芬瑞替尼的生长调节作用包括角质形成细胞的终末分化:口腔鳞状细胞癌化学预防的有利结果

IF 3.3 3区 医学 Q2 ONCOLOGY
Daren Wang, Ping Pei, Fortune Shea, Richard Spinney, Albert Chang, Joerg Lahann, Susan R Mallery
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引用次数: 0

摘要

口腔鳞状细胞癌(OSCC)是一个世界性的健康问题,发病率和死亡率都很高。从患者和社会经济角度来看,预防恶性前口腔上皮内瘤变(OIN)发展为 OSCC 显然是最理想的结果。最佳的 OSCC 化学预防药物具有多种特性,包括耐受性高、生物利用度高、疗效好以及能保留完整的表面上皮。末端分化可引导口腔角质细胞离开增殖池,形成保护性粟粒状包膜,从而在消除生长异常的角质细胞的同时保留保护性上皮屏障。本研究采用人类恶性前口腔角质形成细胞和 OSCC 细胞系来评估合成维甲酸芬瑞替尼 (4HPR) 的分化诱导能力。在概念验证分化研究中,对全厚口腔黏膜外植体进行了评估。研究结果表明,4HPR 能够满足角质形成细胞分化的所有必要条件,即通过与 CRABP-II 结合进行核导入(分子建模)、与视黄酸核受体结合并随后激活(受体激活试验)、增加与角质形成细胞分化相关的基因的表达和翻译(RT-PCR、免疫印迹)、上调对角质包膜形成至关重要的转谷氨酰胺酶(TGM3,功能试验)以及增强人类口腔上皮外植体的末端分化(图像分析量化角质形成细胞脱落)。这些数据建立在 4HPR 的化学预防功能基础之上,其中包括作为小分子激酶抑制剂的功能和抑制基底膜侵袭所必需的重要机制。即将进行的临床试验将评估释放 4HPR 的粘液贴片是否能诱导 OIN 病变的组织学、临床和分子消退,这将为临床提供重要的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Growth modulatory effects of fenretinide encompass keratinocyte terminal differentiation: a favorable outcome for oral squamous cell carcinoma chemoprevention.

Oral squamous cell carcinoma (OSCC) is worldwide health problem associated with high morbidity and mortality. From both the patient and socioeconomic perspectives, prevention of progression of premalignant oral intraepithelial neoplasia (OIN) to OSCC is clearly the preferable outcome. Optimal OSCC chemopreventives possess a variety of attributes including high tolerability, bioavailability, efficacy and preservation of an intact surface epithelium. Terminal differentiation, which directs oral keratinocytes leave the proliferative pool to form protective cornified envelopes, preserves the protective epithelial barrier while concurrently eliminating growth-aberrant keratinocytes. This study employed human premalignant oral keratinocytes and an OSCC cell line to evaluate the differentiation-inducing capacity of the synthetic retinoid, fenretinide (4HPR). Full-thickness oral mucosal explants were evaluated for proof of concept differentiation studies. Results of this study characterize the ability of 4HPR to fulfill all requisite components for keratinocyte differentiation, i.e. nuclear import via binding to cellular RA binding protein-II (molecular modeling), binding to and subsequent activation of retinoic acid nuclear receptors (receptor activation assays), increased expression and translation of genes associated with keratinocyte differentiation [Reverse transcription polymerase chain reaction (RT-PCR), immunoblotting] upregulation of a transglutaminase enzyme essential for cornified envelope formation (transglutaminase 3, functional assay) and augmentation of terminal differentiation in human oral epithelial explants (image-analyses quantified corneocyte desquamation). These data build upon the chemoprevention repertoire of 4HPR that includes function as a small molecule kinase inhibitor and inhibition of essential mechanisms necessary for basement membrane invasion. An upcoming clinical trial, which will assess whether a 4HPR-releasing mucoadhesive patch induces histologic, clinical and molecular regression in OIN lesions, will provide essential clinical insights.

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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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