Abstract:Cutaneous T-cell lymphoma (CTCL) is the most frequently encountered type of skin lymphoma in humans. CTCL encompasses multiple variants, but the most common types are mycosis fungoides (MF) and Sezary syndrome (SS). While most cases of MF run a mild course over a period of many years, other subtypes of CTCL are very aggressive. The rapidly expanding fields of proteomics and genomics have not only helped increase knowledge concerning the carcinogenesis and tumor biology of CTCL but also led to the discovery of … Show more
“…As a key drug in our experiments, rapamycin is a highly specific inhibitor of mTORC1 and has been used as a clinical immunosuppressant in organ transplantation and as an antiangiogenic agent in clinical trials for treatment of cancers and other vascular diseases [44, 45]. Interestingly, rapamycin has been reported to inhibit tumor angiogenesis through impairment of HIF-1α/VEGF production in some human cancer cell lines [46], which is consistent with our experimental results. In our study, rapamycin treatment efficiently reversed the exaggerated angiogenesis resulting from DEPTOR knockdown.…”
Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.
“…As a key drug in our experiments, rapamycin is a highly specific inhibitor of mTORC1 and has been used as a clinical immunosuppressant in organ transplantation and as an antiangiogenic agent in clinical trials for treatment of cancers and other vascular diseases [44, 45]. Interestingly, rapamycin has been reported to inhibit tumor angiogenesis through impairment of HIF-1α/VEGF production in some human cancer cell lines [46], which is consistent with our experimental results. In our study, rapamycin treatment efficiently reversed the exaggerated angiogenesis resulting from DEPTOR knockdown.…”
Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.
“…The diagnosis of CTCL requires a more holistic approach through which molecular findings are to be integrated with clinical, histological, and immunophenotypic data. Multi‐omics technique has been used in the precision medicine and personal diagnosis of CTCL in recent years, including high‐throughput sequencing of T‐cell receptor, transcriptional profiling, proteomic approaches, and metabolomics investigation . In the light of previous omics findings, the presented study aims to explore the pathogenesis of CTCL from metabolomics perspective using an accelerated, untargeted metabolomics data analysis strategy.…”
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms. Clinical management is stage based but diagnosis and prognosis could be extremely challenging. The presented study aims to explore the metabolic profiling of CTCL by an accelerated untargeted metabolomics data analysis tool "Mummichog" to facilitate the discoveries of potential biomarkers for clinical early stage diagnosis, prognosis, and treatments in CTCL. Ultra high-performance liquid chromatography-quadrupole time-of-flight-based untargeted metabolomics were conducted on the skin and plasma of CTCL mice. It showed that the metabolism of skin changed greatly versus control samples in the development of CTCL. Increased l-glutamate and decreased adenosine monophosphate were the most essential metabolic features of CTCL tumor and tumor adjacent skins. Unique metabolism changes in tumor adjacent non-involved skin tissues (ANIT) occurred in the progress of carcinogenesis, including upregulated cytidine-5'-triphosphate, aberrant biosynthesis of prostaglandins, pyrimidine, mevalonate pathway, and tryptophan degradation. Sharply elevated 5-phospho-α-d-ribose 1-diphosphate (PRPP) marked the final state of tumor in CTCL. In the plasma, systematic shifts in corticosterone, sphingolipid, and ceramide metabolism were found. These uncovered aberrant metabolites and metabolic pathways suggested that the metabolic reprogramming of PRPP in tumor tissues may cause the disturbance of cytidine and uridine metabolic homeostasis in ANIT. Accumulative cytidine-5'-triphosphate in ANIT may exert positive feedback on the PRPP level and leads to CTCL further development. In addition, the accelerated data analysis tool "Mummichog" showed good practicability and can be widely used in high-resolution liquid chromatography mass spectrometry-based untargeted metabolomics.
“…Another aspect needs to be pointed out in relation to a glucagonoma that is incidentally found until the dermatologic and metabolic complications are positive (55,56). An increased incidence of incidentalomas is registered all over the world and pancreatic masses are one of the most frequent of this kind (56)(57)(58). The aspect is described in both neuroendocrine and non-neuroendocrine conditions (59)(60)(61).…”
Glucagonoma is a hormonally active rare pancreatic neuroendocrine tumour causing an excess of glucagon. This is a narrative review based on a multidisciplinary approach of the tumour. Typically associated dermatosis is necrolytic migratory erythema (NME) which is most frequently seen at disease onset. Insulin-dependent diabetes mellitus, depression, diarrhoea, deep vein thrombosis are also identified, as parts of so-called 'D' syndrome. Early diagnosis is life saving due to potential aggressive profile and high risk of liver metastasis. NME as paraneoplastic syndrome may be present for months and even years until adequate recognition and therapy; it is remitted after successful pancreatic surgery. Thus the level of practitioners' awareness is essential. If surgery is not curative, debulking techniques may improve the clinical aspects and even the outcome in association with other procedures such as embolization of hepatic metastasis; ablation of radiofrequency type; medical therapy including chemotherapy, targeted therapy with mTOR inhibitors such as everolimus, PRRT (peptide receptor radiotherapy), and somatostatin analogues (including combinations of medical treatments). Increased awareness of the condition involves multidisciplinary practitioners.
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