Expression of Cathepsins B, D, and G in Infantile Hemangioma

Itinteang, Tinte; Chudakova, Daria A.; Dunne, Jonathan C.; Davis, Paul F.; Tan, Swee T.

doi:10.3389/fsurg.2015.00026

Cited by 25 publications

(26 citation statements)

References 30 publications

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“…Total protein extraction, digestion, and mass spectrometry were performed as described previously ( 24 ). Briefly, snap-frozen proliferating ( n = 2) and involuted ( n = 2) IH tissues from the same cohorts used for IHC staining were homogenized with a Dounce Homogenizer (Thomas Co., Philadelphia, PA, USA) in ice-cold RIPA buffer (Sigma-Aldrich, St. Louis, MA, USA) containing Complete Protease inhibitor (Roche Life Science, Penzberg, Germany), and after quantitation (Qubit ® 2.0 Fluorometer, Life Technologies, San Diego, CA, USA), 100 mg of total protein per sample was precipitated overnight at −20°C (ProteoExtract ® Protein Precipitation Kit, Merck Millipore, Billerica, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Elevated Serum Levels of Alpha-Fetoprotein in Patients with Infantile Hemangioma Are Not Derived from within the Tumor

et al. 2016

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AimsThe embryonic-like stem cell origin of infantile hemangioma (IH) and the observed elevated serum levels of alpha-fetoprotein (AFP) in patients with hepatic IH led us to investigate if this tumor was the source of AFP.Materials and methodsWe measured serial serum levels of AFP in patients with problematic proliferating IH treated with surgical excision or propranolol treatment. We also investigated the expression of AFP in extrahepatic IH samples using immunohistochemical staining, mass spectrometry, NanoString gene expression analysis, and in situ hybridization.ResultsSerum levels of AFP normalized following surgical excision or propranolol treatment. Multiple regression analysis for curve fittings revealed a different curve compared to reported normal values in the general populations. AFP was not detected in any of the IH samples examined at either the transcriptional or translational levels.ConclusionThis study demonstrates the association of proliferating IH with elevated serum levels of AFP, which normalized following surgical excision or propranolol treatment. We have shown that IH is not the direct source of AFP. An interaction between the primitive mesoderm-derived IH and the endogenous endodermal tissues, such as the liver, via an intermediary, may explain the elevated serum levels of AFP in infants with extrahepatic IH.

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Section: Methodsmentioning

confidence: 99%

Elevated Serum Levels of Alpha-Fetoprotein in Patients with Infantile Hemangioma Are Not Derived from within the Tumor

et al. 2016

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“…The precise nature of these cells requires further investigation. This localization of functionally active cathepsins B and D suggests the presence of RAS bypass loops in these CSCs, similar to IH, 32 glioblastoma, 36 oral tongue SCC, 37 and metastatic colon adenocarcinoma. 38 …”

Section: Discussionmentioning

confidence: 66%

“…The production of the peptides of the RAS involves many alternative signaling pathways, including enzymes such as cathepsins B, D, and G. 32 Cathepsin B is a lysosomal cysteine protease that processes that cleaves inactive prorenin to renin. 33 Cathepsin D is an aspartyl protease that converts angiotensinogen to ATI, and is functionally homologous to renin.…”

Section: Introductionmentioning

confidence: 99%

“… 34 Cathepsin G, a serine protease, processes angiotensinogen and ATI to form angiotensin II and is functionally homologous to ACE. 35 These cathepsins constitute bypass loops for the RAS and have been identified in different tumor types, including infantile hemangioma (IH), 32 glioblastoma, 36 oral tongue SCC, 37 and metastatic colon adenocarcinoma. 38 …”

Section: Introductionmentioning

confidence: 99%

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Cancer Stem Cells in Head and Neck Cutaneous Squamous Cell Carcinoma Express Cathepsins

Featherston

Brasch

Siljee

et al. 2020

Plastic and Reconstructive Surgery - Global Open

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Background: Cancer stem cell (CSC) subpopulations within moderately differentiated head and neck cutaneous squamous cell carcinoma (MDHNcSCC) express the components of the renin–angiotensin system (RAS). This study investigated the expression of cathepsins B, D, and G, which constitute bypass loops of the RAS, by CSCs in MDHNcSCC. Methods: Immunohistochemical staining was performed on MDHNcSCC tissue samples from 15 patients to determine the expression of cathepsins B, D, and G. Co-localization of these cathepsins with the embryonic stem cell markers Octamer-binding transcription factor 4 (OCT4) and c-MYC was investigated with immunofluorescence staining. Reverse transcription quantitative polymerase chain reaction was performed on 5 MDHNcSCC tissue samples to investigate transcript expression of cathepsins B, D and G. Western blotting and enzymatic activity assays were performed on 5 MDHNcSCC tissue samples and 6 MDHNcSCC-derived primary cell lines to confirm protein expression, transcript expression, and functional activity of these cathepsins, respectively. Results: Immunohistochemical staining demonstrated the expression of cathepsins B, D, and G in all MDHNcSCC tissue samples. Immunofluorescence staining showed localization of cathepsins B and D to the c-MYC+ CSC subpopulations and the OCT4+ CSC subpopulations within the tumor nests and the peritumoral stroma. Cathepsin G was expressed on the tryptase+/c-MYC+ cells within the peritumoral stroma. Reverse transcription quantitative polymerase chain reaction demonstrated transcript expression of cathepsins B, D and G in the MDHNcSCC tissue samples. Western blotting and enzymatic activity assays confirmed protein expression and functional activity of cathepsins B and D in the MDHNcSCC tissue samples and MDHNcSCC-derived primary cell lines, respectively. Conclusions: Cathepsins B, D, and G are expressed in MDHNcSCC with functionally active cathepsins B and D localizing to the CSC subpopulations, and cathepsin G is expressed by mast cells, suggesting the potential use of cathepsin inhibitors in addition to RAS blockade to target CSCs in MDHNcSCC.

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“…2016) with positive effects. The understanding of the regulation of the RAS and CSCs in GB, in particular the expression and function of cathepsin B (Itinteang, Chudakova et al 2015) and the IGF/IGFR-1 pathway (Al Hassan, Fakhoury et al 2018) lead us to propose modulating the RAS, a singular systemic homeostatic pathway, using a combination of drugs (Figure 1), to simultaneously inhibit key steps of the RAS, its bypass loops and crosstalk signaling pathways interacting with the RAS, may offer a novel therapeutic approach for patients with GB (Roth, Wickremesekera et al 2019),…”

Section: Repurposing Drugs That Target the Rasmentioning

confidence: 99%

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-angiotensin System

Tan¹,

Roth²,

Wickremesekera³

et al. 2019

Preprint

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Patients with glioblastoma (GB), a highly aggressive brain tumor, have a median survival of 14.6 months following neurosurgical resection with adjuvant chemoradiotherapy. Quiescent GB cancer stem cells (CSCs) invariably cause local recurrence. These GB CSCs that can be identified by embryonic stem cell markers express components of the renin-angiotensin system and are associated with circulating CSCs. Despite the presence of circulating CSCs, GB rarely develops distant metastasis outside the central nervous system. This paper reviews the current literature on GB growth inhibition in relation to CSCs, circulating CSCs, the RAS and the novel therapeutic approach by repurposing drugs that target the renin-angiotensin system to improve overall symptom-free survival and maintain quality of life.

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Expression of Cathepsins B, D, and G in Infantile Hemangioma

Cited by 25 publications

References 30 publications

Elevated Serum Levels of Alpha-Fetoprotein in Patients with Infantile Hemangioma Are Not Derived from within the Tumor

Elevated Serum Levels of Alpha-Fetoprotein in Patients with Infantile Hemangioma Are Not Derived from within the Tumor

Cancer Stem Cells in Head and Neck Cutaneous Squamous Cell Carcinoma Express Cathepsins

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-angiotensin System

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