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Published on: August 25, 2017
Immunohistochemical Analysis of mTOR Pathway-Related Proteins in Kaposiform Hemangioendothelioma
Zuopeng Wang1, Chao Zheng1, Hongqiang Sun2
1Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China.
Background:
Mammalian target of rapamycin (mTOR) inhibitors have been shown to have excellent effects in the management of kaposiform hemangioendothelioma (KHE); however, the mechanism of action is unclear. This study identified the expressions of mTOR pathway-related proteins in different vascular tumors to provide insight into the pathogenesis of KHE.
Methods:
We retrospectively reviewed the pathologic specimens of 30 patients (KHE, 15; tufted angioma [TA], 5; infantile hemangioma [IH], 5; and lymphatic malformation [LM], 5). The immunohistochemical expression of mTOR-related proteins tuberous sclerosis complex 2 (TSC2), phosphatase and tensin homologue (PTEN), phosphorylated eukaryotic translation initiation factor 4E binding protein 1 (p-4EBP1), phosphorylated mTOR (p-mTOR), and phosphorylated ribosomal protein S6 kinase B1 (p-P70S6K) were analyzed using Image-Pro Plus software. KHE had the following pattern of expression in the spindle vascular endothelial cells: TSC2 (-); PTEN (-); p-4EBP1 (+); p-mTOR (+); and p-P70S6K (+).
Results:
All 3 patients treated with sirolimus had good responses. The TA results were similar to KHE with no significant differences (p-4EBP1: p = 0.0687; p-mTOR: p = 0.0832). The expressions of TSC2, PTEN, p-4EBP1, p-mTOR, and p-P70S6K were negative or weakly positive in IH with a statistically significant difference compared to KHE (p-4EBP1: p < 0.001; p-mTOR: p < 0.001; p-P70S6K: p < 0.001). LM had no significant differences when compared to KHE.
Conclusions:
The absence of TSC2 and PTEN caused abnormal activation of the mTOR signaling pathway and may be involved in the pathogenesis of KHE. The expression of mTOR-related proteins in TA and LM was similar to KHE, unlike IH. The KHE pattern of expression [PTEN (-), TSC2 (-), p-mTOR (+), p-P70S6K (+), and p-4EBP1 (+)] suggested that sirolimus may be a good therapeutic choice.
Insights
The absence of TSC2 and PTEN proteins may cause abnormal mammalian target of rapamycin (mTOR) pathway activation, contributing to kaposiform hemangioendothelioma (KHE) pathogenesis. This finding supports sirolimus as a potential therapeutic option for KHE.
Area of Science:
- Oncology
- Molecular Biology
- Pathology
Background:
- Mammalian target of rapamycin (mTOR) inhibitors show efficacy in treating kaposiform hemangioendothelioma (KHE).
- The precise mechanism underlying mTOR inhibitor action in KHE remains unclear.
- Investigating mTOR pathway protein expression in vascular tumors can elucidate KHE pathogenesis.
Purpose of the Study:
- To identify the expression patterns of key mammalian target of rapamycin (mTOR) pathway-related proteins in kaposiform hemangioendothelioma (KHE).
- To compare mTOR pathway protein expression between KHE and other vascular tumors, including tufted angioma (TA), infantile hemangioma (IH), and lymphatic malformation (LM).
- To provide insights into the molecular mechanisms driving KHE development and inform therapeutic strategies.
Main Methods:
- Retrospective analysis of 30 vascular tumor specimens (15 KHE, 5 TA, 5 IH, 5 LM).
- Immunohistochemical analysis of tuberous sclerosis complex 2 (TSC2), phosphatase and tensin homologue (PTEN), p-4EBP1, p-mTOR, and p-P70S6K protein expression.
- Quantitative analysis of protein expression using Image-Pro Plus software.
Main Results:
- Kaposiform hemangioendothelioma (KHE) demonstrated a distinct expression pattern: negative for TSC2 and PTEN, positive for p-4EBP1, p-mTOR, and p-P70S6K.
- Tufted angioma (TA) and lymphatic malformation (LM) showed similar mTOR pathway protein expression profiles to KHE.
- Infantile hemangioma (IH) exhibited significantly lower expression of p-4EBP1, p-mTOR, and p-P70S6K compared to KHE.
Conclusions:
- The absence of TSC2 and PTEN proteins is implicated in the abnormal activation of the mTOR signaling pathway in KHE.
- The similar expression patterns of mTOR-related proteins in TA and LM suggest shared pathogenic pathways with KHE, distinct from IH.
- The observed KHE protein expression profile supports the use of sirolimus, an mTOR inhibitor, as a potential therapeutic agent.
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