrast, the activation of mitogen-activated protein kinase (MAPK) or AKT were not affected by acidity, and blocking MAPK or AKT with a chemical inhibitor maintained an anti-proliferative effect at low pH. In tumor mouse models, the use of sodium bicarbonate increased mTORC1 activity in cancer cells and potentiated the anti-cancer efficacy of rapamycin. Combining sodium bicarbonate with rapamycin resulted in increased tumor necrosis, increased cancer cell apoptosis and decreased cancer cell proliferation as compared to single treatment. CONCLUSIONS: Taken together, these results emphasize the inefficacy of mTORC1 inhibitors in acidic conditions. They further highlight the potential of combining sodium bicarbonate with mTORC1 inhibitors to improve their anti-tumoral efficacy.

Antitumoral Effect of Sunitinib-eluting Beads in the Rabbit VX2 Tumor Model.

Purpose To measure plasmatic sunitinib concentration (PSC) and intratumoral sunitinib concentration (ITSC) after transcatheter arterial chemoembolization (TACE) with two different sizes of sunitinib-eluting beads (SEBs) in rabbits with VX2 hepatic allografts and to investigate treatment effects on vascular endothelial growth factor receptor type 2 (VEGFR2) phosphorylation, tumor volume, and histopathologic changes. Materials and Methods The protocol was approved by the French Ethics Committee for Animal Experiments (Comité d'Ethique en Expérimentation Animale du Centre INRA de Jouy-en-Josas et AgroParisTech, or COMETHEA, approval no. 11/028). Two experiments were performed. In the first, seven animals received 0.05 mL of 100-300-µm SEBs (1.5 mg of sunitinib) in the hepatic artery, and six animals received saline injections. In the second, eight animals received 0.05 mL of 70-150-µm SEBs (1.5 mg of sunitinib), seven received 0.05 mL of 70-150-µm unloaded beads, and seven received oral sunitinib (6 mg every day). Tumor size was monitored with ultrasonography. PSC, ITSC, and phosphorylation of VEGFR2 were assessed on days 1 and 14. After the animals were sacrificed, histopathologic analysis was performed. The Kruskal-Wallis test, Mann-Whitney U test, and Fisher exact test were used to look for statistically significant differences between groups. Results Maximum PSC after TACE with 100-300-µm SEBs was 0.002 µg/mL on day 1. ITSC was 17.8 µg/g on day 1 and 0.16 µg/g on day 14. After TACE with 70-150-µm SEBs, ITSC was 40.4 µg/g on day 1 and 27.4 µg/g on day 14. Phosphorylation of VEGFR2 was inhibited until day 14 after TACE with both sizes of SEBs. The size of VX2 tumors treated with 70-150-µm SEB TACE increased less (-2%) than that of tumors treated with unloaded beads (+42%) and oral sunitinib (6 mg every day; +1853%; P = .044). Conclusion SEB TACE resulted in minimal PSC, high ITSC, and sustained VEGFR2 phosphorylation inhibition until day 14. (©) RSNA, 2016.

Tumor heterogeneity and cancer stem cell paradigm: updates in concept, controversies and clinical relevance.

Although tumor heterogeneity is widely accepted, the existence of cancer stem cells (CSCs) and their proposed role in tumor maintenance has always been challenged and remains a matter of debate. Recently, a path-breaking chapter was added to this saga when three independent groups reported the in vivo existence of CSCs in brain, skin and intestinal tumors using lineage-tracing and thus strengthens the CSC concept; even though certain fundamental caveats are always associated with lineage-tracing approach. In principle, the CSC hypothesis proposes that similar to normal stem cells, CSCs maintain self renewal and multilineage differentiation property and are found at the central echelon of cellular hierarchy present within tumors. However, these cells differ from their normal counterpart by maintaining their malignant potential, alteration of genomic integrity, epigenetic identity and the expression of specific surface protein profiles. As CSCs are highly resistant to chemotherapeutics, they are thought to be a crucial factor involved in tumor relapse and superficially appear as the ultimate therapeutic target. However, even that is not the end; further complication is attributed by reports of bidirectional regeneration mechanism for CSCs, one from their self-renewal capability and another from the recently proposed concept of dynamic equilibrium between CSCs and non-CSCs via their interconversion. This phenomenon has currently added a new layer of complexity in understanding the biology of tumor heterogeneity. In-spite of its associated controversies, this area has rapidly emerged as the center of attention for researchers and clinicians, because of the conceptual framework it provides towards devising new therapies.

Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer.

Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases.

PI3K and AKT: Unfaithful Partners in Cancer.

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway regulates multiple cellular processes. An overactivation of the pathway is frequently present in human malignancies and plays a key role in cancer progression. Hence, its inhibition has become a promising approach in cancer therapy. However, the development of resistances, such as the abrogation of negative feedback mechanisms or the activation of other proliferative signaling pathways, has considerably limited the anticancer efficacy of PI3K/AKT inhibitors. In addition, emerging evidence points out that although AKT is acknowledged as the major downstream effector of PI3K, both PI3K and AKT can operate independently of each other in cancer, revealing another level of complexity in this pathway. Here, we highlight the complex relationship between PI3K and AKT in cancer and further discuss the consequences of this relationship for cancer therapy.

PGE2-induced colon cancer growth is mediated by mTORC1.

The inflammatory prostaglandin E2 (PGE2) cytokine plays a key role in the development of colon cancer. Several studies have shown that PGE2 directly induces the growth of colon cancer cells and furthermore promotes tumor angiogenesis by increasing the production of the vascular endothelial growth factor (VEGF). The signaling intermediaries implicated in these processes have however not been fully characterized. In this report, we show that the mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in PGE2-induced colon cancer cell responses. Indeed, stimulation of LS174T cells with PGE2 increased mTORC1 activity as observed by the augmentation of S6 ribosomal protein phosphorylation, a downstream effector of mTORC1. The PGE2 EP4 receptor was responsible for transducing the signal to mTORC1. Moreover, PGE2 increased colon cancer cell proliferation as well as the growth of colon cancer cell colonies grown in matrigel and blocking mTORC1 by rapamycin or ATP-competitive inhibitors of mTOR abrogated these effects. Similarly, the inhibition of mTORC1 by downregulation of its component raptor using RNA interference blocked PGE2-induced LS174T cell growth. Finally, stimulation of LS174T cells with PGE2 increased VEGF production which was also prevented by mTORC1 inhibition. Taken together, these results show that mTORC1 is an important signaling intermediary in PGE2 mediated colon cancer cell growth and VEGF production. They further support a role for mTORC1 in inflammation induced tumor growth.

Drug-eluting beads loaded with antiangiogenic agents for chemoembolization: in vitro sunitinib loading and release and in vivo pharmacokinetics in an animal model.

PURPOSE: The combination of embolic beads with a multitargeted tyrosine kinase inhibitor that inhibits tumor vessel growth is suggested as an alternative and improvement to the current standard doxorubicin-eluting beads for use in transarterial chemoembolization. This study demonstrates the in vitro loading and release kinetics of sunitinib using commercially available embolization microspheres and evaluates the in vitro biologic efficacy on cell cultures and the resulting in vivo pharmacokinetics profiles in an animal model. MATERIALS AND METHODS: DC Bead microspheres, 70-150 µm and 100-300 µm (Biocompatibles Ltd., Farnham, United Kingdom), were loaded by immersion in sunitinib solution. Drug release was measured in saline in a USP-approved flow-through apparatus and quantified by spectrophotometry. Activity after release was confirmed in cell culture. For pharmacokinetics and in vivo toxicity evaluation, New Zealand white rabbits received sunitinib either by intraarterial injection of 100-300 µm sized beads or per os. Plasma and liver tissue drug concentrations were assessed by liquid chromatography-tandem mass spectroscopy. RESULTS: Sunitinib loading on beads was close to complete and homogeneous. A total release of 80% in saline was measured, with similar fast-release profiles for both sphere sizes. After embolization, drug plasma levels remained below the therapeutic threshold (< 50 ng/mL), but high concentrations at 6 hours (14.9 µg/g) and 24 hours (3.4 µg/g) were found in the liver tissue. CONCLUSIONS: DC Bead microspheres of two sizes were efficiently loaded with sunitinib and displayed a fast and almost complete release in saline. High liver drug concentrations and low systemic levels indicated the potential of sunitinib-eluting beads for use in embolization.

Reactivation of AKT signaling following treatment of cancer cells with PI3K inhibitors attenuates their antitumor effects.

Targeting the phosphatidylinositol-3-kinase (PI3K) is a promising approach in cancer therapy. In particular, PI3K blockade leads to the inhibition of AKT, a major downstream effector responsible for the oncogenic activity of PI3K. However, we report here that small molecule inhibitors of PI3K only transiently block AKT signaling. Indeed, treatment of cancer cells with PI3K inhibitors results in a rapid inhibition of AKT phosphorylation and signaling which is followed by the reactivation of AKT signaling after 48 h as observed by Western blot. Reactivation of AKT signaling occurs despite effective inhibition of PI3K activity by PI3K inhibitors. In addition, wortmannin, a broad range PI3K inhibitor, did not block AKT reactivation suggesting that AKT signals independently of PI3K. In a therapeutical perspective, combining AKT and PI3K inhibitors exhibit stronger anti-proliferative and pro-apoptotic effects compared to AKT or PI3K inhibitors alone. Similarly, in a tumor xenograft mouse model, concomitant PI3K and AKT blockade results in stronger anti-cancer activity compared with either blockade alone. This study shows that PI3K inhibitors only transiently inhibit AKT which limits their antitumor activities. It also provides the proof of concept to combine PI3K inhibitors with AKT inhibitors in cancer therapy.

Mechanosensitive mTORC1 signaling maintains lymphatic valves.

Homeostatic maintenance and repair of lymphatic vessels are essential for health. We investigated the dynamics and the molecular mechanisms of lymphatic endothelial cell (LEC) renewal in adult mesenteric quiescent lymphatic vasculature using label-retention, lineage tracing, and cell ablation strategies. Unlike during development, adult LEC turnover and proliferation was confined to the valve regions of collecting vessels, with valve cells displaying the shortest lifespan. Proliferating valve sinus LECs were the main source for maintenance and repair of lymphatic valves. We identified mechanistic target of rapamycin complex 1 (mTORC1) as a mechanoresponsive pathway activated by fluid shear stress in LECs. Depending on the shear stress level, mTORC1 activity drives division of valve cells or dictates their mechanic resilience through increased protein synthesis. Overactivation of lymphatic mTORC1 in vivo promoted supernumerary valve formation. Our work provides insights into the molecular mechanisms of maintenance of healthy lymphatic vascular system.