Fibroblast Activation Protein Specific Optical Imaging in Non-Small Cell Lung Cancer.
Fibroblast Activation Protein Specific Optical Imaging in Non-Small Cell Lung Cancer.
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DOI：
10.3389/fonc.2022.834350
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发表时间：
2022
影响因子：
4.7
通讯作者：
Akram AR
中科院分区：
文献类型：
--
作者：
Mathieson L;O'Connor RA;Stewart H;Shaw P;Dhaliwal K;Williams GOS;Megia-Fernandez A;Akram AR
成纤维细胞活化蛋白（FAP）是一种参与细胞外基质调控的细胞表面丙基特异性丝氨酸蛋白酶。虽然FAP在健康组织中表达水平较低，但在一些实体器官恶性肿瘤中，包括非小细胞肺癌和慢性炎症，如肺纤维化和类风湿性关节炎，可以发现FAP在成纤维细胞上的上调。它们的全部作用尚不清楚，但在乳腺癌、结直肠癌、胰腺癌和非小细胞肺癌（NSCLC）中，已经发现表达FAP的癌症相关成纤维细胞（CAFs）与预后差、生存率差有关。使用FAP特异性化学探针的光学成像与临床兼容的成像系统相结合，可以提供FAP活性的读数，从而可以进行疾病监测、预测和潜在的分层治疗。然而，为了获得FAP的特异性信号，任何序列都必须对密切相关的内肽酶（如脯氨酸内肽酶（PREP））保持特异性，并且在活动性炎症区域耐降解。我们描述了FAP光学报告序列的迭代开发，该序列保留FAP特异性，在活化的中性粒细胞蛋白酶存在下具有抗降解能力，并在非小细胞肺癌样本中通过成像平台展示了体外临床可追踪性。
Fibroblast activation protein (FAP) is a cell surface propyl-specific serine protease involved in the regulation of extracellular matrix. Whilst expressed at low levels in healthy tissue, upregulation of FAP on fibroblasts can be found in several solid organ malignancies, including non-small cell lung cancer, and chronic inflammatory conditions such as pulmonary fibrosis and rheumatoid arthritis. Their full role remains unclear, but FAP expressing cancer associated fibroblasts (CAFs) have been found to relate to a poor prognosis with worse survival rates in breast, colorectal, pancreatic, and non-small cell lung cancer (NSCLC). Optical imaging using a FAP specific chemical probe, when combined with clinically compatible imaging systems, can provide a readout of FAP activity which could allow disease monitoring, prognostication and potentially stratify therapy. However, to derive a specific signal for FAP any sequence must retain specificity over closely related endopeptidases, such as prolyl endopeptidase (PREP), and be resistant to degradation in areas of active inflammation. We describe the iterative development of a FAP optical reporter sequence which retains FAP specificity, confers resistance to degradation in the presence of activated neutrophil proteases and demonstrates clinical tractability ex vivo in NSCLC samples with an imaging platform.